Publications by authors named "Chengxue Dang"

75 Publications

RSPO2 silence inhibits tumorigenesis of nasopharyngeal carcinoma by ZNRF3/Hedgehog-Gli1 signal pathway.

Life Sci 2021 Jul 14;282:119817. Epub 2021 Jul 14.

Tumor Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. Electronic address:

R-spondins 2 (RSPO2) protein is a member of RSPO family which plays an essential role in stem cell survival, development and tumorigenicity. There has several evidence suggested that RSPO2 involved in breast, gastric, liver and colorectal cancer. However, the specific function and mechanism of RSPO2 in nasopharyngeal carcinoma (NPC) remain unknown. In the present study, we first observed that RSPO2 expression was elevated in NPC cell lines SUNE-6-10B, SUNE-5-8F, and CNE-1 compared with the normal laryngeal epithelia cell line NP69. Knockdown of RSPO2 significantly inhibits SUNE-6-10B and CNE-1 cell survival and proliferation by using CCK-8 assay and Edu assay, respectively. Further studies verified that RSPO2 silence suppressed migration and invasion of SUNE-6-10B and CNE-1 cells. Further studies suggested that RSPO2 silence suppressed epithelial-to-mesenchymal transition (EMT) related protein E-cadherin expression and promoted Vimentin and N-cadherin expression both in SUNE-6-10B and CNE-1 cells. Molecular mechanism explorations showed that RSPO2 deletion increased ZNRF3 expression and inhibited Gli1 expression. Additionally, knockdown ZNRF3 expression or overexpression Gli1 both reversed the effects of RSPO2 silence on NPC growth and metastasis. Finally, RSPO2 depletion was impaired NPC tumor growth in vivo animal experiments. In conclusion, the present study confirmed that RSPO2 silence inhibits the tumorigenesis of NPC via ZNRF3/Hedgehog-Gli1 signal pathway.
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http://dx.doi.org/10.1016/j.lfs.2021.119817DOI Listing
July 2021

The Early Diagnostic and Prognostic Value of BIRC5 in Clear-Cell Renal Cell Carcinoma Based on the Cancer Genome Atlas Data.

Urol Int 2021 Jul 15:1-8. Epub 2021 Jul 15.

Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Purpose: The aim of this study was to investigate the role of BIRC5 for early diagnosis and prognosis in clear-cell renal cell carcinoma (ccRCC) by studying the expression of BIRC5 and the correlation between BIRC5 expression and clinicopathological parameters and prognosis in ccRCC.

Methods: The BIRC5 expression in ccRCC tissues and normal kidney tissues was measured using the Cancer Genome Atlas database and the Human Protein Atlas database. The correlation between BIRC5 expression and clinicopathological parameters and prognosis in ccRCC was analyzed using UALCAN, the Kaplan-Meier plotter, GEPIA, and SurvExpress. Thirteen-paired ccRCC plasma samples were used to verify the BIRC5 early diagnosis value of ccRCC.

Results: The BIRC5 expression is significantly higher in ccRCC than in normal kidney tissues, and is correlated with the clinical stage and pathological grade of ccRCC (p < 0.05). The result of analyzing the relationship between BIRC5 expression and outcomes in ccRCC indicates that a high BIRC5 expression is an independent prognostic factor affecting the overall survival and disease-free survival of ccRCC (p < 0.05). Compared with normal kidney tissues, the immunohistochemical test shows that BIRC5 is significantly upregulated in ccRCC tissues. mRNA expression levels of BIRC5 were significantly higher in the ccRCC plasma than normal (p < 0.05).

Conclusions: The high expression of BIRC5 is an important indicator for the prognosis of ccRCC, which makes BIRC5 an effective biomarker for predicting the prognosis of patients in ccRCC. BIRC5 may be a great potential biomarker for early diagnosis of ccRCC.
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http://dx.doi.org/10.1159/000517310DOI Listing
July 2021

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

Lancet Oncol 2021 Aug 9;22(8):1081-1092. Epub 2021 Jul 9.

Department of General Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China.

Background: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy.

Methods: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral capecitabine 1000 mg/m twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546.

Findings: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported.

Interpretation: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer.

Funding: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00297-7DOI Listing
August 2021

Postoperative oxaliplatin-based hyperthermic intraperitoneal chemotherapy: an effective and safe palliative treatment option for colorectal cancer with peritoneal metastasis.

World J Surg Oncol 2021 Jul 6;19(1):200. Epub 2021 Jul 6.

Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Yanta west street No.277, Xi'an, 710061, Shaanxi, China.

Background: The prognosis of patients with colorectal cancer and peritoneal metastasis (CRC-PM) after incomplete cytoreductive surgery (CRS) or palliative surgery is poor. Novel and effective therapies are urgently needed. This study aimed to assess the effects of palliative postoperative hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with CRC-PM.

Methods: This retrospective study included patients with CRC-PM at the First Affiliated Hospital of Xi'an Jiaotong University in 05/2014-05/2019. Observation indicators included overall survival (OS), ascites-free survival, peritoneal cancer index (PCI), and completeness of cytoreduction (CC). Kaplan-Meier survival curves and multivariable Cox regression models were used to determine the factors associated with OS and ascites-free survival. The ascites-specific quality of life (QoL) was measured using the Functional Assessment of Chronic Illness Therapy-Ascites Index (FACIT-AI).

Results: Eighty-two patients were included, including 37 and 45 in the HIPEC and non-HIPEC groups, respectively. Mean OS was 10.3±3.7 (95% CI 9.5-11.2) months. Multivariable Cox proportional hazard regression suggested that PCI (HR=6.086, 95% CI 3.187-11.620, P < 0.0001) was independently associated with OS. The degree of ascites (HR=2.059, 95% CI 1.412-3.005, P < 0.0001), PCI (HR=6.504, 95% CI 2.844-14.875, P < 0.0001), and HIPEC (HR=0.328, 95% CI 0.191-0.562, P < 0.0001) were independently associated with ascites-free survival. In patients with survival >6 months, postoperative ascites-specific QoL was significantly improved after HIPEC compared with the non-HIPEC group (P < 0.001). Oxaliplatin-based HIPEC significantly increased the rates of neutropenia and peripheral neurotoxicity (both P < 0.05).

Conclusion: These data indicate that postoperative oxaliplatin-based HIPEC might help increase ascites-free survival in CRC-PM patients after incomplete CRS or palliative surgery, with improved QoL after 6 months of follow-up.
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http://dx.doi.org/10.1186/s12957-021-02320-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262040PMC
July 2021

Mist1 Inhibits Epithelial-Mesenchymal Transition in Gastric Adenocarcinoma via Downregulating the Wnt/β-catenin Pathway.

J Cancer 2021 1;12(15):4574-4584. Epub 2021 Jun 1.

Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.

As a secretory cell transcription factor, muscle intestine stomach expression 1 (Mist1) is associated with serous secretory cell development and gastric chief cell maturation. Here, we focus on the function of Mist1 in gastric adenocarcinoma carcinogenesis. Based on clinical data and a mouse model of gastric cancer, we found that Mist1 expression was reduced in gastric cancer. Then, we overexpressed Mist1 using a lentivirus system and found that overexpression of Mist1 could inhibit gastric cancer cell proliferation, migration and invasion Additionally, , we assessed the function of Mist1 in a gastric cancer xenograft model and distant pulmonary metastasis model. Overexpression of Mist1 decreased tumour growth and distant metastasis , suggesting that Mist1 acts as a tumour suppressor in gastric carcinogenesis. Furthermore, Mist1 overexpression inhibited epithelial-mesenchymal transition (EMT) in gastric cancer by suppressing β-catenin transcription activity and then the Wingless and INT-1 (Wnt)/β-catenin signalling pathway, which could be reversed by a Wnt/β-catenin-specific agonist. In conclusion, this study indicated that overexpression of Mist1 could reverse EMT in gastric carcinogenesis by inhibiting the Wnt/β-catenin signalling pathway and that Mist1 might be a novel marker for early gastric cancer screening.
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http://dx.doi.org/10.7150/jca.59138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210560PMC
June 2021

METTL3‑mediated m6A modification of Bcl‑2 mRNA promotes non‑small cell lung cancer progression.

Oncol Rep 2021 Aug 16;46(2). Epub 2021 Jun 16.

Department of Oncology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

Methyltransferase‑like 3 (METTL3) is an RNA methyltransferase that mediates modification of N6‑methyladenosine (m6A), which serves as an oncogene in various types of cancer. The role of m6A modification in the onset and progression of cancer has attracted growing attention. However, the functional and regulatory mechanisms of METTL3 in non‑small cell lung cancer (NSCLC) progression are still poorly understood. In the present study, METTL3 expression in NSCLC tissue was analyzed using the Gene Expression Profiling Interactive Analysis database. Western blotting and reverse transcription‑quantitative PCR were performed to evaluate the expression of METTL3 in NSCLC tissue and cell lines. Here, knockdown and overexpression of METTL3 notably decreased NSCLC cell viability, apoptosis and migration and, as well as tumorigenicity . Expression of METTL3 was upregulated in NSCLC tissue. METTL3 overexpression promoted cell viability and migration in NSCLC, while knockdown of METTL3 yielded the opposite result and . METTL3 increased Bcl‑2 translation via m6A modification, which increased viability and enhanced migration of NSCLC cells. METTL3 served as an oncogene in NSCLC via METTL3‑mediated Bcl‑2 mRNA m6A modification, which indicated that targeting METTL3 may be an effective therapeutic strategy for clinical management of NSCLC.
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http://dx.doi.org/10.3892/or.2021.8114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218297PMC
August 2021

Anlotinib Monotherapy for Refractory Metastatic Colorectal Cancer: A Double-Blinded, Placebo-Controlled, Randomized Phase III Trial (ALTER0703).

Oncologist 2021 Jun 8. Epub 2021 Jun 8.

Department of Medical Oncology, Liuzhou Worker's Hospital, Liuzhou, People's Republic of China.

Background: Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC.

Materials And Methods: This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1-14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety.

Results: A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4-4.5) over placebo group (1.5 months; 95% CI, 1.4-1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27-0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8-9.7 vs. 7.2 months; 95% CI, 6.2-8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%).

Conclusion: Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients.

Implications For Practice: In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.
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http://dx.doi.org/10.1002/onco.13857DOI Listing
June 2021

Correlations between tumor mutation burden and immune infiltrates and their prognostic value in pancreatic cancer by bioinformatic analysis.

Life Sci 2021 Jul 16;277:119505. Epub 2021 Apr 16.

Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address:

Purpose: We aimed to investigate the patterns and prognostic roles of tumor mutation burden and immune microenvironment in pancreatic cancer.

Methods: The somatic mutation data, transcriptome profiles and clinical information were downloaded from the Cancer Genome Atlas database. Gene expression difference, Gene ontology, KEGG, gene set enrichment analyses and "CIBERSORT" algorithm were performed to screen differentially expressed genes, enriched functions or pathways and immune infiltrates differences between high and low TMB groups. Single sample gene set enrichment and unsupervised consensus clustering analyses were used for immunity grouping. Immune cell infiltration and expressions of HLA and checkpoint genes were investigated. Finally, a nomogram model integrating TMB and immune infiltration was established.

Results: A total of 608 differentially expressed genes were identified between high and low TMB groups, KEGG base excision repair and DNA replication pathways were enriched in high TMB group. Infiltration levels of M0 macrophages were higher and dendritic resting cells were lower in high TMB group. The risk model based on TMB-related immune genes, FAM19A2 and SLC22A17 was established and high risk scores indicated poorer prognosis. The expressions of HLA genes and immune checkpoint genes were higher in high immunity group. The nomogram showed remarkable ability for individualized survival estimation with good AUC values (0.794 and 0.800, respectively) for 3- and 5-year survival rates prediction.

Conclusions: The characteristics of tumor mutation burden and immune infiltration in pancreatic cancer provide new insights into the tumor microenvironment, immunotherapies and a novel prognostic nomogram model for pancreatic cancer patients.
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http://dx.doi.org/10.1016/j.lfs.2021.119505DOI Listing
July 2021

Correlations Between Tumor Mutation Burden and Immunocyte Infiltration and Their Prognostic Value in Colon Cancer.

Front Genet 2021 16;12:623424. Epub 2021 Feb 16.

Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background: Colon cancer has a huge incidence and mortality worldwide every year. Immunotherapy could be a new therapeutic option for patients with advanced colon cancer. Tumor mutation burden (TMB) and immune infiltration are considered critical in immunotherapy but their characteristics in colon cancer are still controversial.

Methods: The somatic mutation, transcriptome, and clinical data of patients with colon cancer were obtained from the TCGA database. Patients were divided into low or high TMB groups using the median TMB value. Somatic mutation landscape, differentially expressed genes, and immune-related hub genes, Gene Ontology and KEGG, gene set enrichment, and immune infiltration analyses were investigated between the two TMB groups. Univariate and multivariate Cox analyses were utilized to construct a prognostic gene signature. The differences in immune infiltration, and the expression of HLA-related genes and checkpoint genes were investigated between the two immunity groups based on single sample gene set enrichment analysis. Finally, a nomogram of the prognostic prediction model integrating TMB, immune infiltration, and clinical parameters was established. Calibration plots and receiver operating characteristic curves (ROC) were drawn, and the C-index was calculated to assess the predictive ability.

Results: Missense mutations and single nucleotide polymorphisms were the major variant characteristics in colon cancer. The TMB level showed significant differences in N stage, M stage, pathological stage, and immune infiltration. CD8 T cells, activated memory CD4 T cells, activated NK cells, and M1 macrophages infiltrated more in the high-TMB group. The antigen processing and presentation signaling pathway was enriched in the high-TMB group. Two immune related genes (CHGB and SCT) were identified to be correlated with colon cancer survival (HR = 1.39, = 0.01; HR = 1.26, = 0.02, respectively). Notably, the expression of SCT was identified as a risk factor in the immune risk model, in which high risk patients showed poorer survival ( = 0.04). High immunity status exhibited significant correlations with immune response pathways, HLA-related genes, and immune checkpoint genes. Finally, including nine factors, our nomogram prediction model showed better calibration (C-index = 0.764) and had an AUC of 0.737.

Conclusion: In this study, we investigated the patterns and prognostic roles of TMB and immune infiltration in colon cancer, which provided new insights into the tumor microenvironment and immunotherapies and the development of a novel nomogram prognostic prediction model for patients with colon cancer.
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http://dx.doi.org/10.3389/fgene.2021.623424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921807PMC
February 2021

Patients' Responses to the Sudden Interruption of Chemotherapy During the Outbreak of the Novel Coronavirus: A Cross-Sectional Study.

Cancer Manag Res 2021 13;13:351-358. Epub 2021 Jan 13.

Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China.

Purpose: This cross-sectional study aimed to describe the responses of cancer patients' indifferent chemotherapy cycles to the unstructured treatment interruption during the COVID-19 pandemic in China.

Patients And Methods: Data from 156 adult patients with common solid tumors undergoing chemotherapy or ready to begin chemotherapy after surgery before the COVID-19 outbreak were analyzed in the study. Patients' responses to the chemotherapy interruption and their anxiety were assessed.

Results: Overall, 141 (90%) patients completed the study, and 115 (81.6%) accepted a switch from their previous intravenous chemotherapy to oral chemotherapy. Of these, 29 (65.9%) patients with lung cancer, 25 (86.2%) with gastric cancer, 33 (89.2%) with colorectal cancer and 28 (90.3%) with breast cancer switched from intravenous to oral treatment, heeding their doctor's advice. Of the participants, 85 (60.3%) patients reported that they had taken at least one kind of complementary and alternative medicine (CAM). The hospital anxiety and depression scale (HADS) scores increased in patients with advanced refractory cancer compared with the scores of adjuvant chemotherapy patients ( < 0.05). The prevalence of anxiety was high in cancer patients aged 60 years or older. Furthermore, anxiety was associated with advanced incurable cancer (< 0.05), and this finding remained after adjusting for chronic pain. In addition, there were significantly increased scores of anxiety in patients with lung cancer (<0 0.05).

Conclusion: Our study shows that most cancer patients remained relatively stable and had switched from intravenous to oral treatment at home. Among them, an increasing number of patients began to seek CAM as a complementary therapeutic approach. Patients with advanced refractory cancer were more likely to experience anxiety, and lung cancer patients should receive special attention.
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http://dx.doi.org/10.2147/CMAR.S274525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812525PMC
January 2021

SNHG6 Interacted with miR-325-3p to Regulate Cisplatin Resistance of Gastric Cancer by Targeting GITR.

Onco Targets Ther 2020 25;13:12181-12193. Epub 2020 Nov 25.

Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.

Background: Cisplatin resistance results in the failure of platinum-based chemotherapy and relapse of gastric cancer. We aimed to investigate the potential regulating role of SNHG6/miR-325-3p/GITR in reversing cisplatin resistance.

Patients And Methods: A total of 137 gastric cancer patients were recruited. qRT-PCR and ELISA were used to test the expression of target genes. CCK-8 and caspase 3/7 kit were used to test the cell viability and apoptosis rate. Dual luciferase reporter gene and RNA-pull down assay were used to investigate the potential interaction between target genes.

Results: SNHG6 and GITR were up regulated in gastric cancer; however, miR-325-3p was down-regulated. Besides, SNHG6, miR-325-3p and GITR expression were associated with gastric cancer prognosis. Then, we found that GITR and SNHG6 promoted proliferation and inhibited apoptosis of MKN45 and MKN45 cisplatin resistance cell line; however, miR-325-3p inhibited proliferation and promoted apoptosis of these cell lines. Furthermore, SNHG6 might bind to miR-325-3p to regulate its expression, and miR-325-3p directly interacted with the 3`UTR of GITR.

Conclusion: SNHG6 binds to miR-325-3p, which directly interacted with GITR to regulate cisplatin resistance of gastric cancer.
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http://dx.doi.org/10.2147/OTT.S262896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701159PMC
November 2020

A glycolysis-related gene signature predicts prognosis of patients with esophageal adenocarcinoma.

Aging (Albany NY) 2020 11 25;12(24):25828-25844. Epub 2020 Nov 25.

Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China.

Background: Esophageal adenocarcinoma (EAC) is a growing problem with a rapidly rising incidence and carries a poor prognosis. We aimed to develop a glycolysis-related gene signature to predict the prognostic outcome of patients with EAC.

Results: Five genes (CLDN9, GFPT1, HMMR, RARS and STMN1) were correlated with prognosis of EAC patients. Patients were classified into high-risk and low-risk groups calculated by Cox regression analysis, based on the five gene signature risk score. The five-gene signature was an independent biomarker for prognosis and patients with low risk scores showed better prognosis. Nomogram incorporating the gene signature and clinical prognostic factors was effective in predicting the overall survival.

Conclusion: An innovative identified glycolysis-related gene signature and an effective nomogram reliably predicted the prognosis of EAC patients.

Methods: The Cancer Genome Atlas database was investigated for the gene expression profile of EAC patients. Glycolytic gene sets difference between EAC and normal tissues were identified via Gene set enrichment analysis (GSEA). Univariate and multivariate Cox analysis were utilized to construct a prognostic gene signature. The signature was evaluated by receiver operating characteristic curves and Kaplan-Meier curves. A prognosis model integrating clinical parameters with the gene signature was established with nomogram.
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http://dx.doi.org/10.18632/aging.104206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803571PMC
November 2020

Obesity and metabolic syndrome related macrophage promotes PD-L1 expression in TNBC through IL6/JAK/STAT pathway and can be reversed by telmisartan.

Cancer Biol Ther 2020 12 20;21(12):1179-1190. Epub 2020 Nov 20.

Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi, China.

Breast cancer is the most common malignant tumor in women. Its incidence is associated with obesity and metabolic syndrome (MetS), which are highly prevalent world widely and have been identified as poorer prognosis factors in breast cancer including triple-negative breast cancer (TNBC), which has poorer response to chemotherapy, radiotherapy, and endocrine therapy. Programmed death ligand 1 (PD-L1) is one of the immune checkpoints ligands that facilitates tumor escape and progress. Obesity/MetS could cause systemic inflammation and immune disorders, however, whether and how obesity/MetS affect PD-L1 expression in breast cancer had not been clarified. In the present study, we examined the PD-L1 expression profile in breast cancer either in online database or cell lines. We found higher PD-L1 mRNA level but not DNA copy number in breast cancer than normal breast tissue, and higher PD-L1 expression in TNBC than other subtypes. Moreover, we found a positive relationship between PD-L1 expression in TNBC and metabolic complications in patients. Next, obesity/MetS related M1 macrophage was found to promote the expression of PD-L1 in breast cancer cells cocultured with polarized macrophages derived from either monocyte-like cell line THP-1 or Wistar rat models. IL6/JAK/STAT pathway was further identified to be involved in the process. In addition, we discovered that the PD-L1 expression promoted by obesity/MetS could be restored by telmisartan, one of the angiotensin II receptor blockers (ARBs) and could affect macrophage polarization, through its selective peroxisome proliferator-activated receptor-gamma (PPARG) activation and NFKB p65 inhibition and therefore downregulates IL6 secretion from M1 macrophage.
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http://dx.doi.org/10.1080/15384047.2020.1838032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722790PMC
December 2020

miR-183-5p promotes proliferation and migration in hepatocellular carcinoma by targeting IRS1 and its association with patient survival.

Int J Biol Markers 2020 Sep 12;35(3):83-89. Epub 2020 Sep 12.

Department of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China.

Background: MiR-183-5p plays an important role in the pathophysiology of many tumors, while the role of MiR-183-5p in liver cancer is unclear.

Methods: In this study, quantitative reverse transcription-polymerase chain reaction and Western blotting were used to detect the expression of miR-183-5p in liver cancer cell lines, liver cancer tissues, and normal tissues adjacent to the cancer, and to explore the mechanism of miR-183-5p regulating liver cancer progression. The in vitro effects of miR-183-5p were evaluated by CCK-8, colony formation test, and wound healing test. Various databases were used to predict the target mRNA of miR-183-5p and verified by luciferase report analysis. In addition, the effects of miR-183-5p and its target gene on the survival of patients with liver cancer were also analyzed.

Results: miR-183-5p was highly expressed in hepatocellular carcinoma cells and tissues, and was related to some clinicopathological features. MiR-183-5p can promote the proliferation and migration of liver cancer cells. Using the bioinformatics database, we proved that miR-183-5p is related to the survival of liver cancer patients. Insulin receptor substrate 1 (IRS1) is a target of miR-183-5p, and luciferase analysis confirmed that miR-183-5p combines with the 3'-untranslated region (3'-UTR) of IRS1.

Conclusion: The miR-183-5p/IRS1 axis may be a new target for liver cancer research.
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http://dx.doi.org/10.1177/1724600820951572DOI Listing
September 2020

MicroRNA‑216a‑5p suppresses esophageal squamous cell carcinoma progression by targeting KIAA0101.

Oncol Rep 2020 Nov 4;44(5):1971-1984. Epub 2020 Sep 4.

Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shannxi 710061, P.R. China.

The KIAA0101 protein (also referred to as NS5ATP9 or Paf15) is overexpressed in esophageal squamous cell carcinoma (ESCC) and is associated with disease progression and poor patient survival, but how KIAA0101 expression is regulated remains unknown. The relationship between tumor miR‑216a‑5p expression and prognosis in patients with ESCC was revealed by survival analyses. Quantitative reverse‑transcriptase PCR and western blot analysis were used to evaluate miR‑216a‑5p and KIAA0101 expression in human ESCC tissues and cell lines. The targeting of KIAA0101 by miR‑216a‑5p was verified by dual‑luciferase reporter assays. The EC9706 and TE1 cell lines were transfected with miR‑216a‑5p mimics and inhibitor, or KIAA0101‑specific shRNA and KIAA0101‑expressing plasmids, in order to evaluate the effect of manipulating miR‑216a‑5p and KIAA0101 expression on ESCC cell proliferation, cell cycle progression, migration, and invasion. miR‑216a‑5p was lowly expressed and inversely correlated with KIAA0101 protein expression in ESCC tissues and cell lines. Lower miR‑216a‑5p expression was associated with worse prognosis in patients with ESCC. miR‑216a‑5p negatively regulated KIAA0101 expression by directly targeting the 3'‑untranslated region of the KIAA0101 mRNA. Overexpression of miR‑216a‑5p suppressed the proliferation, migration, and invasion of the ESCC cell lines, whereas inhibition of miR‑216a‑5p had the opposite effects. Meanwhile, KIAA0101 promoted ESCC migration and invasion, and its overexpression abolished the antitumor effects of miR‑216a‑5p mimics. As a tumor suppressor, miR‑216a‑5p targets KIAA0101 to inhibit the proliferation, migration, and invasion of ESCC. Therefore, the miR‑216a‑5p/KIAA0101 axis may be a potential target for ESCC treatment.
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http://dx.doi.org/10.3892/or.2020.7751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551273PMC
November 2020

The Novel Notch-induced Long Noncoding RNA LUNAR1 Determines the Proliferation and Prognosis of Colorectal Cancer.

Sci Rep 2019 12 27;9(1):19915. Epub 2019 Dec 27.

Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

In contrast to what is known about the complicated roles of Notch signalling in human malignancies, the direct target genes of Notch signalling are still unclear. Recently, long noncoding RNAs (lncRNAs) have been found to play various roles in the post-transcriptional regulation of gene expression. In the present study, we investigated the potential role of the Notch-induced lncRNA LUNAR1 in colorectal cancer (CRC). We recruited 196 cases of clinical CRC specimens and investigated LUNAR1 levels in these specimens. The associations of LUNAR1 with tumour aggressiveness and clinical outcomes were evaluated. Moreover, the impact of LUNAR1 on the malignant behaviour of tumour cells was tested in cell lines. Significantly increased expression of LUNAR1 in clinical CRC specimens was detected compared with that in matching normal tissues. LUNAR1 expression in CRC was found to be associated with the tumour aggressiveness, disease-free survival and overall survival of patients. The downregulation of LUNAR1 in SW620 cells inhibited cell proliferation, migration, invasion and tumour growth while inducing apoptosis. Moreover, the inhibition of LUNAR1 can significantly suppress IGF1 signalling in CRC. These results indicated that LUNAR1 was increased in CRC and might promote tumour progression. Thus, LUNAR1 may constitute a promising prognostic marker for the clinical management of CRC.
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http://dx.doi.org/10.1038/s41598-019-56536-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934546PMC
December 2019

miR-491 inhibits BGC-823 cell migration via targeting HMGA2.

Int J Biol Markers 2019 Dec 31;34(4):364-372. Epub 2019 Oct 31.

Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.

Purpose: miR-491 functions as a tumor suppressor in several types of cancer. However, its function and mechanism in gastric cancer proliferation and metastasis have not been well defined. The aim of this study was to explore the role and regulatory mechanism of miR-491 in cell proliferation and migration in gastric cancer.

Methods: Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to detect the expression pattern of miR-491 in gastric cancer tissues. miR-491 overexpression vector, miR-491 inhibitor, and siHMGA2 were used; and MTT, wound healing, and transwell assays were employed to examine proliferation and migration for BGC-823 cells. A dual-luciferase reporter gene was used to measure the target relationship between miR-491 and HMGA2.

Results: Most gastric cancer patients exhibit decreased miR-491 expression. miR-491 overexpression inhibited cell proliferation and migration, whereas miR-491 inhibitor treatment produced the opposite effect. Mechanistically, HMGA2 was identified as a direct target of miR-491. Moreover, HMGA2 knockdown inhibited cell proliferation and migration, which was similar to the effect of miR-491 overexpression. HMGA2 was decreased after transfection of the miR-491 vector and increased after transfection of the miR-491 inhibitor.

Conclusion: Our results suggest that miR-491 suppressed cell proliferation and cell motility in gastric cancer by targeting HMGA2. Silencing HMGA2 produced a similar effect to miR-491 overexpression on cell proliferation and migration. miR-491/HMGA2 signaling may be a potential therapeutic target for gastric cancer patients with decreased miR-491 expression.
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http://dx.doi.org/10.1177/1724600819874488DOI Listing
December 2019

Young age increases the risk for lymph node metastasis in patients with early Colon Cancer.

BMC Cancer 2019 Aug 14;19(1):803. Epub 2019 Aug 14.

Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.

Background: The risk of lymph node positivity in early-stage colon cancer is a parameter that impacts therapeutic recommendations. However, little is known about the effect of age on lymph node positivity in colon cancer with mucosal invasion. In this study, we aimed to quantify the effect of younger age on lymph node positivity in colon cancer with mucosal invasion.

Methods: All patients were identified between 2004 and 2014 in the Surveillance, Epidemiology, and End Results database. Patients were stage T1-T2, did not undergo preoperative radiotherapy, had at least one lymph node examined, and underwent a standard colon cancer operation. Demographics and pathological data were compared between different age ranges. A nomogram model was built to estimate the probability of nodal involvement according to different characteristics. Decision curve analysis was performed by calculating the net benefits for a range of threshold probabilities.

Results: This study identified 41,490 patients who met the eligibility criteria for our study. 1.4% (n = 620) of patients were under 40 years old; 5.9% (n = 2571) were between 40 and 49 years old. Within each T stage, positive lymph node rates decreased with increasing age. In univariate analyses, the positive lymph node rates for patients 20 to 39 years of age were significantly higher than in patients in the reference group for stages T1 and T2. After dividing the colon into the left and right parts, these trends remained. The lymph node metastatic rate was higher in the right colon than in the left colon in terms of different age ranges. The nomogram prediction system represents a novel model with which to estimate lymph node metastasis in early T stage colon adenocarcinomas based on four risk factors with a C-index of 0.657 (95% CI: 0.658-0666).

Conclusions: Our study demonstrates that the risk of lymph node metastasis was higher in young (< 40 years) patients with early-stage colon adenocarcinomas. Therefore, more aggressive screening and therapeutic strategies should be considered for young patients with colon adenocarcinoma.
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http://dx.doi.org/10.1186/s12885-019-5995-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693219PMC
August 2019

Discovery of Glabridin as Potent Inhibitor of Epidermal Growth Factor Receptor in SK-BR-3 Cell.

Pharmacology 2019 5;104(3-4):113-125. Epub 2019 Jun 5.

Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China,

The breast cancer is the leading cause of death in women. Therefore, objective of the present study was to examine the antibreast cancer effect of glabridin (GBN) and to evaluate its mechanism of action. In this study, we have demonstrated that GBN causes reduction of cellular viability of human breast cancer SK-BR-3 in MTT assay. Results from Hoechst 33342 and propidium iodide staining assay suggested that GBN causes significant enhancement in the apoptosis. At the molecular level, in western blot analysis, GBN causes significant increase in c-PARP and c-caspases 3, 8, and 9 concentrations in a dose-dependent manner in breast cancer cells. The GBN further showed reduced level of p-epidermal growth factor receptor, p-AKT, p-ERK1/2, and cyclin D1 as the concentration rose in treated cells. Subsequent to this, GBN showed beneficial effect in 7,12-dimethylbenz[a]anthracene-induced breast cancer in experimental mice as confirmed by increase in body weight, reduction in tumor volume, oxidative stress, and dose-dependent restoration of all tested enzymes (phase I and II) in the treated group. GBN may, thus, play a protective role as an antibreast cancer drug for the prevention of breast cancer.
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http://dx.doi.org/10.1159/000496798DOI Listing
January 2020

Downregulation of APE1 potentiates breast cancer cells to olaparib by inhibiting PARP-1 expression.

Breast Cancer Res Treat 2019 Jul 15;176(1):109-117. Epub 2019 Apr 15.

Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, 710004, Shanxi, China.

Purpose: Targeting DNA repair mechanisms to induce apoptosis may be a promising strategy for breast cancer treatment. Olaparib is proved to have anticancer effect by inhibiting DNA repairing protein poly (ADP-ribose) polymerase (PARP). However, the cytotoxicity of olaparib is very limited to homologous recombination-proficient cells. This study aims to examine the effect and mechanism of olaparib treatment in breast cancer cell lines.

Methods: We investigated the cytotoxic effect of various doses of olaparib treatment to MCF-7 and ZR-75-1 cells in vitro. mRNA and protein levels of PARP and APE1 were examined by real-time PCR and western blot, respectively. APE1-deficient cell lines were created by RNA interference and used for in vitro cytotoxicity study as well as in vivo study.

Results: 2 µM or higher concentrations of olaparib lead to significant cell death and ROS production. Moreover, olaparib treatment not only inhibits PARP1, but also reduces the expression of APE1 in both mRNA and protein levels. Deficiency of APE1 resulted in increased sensitivity of MCF-7 and ZR-75-1 cells to olaparib treatment. In vivo study showed that reduction of APE1 significantly reduced the volume and weight of MCF-7 xenografted tumors when treated with olaparib, which suggests the synergistic function of inhibition of APE1 in promoting antitumor effects of olaparib treatment.

Conclusion: To acquire better benefits for HR-proficient breast cancer patients, developing chemotherapeutic drugs antagonize APE1 would be an effective strategy to improve the clinical outcome of PARP inhibitors.
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http://dx.doi.org/10.1007/s10549-019-05189-wDOI Listing
July 2019

Activation of EGFR-DNA-PKcs pathway by IGFBP2 protects esophageal adenocarcinoma cells from acidic bile salts-induced DNA damage.

J Exp Clin Cancer Res 2019 Jan 9;38(1):13. Epub 2019 Jan 9.

Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136-1015, USA.

Background: The incidence of esophageal adenocarcinoma (EAC) is rising rapidly in the US and Western countries. The development of Barrett's esophagus (BE) and its progression to EAC have been linked to chronic gastroesophageal reflux disease (GERD). Exposure of BE and EAC cells to acidic bile salts (ABS) in GERD conditions induces high levels of oxidative stress and DNA damage. In this study, we investigated the role of insulin-like growth factor binding protein 2 (IGFBP2) in regulating ABS-induced DNA double-strand breaks.

Methods: Real-time RT-PCR, western blot, immunohistochemistry, immunofluorescence, co-immunoprecipitation, flow cytometry, and cycloheximide (CHX) chase assays were used in this study. To mimic GERD conditions, a cocktail of acidic bile salts (pH 4) was used in 2D and 3D organotypic culture models. Overexpression and knockdown of IGFBP2 in EAC cells were established to examine the functional and mechanistic roles of IGFBP2 in ABS-induced DNA damage.

Results: Our results demonstrated high levels of IGFBP2 mRNA and protein in EAC cell lines as compared to precancerous Barrett's cell lines, and IGFBP2 is frequently overexpressed in EACs (31/57). Treatment of EAC cells with ABS, to mimic GERD conditions, induced high levels of IGFBP2 expression. Knocking down endogenous IGFBP2 in FLO1 cells (with constitutive high levels of IGFBP2) led to a significant increase in DNA double-strand breaks and apoptosis, following transient exposure to ABS. On the other hand, overexpression of exogenous IGFBP2 in OE33 cells (with low endogenous levels of IGFBP2) had a protective effect against ABS-induced double-strand breaks and apoptosis. We found that IGFBP2 is required for ABS-induced nuclear accumulation and phosphorylation of EGFR and DNA-PKcs, which are necessary for DNA damage repair activity. Using co-immunoprecipitation assay, we detected co-localization of IGFBP2 with EGFR and DNA-PKcs, following acidic bile salts treatment. We further demonstrated, using cycloheximide chase assay, that IGFBP2 promotes EGFR protein stability in response to ABS exposure.

Conclusions: IGFBP2 protects EAC cells against ABS-induced DNA damage and apoptosis through stabilization and activation of EGFR - DNA-PKcs signaling axis.
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http://dx.doi.org/10.1186/s13046-018-1021-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327430PMC
January 2019

[Screening of cell cycle-related genes regulated by KIAA0101 in gastric cancer].

Nan Fang Yi Ke Da Xue Xue Bao 2018 Sep;38(10):1151-1158

First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an 710061, China.

Objective: To screen the genes related to cell cycle under regulation by KIAA0101 in gastric cancer.

Methods: RT-PCR was used to detect the expression level of KIAA0101 gene in gastric cancer tissue and paired adjacent tissues. GO function enrichment analysis and KEGG pathway enrichment analysis were carried out using DAVID database. KEGG was used to map the pathways and the corresponding genes were analyzed. The list of genes associated with the KIAA0101 expression pattern was imported into TCGA cBioPortal to analyze the relationship between the interacting genes and generate a genetic topology map. The candidate genes were screened by RT-PCR.

Results: The expression level of KIAA0101 mRNA was significantly higher in cancer tissues than in paired adjacent tissues (1.104 ± 0.379 0.421 ± 0.172; =0.0179). The system screened genes related with KIAA0101 from 478 tissues by pooled analysis of the expression intensity of all the gene probes. GO function analysis showed that the differential genes were mainly enriched in protein phosphorylation, RNA processing, cell cycle, DNA metabolism, protein transport, acetylation, apoptosis, proteolysis, and redox. The changes in the expression level of KIAA0101 mainly affect the gastric cancer-related pathways including cell cycle, spliceosome, DNA replication, and p53 signal transduction pathway. KEGG pathway maps and gene topology maps showed that the genes related to KIAA0101 (such as BUB1B, MAD2L1, CDC45, CDK1, CCNE1 and CCNB2) were also related to cell cycle. RT-PCR results confirmed significant increments of the expression levels of BUB1B, MAD2L, CDK1, CCNE1, and CCNB2 mRNA in gastric cancer tissues as compared with the paired adjacent gastric tissues ( < 0.05), but CDC45 mRNA did not show significant differential expression in gastric cancer tissues ( > 0.05).

Conclusions: KIAA0101 may affect cell cycle by regulating the expression of BUB1B, MAD2L1, CDK1, CCNE1 and CCNB2, and this finding may provide evidence for understanding how KIAA0101 affects cell cycle and for screening of tumor markers and selection of drug targets.
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http://dx.doi.org/10.3969/j.issn.1673-4254.2018.10.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744063PMC
September 2018

Treatment strategies and predicting prognoses in elderly patients with breast cancer.

Cancer Manag Res 2018 4;10:3207-3218. Epub 2018 Sep 4.

Division of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China,

Objective: The prevalence of breast cancer in elderly women (older than 80 years) is expected to rise more dramatically than its incidence. In this study, we evaluated the evidence for treatment guidelines for elderly breast cancer patients.

Patients And Methods: All included patients were enrolled from 2010 to 2013 from the Surveillance, Epidemiology, and End Results (SEER) database. The Akaike information criterion (AIC) and Harrell's statistic were used to perform comparisons. In addition, a propensity score analysis was used to avoid bias caused by data selection criteria. Prognostic factors were selected as nomogram parameters to develop a model to predict survival.

Results: A total of 16998 patients included in the SEER database from 2010 to 2013 had breast cancer and fulfilled the study criteria. Of whom, 13007 patients underwent surgery. Overall survival and cancer-specific survival were significantly better in patients who underwent surgery and/or radiotherapy than in those who did not (<0.001). In addition, a nomogram system with a index of 0.83 and an AIC index of 11112.85 was better able to predict prognoses and estimate cancer-specific survival in elderly patients with breast cancer.

Conclusion: A localized surgical approach might provide better results in elderly breast cancer patients. However, radiotherapy improved cancer-specific survival and overall survival in these patients. In addition, a prognostic nomogram directly quantified patient risk by accounting for various prognostic factors without forming risk groups and was better able to estimate cancer-specific survival.
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http://dx.doi.org/10.2147/CMAR.S160578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130285PMC
September 2018

Itraconazole inhibits the proliferation of gastric cancer cells and improves patient survival.

Oncol Lett 2018 Sep 4;16(3):3651-3657. Epub 2018 Jul 4.

Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, P.R. China.

Itraconazole is a Food and Drug Administration-approved antifungal drug belonging to the azole family. Recent studies reported that itraconazole has potential anticancer activity. Whether combining itraconazole with other anticancer compounds such as 5-fluorouracil (5-FU), a potent drug used in the treatment of gastric cancer, is unknown and warrants further study. In the present study, SGC-7901 gastric cancer cells were chosen to assess the anticancer effects of itraconazole in combination with 5-FU. Cell proliferation was assessed by a Cell Counting Kit-8 assay, and apoptosis was assessed by Annexin V/propidium iodide (PI) staining and flow cytometry. Cell cycle distribution was determined by PI staining and flow cytometer. Single-cell gel electrophoresis was used to estimate DNA damage. Medical records of patients with gastric cancer were retrospectively reviewed, and the patients treated with itraconazole were selected for the present study. Itraconazole treatment inhibited the proliferation and altered cell cycle in SGC-7901 cells while promoting early apoptosis and DNA damage. These effects were promoted in cells treated with both itraconazole and 5-FU. Combination itraconazole and 5-FU treatment showed a synergetic anticancer effect in SGC-7901 cells. , itraconazole was able to improve the outcome of 5-FU-based chemotherapy. Itraconazole alone and in combination with 5-FU was able to inhibit the growth of gastric cancer , and it was able to prolong the survival of patients with gastric cancer.
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http://dx.doi.org/10.3892/ol.2018.9072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096255PMC
September 2018

ABCA1 inhibits PDGF-induced proliferation and migration of rat airway smooth muscle cell through blocking TLR2/NF-κB/NFATc1 signaling.

J Cell Biochem 2018 09 18;119(9):7388-7396. Epub 2018 May 18.

Department of Oncology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China.

Airway remodeling is a key feature of asthma, characterized by abnormal proliferation and migration of airway smooth muscle cells (ASMCs). ABCA1, a member of the ATP-binding cassette family of active transporters, plays an essential role in the progression of lung diseases. However, the contributions of ABCA1 in ASMCs remain to be explored. The purpose of the present study was to investigate the functional role and potential molecular mechanism of ABCA1 in platelet derived growth factor (PDGF)-induced primary rat ASMC proliferation and migration. We observed that PDGF- led to a significant decrease in the expression of ABCA1. Overexpression of ABCA1 strikingly suppressed PDGF-induced ASMC proliferation accompanied by a decrease in the expression of PCAN stimulated by PDGF. Additionally, augmentation of ABCA1 dramatically restrained PDGF-induced migration concomitant with attenuate the accumulation of MMP-2 and MMP-9 in response to PDGF. Furthermore, forced expression of ABCA1 enhanced contractile phenotype markers proteins including α-SMA along with sm-MHC, sm-α-actin, and calponin reduced by PDGF. Meanwhile, introduction of ABCA1 depressed ECM over-deposition induced by PDGF as reflected by a decrease in the expression of ECM protein collagen I and fibronectin. More importantly, addition of ABCA1 effectively suppressed the activity of TLR2/NF-κB signaling as well as diminished the expression of NFATc1 in rat ASMCs after PDGF stimulation. Interestingly, blockage of TLR2/NF-κB signaling effectively inhibited PDGF-induced proliferation and migration, these effects were similar to ABCA1. Taken together, these data implicated that ABCA1 suppressed PDGF-induced proliferation, migration, and contraction in rat ASMCs at least partly through TLR2/NF-κB/NFATc1 signaling, which might offer hope for the future treatment of airway remodeling in asthma.
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http://dx.doi.org/10.1002/jcb.27046DOI Listing
September 2018

MEG3/miR‑21 axis affects cell mobility by suppressing epithelial‑mesenchymal transition in gastric cancer.

Oncol Rep 2018 Jul 8;40(1):39-48. Epub 2018 May 8.

Department of Surgical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

The prognosis of patients with gastric cancer remains poor mainly due to distant metastasis. Maternally expressed gene 3 (MEG3), a long non‑coding RNA (lncRNA), is downregulated in various tumor tissues and suppresses tumor progression. miR‑21 is a microRNA which is expressed highly in tumor tissues. In the present study, we investigated the relationship between MEG3 and miR‑21 in regards to the cell mobility of gastric cancer. Our data demonstrated that MEG3 was downregulated while miR‑21 was upregulated in gastric cancer tissues and cell lines by qRT‑PCR. Overexpression of MEG3 suppressed cell mobility of gastric cancer cells (AGS) by downregulating the expression of MMP‑3, MMP‑9 and VEGF. As shown by western blot analysis, overexpression of MEG3 also suppressed epithelial‑mesenchymal transition (EMT) by increasing the expression of an epithelial marker (E‑cadherin) and downregulating the expression of mesenchymal markers (N‑cadherin, Snail and β‑catenin), indicating that MEG3 suppressed cell mobility through the inhibition of EMT in gastric cancer. The expression of miR‑21 was negatively regulated by MEG3 and overexpression of miR‑21 promoted cell mobility of AGS through activation of EMT. Co‑transfection of lncRNA‑MEG3 and miR‑21 mimic counteracted the inhibitory effect on the cell mobility attributed to MEG3, suggesting that the MEG3/miR‑21 axis affects cell mobility by suppressing EMT in gastric cancer. Using a mouse xenograft tumor model, we found that the overexpression of MEG3 suppressed tumor growth and metastasis while overexpression of miR‑21 had the opposite effects. The MEG3/miR‑21 axis affected gastric cancer growth and metastasis through inhibition of EMT in vivo. In conclusion, we demonstrated that the MEG3/miR‑21 axis participates in the tumor progression and metastasis of gastric cancer through the regulation of EMT.
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http://dx.doi.org/10.3892/or.2018.6424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059753PMC
July 2018

Methylation-induced silencing of SPG20 facilitates gastric cancer cell proliferation by activating the EGFR/MAPK pathway.

Biochem Biophys Res Commun 2018 06 18;500(2):411-417. Epub 2018 Apr 18.

Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 227W, Yanta Road, Xi'an, Shaanxi, China. Electronic address:

Spastic paraplegia 20 methylation was characterized in gastric cancer in our previous study. However, its mechanism remains unknown. Cell proliferation, colony formation, flow cytometry, wound healing, in vitro Transwell assays and in vivo xenografts were performed. A nomogram model was established to make a more accurate prognostic prediction for gastric cancer patients. Knockout of Spastic paraplegia 20 promoted gastric cancer cell proliferation, G2/M arrest in vitro and tumor growth in vivo. The EGFR/MAPK pathway was activated as a consequence of Spastic paraplegia 20 deletion. EGFR kinase or ERK1/2 inhibitors impaired Spastic paraplegia 20 knockout-induced cancer cell growth. Gastric cancer patients with poor spartin expression (72/161, 44.7%) exhibited a worse prognosis compared with the high expression group with median survival times of 16 and 54 months, respectively. The nomogram model stratified gastric cancer patients into 3 distinct prognostic groups with 3-year survival rates of 100%, 77%, and 35%. Furthermore, it had a better discrimination than the TNM staging system (C index: 0.785, AIC: 752.8708 VS. C index: 0.712; AIC: 775.1223). Methylation-induced Spastic paraplegia 20 silencing facilitates gastric cancer cell proliferation by activating the EGFR/MAPK signaling pathway. The nomogram based on spartin expression provided significantly better discrimination compared with the traditional AJCC TNM staging system and provided an individualized prediction of the survival for gastric cancer patient survival.
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http://dx.doi.org/10.1016/j.bbrc.2018.04.089DOI Listing
June 2018

Differences between carcinoma of the cecum and ascending colon: Evidence based on clinical and embryological data.

Int J Oncol 2018 Jul 12;53(1):87-98. Epub 2018 Apr 12.

Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

Developing rapidly from the cecal diverticulum in a 5-week-old embryo, the cecum, which is developed from the caudal limb of the midgut loop, is different from the ascending colon. The aim of this study was to analyze the different clinicopathological and biological characteristics of patients with carcinoma of the cecum and ascending colon. We accessed data for 59,035 patients with adenocarcinomas of the cecum and ascending colon from the Surveillance, Epidemiology and End Results database to explore the potential associations between the clinicopathological characteristics and overall survival. Furthermore, we analyzed the differences in gene expression between the two segments in the Gene Expression Omnibus database. The results were validated in The Cancer Genome Atlas database, as well as with another independent dataset from the First Affiliated Hospital of Xi'an Jiaotong University. The results of this study revealed the potential prognostic differences between adenocarcinoma of the cecum and ascending colon, which may be caused by the differential expression levels of the SLCO1B3 gene. When including the expression levels of SLCO1B3 in intraoperatively examined lymph nodes, 8 factors were found able to predict the prognosis of patients with carcinomas of the cecum and ascending colon. As regards the surgical therapeutic strategies, the resection of >15 local lymph nodes is appropriate for improving the prognosis of patients.
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http://dx.doi.org/10.3892/ijo.2018.4366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958713PMC
July 2018

Effects of rat bone marrow-derived mesenchymal stem cells on breast cancer cells with differing hormone receptor status.

Oncol Lett 2017 Dec 3;14(6):7269-7275. Epub 2017 Oct 3.

Department of Oncology, The First Hospital Affiliated to The School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.

Breast cancer is a heterogeneous disease that can be classified into several molecular intrinsic subtypes according to hormone markers, including estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2. Breast cancer cases with different hormone status vary with respect to patient morbidity, metastasis organotropism and disease progression. It is well known that the most preferential relapse site of breast cancer is in the bone, but the metastatic incidence is markedly higher in hormone receptor-positive cancer compared with that in hormone receptor-negative cancers. Bone marrow-derived mesenchymal stem cells (BMSCs) perform important roles at the site of metastasis; however, the effects in different tumors or tumor subtypes are controversial. The present study aimed to explore the various effects of BMSCs on the biological characteristics of different hormone receptor statuses. BMSCs were obtained from female rats and characterized by cell lineage-specific antigens. The MCF-7 and MDA-MB-231 breast cancer cell lines, which are hormone receptor-positive and -negative, respectively, were employed in the present study. The cancer cells were co-cultured with BMSCs, and changes in the biological characteristic of cell growth, apoptosis, migration and epithelial-mesenchymal transition (EMT) were assessed. BMSCs exhibited chemotactic attraction to MCF-7, promoted the proliferation of MCF-7 cells and reduced MCF-7 cell apoptosis. By contrast, BMSCs exerted no marked effects on these behaviors of MDA-MB-231 cells. However, following co-culture with BMSCs, the migratory ability was enhanced in the two cell lines. Furthermore, the expression of epithelial markers (epithelial-cadherin and occludin) was decreased, and mesenchymal marker vimentin was markedly increased in the two cell lines. Notably, the migratory ability of MDA-MB-231 cells was attenuated compared with that of MCF-7 cells. The results from the present study indicated that BMSCs may favor receptor-positive cancer cell proliferation in bone and promote enhanced invasiveness of receptor-negative compared with receptor-positive cancer cells.
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http://dx.doi.org/10.3892/ol.2017.7130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754910PMC
December 2017

p38 predicts depression and poor outcome in esophageal cancer.

Oncol Lett 2017 Dec 3;14(6):7241-7249. Epub 2017 Oct 3.

Department of Surgical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, P.R. China.

p38 mitogen-activated protein kinase (MAPK) signaling has been implicated in the cancer development and progression. However, the precise mechanism of this association remains unknown. The aim of the present study was to evaluate the association between p38 and cancer progression, including investigations into the effects on cell proliferation, resistance to thalidomide, indoleamine 2,3-dioxygenase (IDO) expression and prognosis in patients with esophageal cancer. The present retrospective study included patients with stage I-III esophageal cancer. A total of 228 patients with esophageal cancer were recruited to analyze the expression of phosphorylated (p)-p38 and IDO in tumor, and normal tissues through immunohistochemistry. Depression status was measured using the Zung Self-Rating Depression Scale. P38 cDNA was transfected into esophageal cancer cells to assess tumor cell viability, sensitivity to thalidomide treatment and IDO gene expression. Western blotting and flow cytometry was used to analyze protein expression alterations, and apoptosis in esophageal cancer cells. P-p38 protein was expressed in 68.9% of cancer tissues, and was significantly associated with depressive symptoms, tumor recurrence and poor survival of patients. experiments revealed that the expression of p-p38 induced esophageal cancer Eca-109 and TE-1 cell viability, and resistance to thalidomide treatment, as well as in the expression of IDO without the application of lipopolysaccharides. Further follow-up of patients revealed that depression was also an independent factor for early recurrence and overall survival rate. Altered p38 MAPK expression was associated with poor outcome in patients with esophageal cancer. p38 may be a potential biomarker for the prediction of depressive symptoms and prognosis in patients with esophageal cancer.
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http://dx.doi.org/10.3892/ol.2017.7129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754885PMC
December 2017
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