Publications by authors named "Daiming Fan"

581 Publications

Tumorigenicity Assay in Nude Mice.

Bio Protoc 2017 Jul 5;7(13):e2364. Epub 2017 Jul 5.

State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Tumorigenicity refers to the ability of cultured cells to develop viable tumors in immune-deficient animals. The goal of this protocol is to illustrate tumorigenicity assay by subcutaneous tumor-cell-transplantation in nude mice. Target cells are transplanted to 6-week-old nude mice subcutaneously and the tumor growth is monitored over a period of observation or treatment. When tumor grows to a pre-determined size or by the end of the limited period, the nude mice will be euthanatized and the xenograft will be removed for further examination.
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http://dx.doi.org/10.21769/BioProtoc.2364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413503PMC
July 2017

Soft Agar Colony Formation Assay as a Hallmark of Carcinogenesis.

Bio Protoc 2017 Jun 20;7(12):e2351. Epub 2017 Jun 20.

State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Soft agar colony formation assay is established to estimate the anchorage-independent growth ability of cells. In this assay, a bottom layer of agar with complete media is poured and solidified first, followed by an upper layer containing a specified number of cells suspended in medium-agar mixture. After two weeks of incubation, the number of colonies will be counted, serving as an indicator of malignancy of tumor cells.
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http://dx.doi.org/10.21769/BioProtoc.2351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410321PMC
June 2017

Silencing of ER-resident oxidoreductase PDIA3 inhibits malignant biological behaviors of multidrug-resistant gastric cancer.

Acta Biochim Biophys Sin (Shanghai) 2021 Aug;53(9):1216-1226

Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.

Glycosylation is a common posttranslational modification of proteins, which plays a role in the malignant transformation, growth, progression, chemoresistance, and immune response of tumors. Disulfide isomerase family A3 (PDIA3) specifically acts on newly synthesized glycoproteins to promote the correct folding of sugar chains. Studies have shown that PDIA3 participates in multidrug-resistant gastric cancer (MDR-GC). In this study, we performed western blot analysis and immunohistochemistry to identify PDIA3 expression. Cell proliferation was assessed by CCK-8 assay. Transwell assays were used to detect the migration and invasion abilities of cells. Immunoprecipitation coupled to mass spectrometry (IP-MS) analysis was employed to identify PDIA3-interacting proteins and the associated pathways in MDR-GC cells. Glycoprotein interactions and translocation were detected by immunofluorescence assay. The results showed that PDIA3 knockdown significantly inhibited the proliferation, invasion, and migration abilities of MDR-GC cells. Kyoto Encyclopedia of Genes and Genomes analysis of the IP-MS results showed that PDIA3 was closely associated with focal adhesion pathways in MDR-GC cells. Additionally, important components of focal adhesion pathways, including fibronectin-1 (FN1) and integrin α5 (ITGA5), were identified as pivotal PDIA3-binding glycoproteins. Knockdown of PDIA3 altered the cellular locations of FN1 and ITGA5, leading to abnormal accumulation. In conclusion, our results suggest that knockdown of PDIA3 inhibited the malignant behaviors of MDR-GC cells and influenced the translocation of FN1 and ITGA5.
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http://dx.doi.org/10.1093/abbs/gmab101DOI Listing
August 2021

Development and validation of a survival model for esophageal adenocarcinoma based on autophagy-associated genes.

Bioengineered 2021 12;12(1):3434-3454

Division of Digestive Surgery, State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China.

Autophagy is a highly conserved catabolic process which has been implicated in esophageal adenocarcinoma (EAC). We sought to investigate the biological functions and prognostic value of autophagy-related genes (ARGs) in EAC. A total of 21 differentially expressed ARGs were identified between EAC and normal samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were then applied for the differentially expressed ARGs in EAC, and the protein-protein interaction (PPI) network was established. Cox survival analysis and Lasso regression analysis were performed to establish a prognostic prediction model based on nine overall survival (OS)-related ARGs (CAPN1, GOPC, TBK1, SIRT1, ARSA, BNIP1, ERBB2, NRG2, PINK1). The 9-gene prognostic signature significantly stratified patient outcomes in The Cancer Genome of Atlas (TCGA)-EAC cohort and was considered as an independently prognostic predictor for EAC patients. Moreover, Gene set enrichment analysis (GSEA) analyses revealed several important cellular processes and signaling pathways correlated with the high-risk group in EAC. This prognostic prediction model was confirmed in an independent validation cohort (GSE13898) from The Gene Expression Omnibus (GEO) database. We also developed a nomogram with a concordance index of 0.78 to predict the survival possibility of EAC patients by integrating the risk signature and clinicopathological features. The calibration curves substantiated favorable concordance between actual observation and nomogram prediction. Last but not least, Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2), a member of the prognostic gene signature, was identified as a potential therapeutic target for EAC patients. To sum up, we established and verified a novel prognostic prediction model based on ARGs which could optimize the individualized survival prediction in EAC.
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http://dx.doi.org/10.1080/21655979.2021.1946235DOI Listing
December 2021

Distinct Basal Brain Functional Activity and Connectivity in the Emotional-Arousal Network and Thalamus in Patients With Functional Constipation Associated With Anxiety and/or Depressive Disorders.

Psychosom Med 2021 Sep;83(7):707-714

From the Center for Brain Imaging, School of Life Science and Technology (G. Li, W. Zhang, Hu, J. Wang, J. Li, Jia, L. Zhang, Deneen, Y. Zhang), Xidian University; and State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases (Sun, Wu, Fan, Nie), Department of Radiology, Tangdu Hospital (Duan, Cui), and Department of Psychiatry, Xijing Hospital (H. Wang), the Fourth Military Medical University, Xi'an, Shaanxi, China. G.L. and W.Z. contributed equally to this work.

Objective: Functional constipation (FC) is a common gastrointestinal disorder. Anxiety and/or depressive disorders are common in patients with FC (FCAD). Brain dysfunction may play a role in FC, but the contribution of comorbid anxiety and/or depression in patients with FC is poorly understood.

Methods: Sixty-five FC patients and 42 healthy controls (HCs) were recruited, and a hierarchical clustering algorithm was used to classify FC patients into FCAD and patients without anxiety/depressive status (FCNAD) based on neuropsychological assessment. Resting-state functional magnetic resonance imaging measures including fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity were used to investigate brain functional differences.

Results: Thirty-seven patients were classified as FCAD, and 28 patients were classified as FCNAD; as compared with HC, both groups showed decreased activity (fALFF) in the perigenual anterior cingulate cortex (pACC), dorsomedial prefrontal cortex (DMPFC), and precuneus; enhanced precentral gyrus-thalamus connectivity and attenuated precuneus-thalamus connectivity in FCAD/FCNAD highlighted the thalamus as a critical connectivity node in the brain network (pFWE < .05). In comparison with FCNAD/HC, the FCAD group also had decreased fALFF in the orbitofrontal cortex (OFC) and thalamus, and increased OFC-hippocampus connectivity. In the FCNAD group, brain activities (pACC/DMPFC) and connection (precuneus-thalamus) had correlations only with symptoms; in the FCAD group, brain activities (OFC, pACC/DMPFC) and connectivities (OFC-hippocampus/precentral gyrus-thalamus) showed correlations with both constipation symptoms and anxiety/depressive status ratings. Mediation analysis indicated that the relationship between abdominal distension and OFC activity was completely mediated by anxiety in FCAD.

Conclusions: These findings provide evidence of differences in brain activity and functional connectivity between FCAD and FCNAD, potentially providing important clues for improving treatment strategies.
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http://dx.doi.org/10.1097/PSY.0000000000000958DOI Listing
September 2021

IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R.

Cell Death Dis 2021 06 1;12(6):564. Epub 2021 Jun 1.

Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.

Metastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.
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http://dx.doi.org/10.1038/s41419-021-03833-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169856PMC
June 2021

Correction: SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7.

Oncogene 2021 Jun;40(24):4242-4243

Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.

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http://dx.doi.org/10.1038/s41388-021-01828-zDOI Listing
June 2021

Prognostic biomarkers and therapeutic targets in oral squamous cell carcinoma: a study based on cross-database analysis.

Hereditas 2021 Apr 23;158(1):15. Epub 2021 Apr 23.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, No.127, Changle West Road, Xi'an, 710032, Shaanxi Province, China.

Background: Oral squamous cell carcinoma (OSCC) is a malignant cancer, the survival rate of patients is disappointing. Therefore, it is necessary to identify the driven-genes and prognostic biomarkers in OSCC.

Methods: Four Gene Expression Omnibus (GEO) datasets were integratedly analyzed using bioinformatics approaches, including identification of differentially expressed genes (DEGs), GO and KEGG analysis, construction of protein-protein interaction (PPI) network, selection of hub genes, analysis of prognostic information and genetic alterations of hub genes. ONCOMINE, The Cancer Genome Atlas (TCGA) and Human Protein Atlas databases were used to evaluate the expression and prognostic value of hub genes. Tumor immunity was assessed to investigate the functions of hub genes. Finally, Cox regression model was performed to construct a multiple-gene prognostic signature.

Results: Totally 261 genes were found to be dysregulated. 10 genes were considered to be the hub genes. The Kaplan-Meier analysis showed that upregulated SPP1, FN1, CXCL8, BIRC5, PLAUR, and AURKA were related to poor outcomes in OSCC patients. FOXM1 and TPX2 were considered as the potential immunotherapeutic targets with future clinical significance. Moreover, we constructed a nine-gene signature (TEX101, DSG2, SCG5, ADA, BOC, SCARA5, FST, SOCS1, and STC2), which can be utilized to predict prognosis of OSCC patients effectively.

Conclusion: These findings may provide new clues for exploring the molecular mechanisms and targeted therapy in OSCC. The hub genes and risk gene signature are helpful to the personalized treatment and prognostic judgement.
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http://dx.doi.org/10.1186/s41065-021-00181-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066950PMC
April 2021

The FENDRR/FOXC2 Axis Contributes to Multidrug Resistance in Gastric Cancer and Correlates With Poor Prognosis.

Front Oncol 2021 22;11:634579. Epub 2021 Mar 22.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

The dysregulation of long non-coding RNAs (lncRNAs) and transcription factors (TFs) is closely related to the development and progression of drug resistance in cancer chemotherapy. However, their regulatory interactions in the multidrug resistance (MDR) of gastric cancer (GC) has largely remained unknown. In this study, we report a novel oncogenic role of lncRNA FENDRR in conferring MDR in GC by coordinated regulation of FOXC2 expression at the transcriptional and posttranscriptional levels. and experiments demonstrated that downregulation of FENDRR expression remarkably decreased drug resistant ability of GC MDR cells while upregulation of FENDRR expression produced the opposite effect. FENDRR overexpression was observed in MDR GC cell lines, patient-derived xenografts, and clinical samples. And the high levels of FENDRR expression were correlated with poor prognosis in GC patients. Regarding the mechanism, FENDRR was revealed to increase proto-oncogene FOXC2 transcription by performing an enhancer-like role in the nucleus and by sponging miR-4700-3p in the cytoplasm. Both FOXC2 and miR-4700-3p were shown to be functionally involved in the FENDRR-induced chemoresistance. In addition, there is a positive correlation between FENDRR and FOXC2 expression in clinic and the overexpressed FOXC2 indicated a poor prognosis in GC patients. Collectively, our findings provide a new perspective for the lncRNA-TF regulatory interaction involved in MDR, suggesting that targeting the FENDRR/FOXC2 axis may be an effective approach to circumvent GC chemoresistance.
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http://dx.doi.org/10.3389/fonc.2021.634579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044876PMC
March 2021

Insights into the role of ERp57 in cancer.

J Cancer 2021 1;12(8):2456-2464. Epub 2021 Mar 1.

Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.

Endoplasmic reticulum resident protein 57 (ERp57) has a molecular weight of 57 kDa, belongs to the protein disulfide-isomerase (PDI) family, and is primarily located in the endoplasmic reticulum (ER). ERp57 functions in the quality control of nascent synthesized glycoproteins, participates in major histocompatibility complex (MHC) class I molecule assembly, regulates immune responses, maintains immunogenic cell death (ICD), regulates the unfolded protein response (UPR), functions as a 1,25-dihydroxy vitamin D (1,25(OH)D) receptor, regulates the NF-κB and STAT3 pathways, and participates in DNA repair processes and cytoskeletal remodeling. Recent studies have reported ERp57 overexpression in various human cancers, and altered expression and aberrant functionality of ERp57 are associated with cancer growth and progression and changes in the chemosensitivity of cancers. ERp57 may become a potential biomarker and therapeutic target to combat cancer development and chemoresistance. Here, we summarize the available knowledge of the role of ERp57 in cancer and the underlying mechanisms.
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http://dx.doi.org/10.7150/jca.48707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974888PMC
March 2021

Anticoagulation and Transjugular Intrahepatic Portosystemic Shunt for the Management of Portal Vein Thrombosis in Cirrhosis: A Prospective Observational Study.

Am J Gastroenterol 2021 07;116(7):1447-1464

Department of Liver Diseases and Digestive Interventional Radiology, National Clinical Research Centre for Digestive Diseases and Xi'an International Medical Center Hospital of Digestive Diseases, Northwestern University, Xi'an, China.

Introduction: Current guidelines recommend anticoagulation as the mainstay of portal vein thrombosis (PVT) treatment in cirrhosis. However, because of the heterogeneity of PVT, anticoagulation alone does not always achieve satisfactory results. This study aimed to prospectively evaluate an individualized management algorithm using a wait-and-see strategy (i.e., no treatment), anticoagulation, and transjugular intrahepatic portosystemic shunt (TIPS) to treat PVT in cirrhosis.

Methods: Between February 2014 and June 2018, 396 consecutive patients with cirrhosis with nonmalignant PVT were prospectively included in a tertiary care center, of which 48 patients (12.1%) were untreated, 63 patients (15.9%) underwent anticoagulation, 88 patients (22.2%) underwent TIPS, and 197 patients (49.8%) received TIPS plus post-TIPS anticoagulation. The decision of treatment option mainly depends on the stage of liver disease (symptomatic portal hypertension or not) and degree and extension of thrombus.

Results: During a median 31.7 months of follow-up period, 312 patients (81.3%) achieved partial (n = 25) or complete (n = 287) recanalization, with 9 (3.1%) having rethrombosis, 64 patients (16.2%) developed major bleeding (anticoagulation-related bleeding in 7 [1.8%]), 88 patients (22.2%) developed overt hepatic encephalopathy, and 100 patients (25.3%) died. In multivariate competing risk regression models, TIPS and anticoagulation were associated with a higher probability of recanalization. Long-term anticoagulation using enoxaparin or rivaroxaban rather than warfarin was associated with a decreased risk of rethrombosis and an improved survival, without increasing the risk of bleeding. However, the presence of complete superior mesenteric vein thrombosis was associated with a lower recanalization rate, increased risk of major bleeding, and poor prognosis.

Discussion: In patients with cirrhosis with PVT, the individualized treatment algorithm achieves a high-probability recanalization, with low rates of portal hypertensive complications and adverse events.
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http://dx.doi.org/10.14309/ajg.0000000000001194DOI Listing
July 2021

Association of systemic inflammation and body mass index with survival in patients with resectable gastric or gastroesophageal junction adenocarcinomas.

Cancer Biol Med 2021 02;18(1):283-297

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Medical University of PLA, Xi'an 710032, China.

Objective: The systemic inflammation index and body mass index (BMI) are easily accessible markers that can predict mortality. However, the prognostic value of the combined use of these two markers remains unclear. The goal of this study was therefore to evaluate the association of these markers with outcomes based on a large cohort of patients with gastric cancer.

Methods: A total of 2,542 consecutive patients undergoing radical surgery for gastric or gastroesophageal junction adenocarcinoma between 2009 and 2014 were included. Systemic inflammation was quantified by the preoperative neutrophil-to-lymphocyte ratio (NLR). High systemic inflammation was defined as NLR ≥ 3, and underweight was defined as BMI < 18.5 kg/m.

Results: Among 2,542 patients, NLR ≥ 3 and underweight were common [627 (25%) and 349 (14%), respectively]. In the entire cohort, NLR ≥ 3 or underweight independently predicted overall survival (OS) [hazard ratio (HR): 1.236, 95% confidence interval (95% CI): 1.069-1.430; and HR: 1.600, 95% CI: 1.350-1.897, respectively] and recurrence-free survival (RFS) (HR: 1.230, 95% CI: 1.054-1.434; and HR: 1.658, 95% CI: 1.389-1.979, respectively). Patients with both NLR ≥ 3 and underweight ( neither) had much worse OS (HR: 2.445, 95% CI: 1.853-3.225) and RFS (HR: 2.405, 95% CI: 1.802-3.209). Furthermore, we observed similar results in subgroup analyses according to pathological stage, age, and postoperative chemotherapy.

Conclusions: Our results showed that preoperative elevated NLR and decreased BMI had a significant negative effect on survival. Underweight combined with severe inflammation could enhance prognostication. Taking active therapeutic measures to reduce inflammation and increase nutrition may help improve outcomes.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877168PMC
February 2021

CXCL12-mediated HOXB5 overexpression facilitates Colorectal Cancer metastasis through transactivating CXCR4 and ITGB3.

Theranostics 2021 1;11(6):2612-2633. Epub 2021 Jan 1.

State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.

Metastasis is the major reason for the high mortality of colorectal cancer (CRC). However, the molecular mechanism underlying CRC metastasis remains unclear. Here, we report a novel role of homeobox B5 (HOXB5), a member of the HOX family, in promoting CRC metastasis. The expression of HOXB5 and its target genes were examined by immunohistochemistry in human CRC. Chromatin immunoprecipitation and luciferase reporter assays were performed to measure the transcriptional regulation of target genes by HOXB5. The metastatic capacities of CRC cells were evaluated by lung and liver metastatic models. The elevated expression of HOXB5 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in CRC patients. HOXB5 expression was an independent and significant risk factor for the recurrence and survival in CRC patients. Overexpression of HOXB5 promoted CRC metastasis by transactivating metastatic related genes, C-X-C motif chemokine receptor 4 (CXCR4) and integrin subunit beta 3 (ITGB3). C-X-C motif chemokine ligand 12 (CXCL12), which is the ligand of CXCR4, upregulated HOXB5 expression through the extracellular regulated protein kinase (ERK)/ETS proto-oncogene 1, transcription factor (ETS1) pathway. The knockdown of HOXB5 decreased CXCL12-enhanced CRC metastasis. Furthermore, AMD3100, a specific CXCR4 inhibitor, significantly suppressed HOXB5-mediated CRC metastasis. HOXB5 expression was positively correlated with CXCR4 and ITGB3 expression in human CRC tissues, and patients with positive co-expression of HOXB5/CXCR4, or HOXB5/ITGB3 exhibited the worst prognosis. Our study implicates HOXB5 as a prognostic biomarker in CRC, and defines a CXCL12-HOXB5-CXCR4 positive feedback loop that plays an important role in promoting CRC metastasis.
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http://dx.doi.org/10.7150/thno.52199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806482PMC
July 2021

Biological Implications and Clinical Potential of Metastasis-Related miRNA in Colorectal Cancer.

Mol Ther Nucleic Acids 2021 Mar 22;23:42-54. Epub 2020 Oct 22.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.

Colorectal cancer (CRC), ranking as the third commonest cancer, leads to extremely high rates of mortality. Metastasis is the major cause of poor outcome in CRC. When metastasis occurs, 5-year survival rates of patients decrease sharply, and strategies to enhance a patient's lifetime seem limited. MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that are significantly involved in manipulation of CRC malignant phenotypes, including proliferation, invasion, and metastasis. To date, accumulating studies have revealed the mechanisms and functions of certain miRNAs in CRC metastasis. However, there is no systematic discussion about the biological implications and clinical potential (diagnostic role, prognostic role, and targeted therapy potential) of metastasis-related miRNAs in CRC. This review mainly summarizes the recent advances of miRNA-mediated metastasis in CRC. We also discuss the clinical values of metastasis-related miRNAs as potential biomarkers or therapeutic targets in CRC. Moreover, we envisage the future orientation and challenges in translating these findings into clinical applications.
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http://dx.doi.org/10.1016/j.omtn.2020.10.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723777PMC
March 2021

Biological functions and theranostic potential of HMGB family members in human cancers.

Ther Adv Med Oncol 2020 10;12:1758835920970850. Epub 2020 Nov 10.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China.

The high mobility group box (HMGB) protein family consists of four members: HMGB1, 2, 3, and 4. They share similar amino acid sequences and identical functional regions, especially HMGB1, 2, and 3. The homology in structure may lead to similarity in function. In fact, though their targets may be different, they all possess the fundamental function of binding and distorting target DNAs. However, further research confirmed they are distributed differently in tissues and involved in various distinct physiological and pathological cellular processes, including cell proliferation, division, migration, and differentiation. Recently, the roles of HMGB family members in carcinogenesis has been widely investigated; however, systematic discussion on their functions and clinical values in malignant tumors is limited. In this review, we mainly review and summarize recent advances in knowledge of HMGB family members in terms of structure, distribution, biochemical cascades, and specific mechanisms regarding tumor progression. Importantly, the diagnostic, prognostic, and therapeutic value of these proteins in cancers is discussed. Finally, we envisage the orientation and challenges of this field in further studies.
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http://dx.doi.org/10.1177/1758835920970850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659026PMC
November 2020

Development and validation of a survival model based on autophagy-associated genes for predicting prognosis of hepatocellular carcinoma.

Am J Transl Res 2020 15;12(10):6705-6722. Epub 2020 Oct 15.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University Xi'an 710032, Shaanxi Province, China.

Objective: This study aimed to identify the novel prognostic gene signature based on autophagy-associated genes (ARGs) in hepatocellular carcinoma (HCC).

Methods: The RNA sequencing data and clinical information of HCC and normal tissues were obtained from The Cancer Genome Atlas (TCGA) database. The differentially expressed ARGs were screened by the Wilcoxon signed-rank test. Cox regression analysis and Lasso regression analysis were performed to screen the ARGs and establish the prognostic prediction model. Kaplan-Meier and receiver operating characteristic (ROC) curves were both used to evaluate the accuracy of the model. GSE14520 dataset (testing cohort) was used to validate the prognostic risk model in TCGA. A clinical nomogram was established to predict the survival rate of HCC patients.

Results: Totally 27 differentially expressed ARGs were identified. Three OS-related ARGs (SQSTM1, HSPB8, and BIRC5) were identified via the Cox regression and Lasso regression analyses. Based on these three ARGs, a prognostic prediction model was constructed. HCC patients with high risk score present poorer prognosis than those with low risk score both in TCGA cohort (P=4.478e-04) and testing cohort (P=1.274e-03). Moreover, the risk score curve shows a well feasibility in predicting the patients' survival both in TCGA and GEO cohort with the area under the ROC curve (AUC) of 0.756 and 0.672, respectively. Besides, the calibration curves and C-index indicated that the clinical nomogram performs well to predict survival rate in HCC patients.

Conclusions: The survival model based on the ARGs may be a promising tool to predict the prognosis in HCC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653605PMC
October 2020

Effects of Early Placement of Transjugular Portosystemic Shunts in Patients With High-Risk Acute Variceal Bleeding: a Meta-analysis of Individual Patient Data.

Gastroenterology 2021 01 24;160(1):193-205.e10. Epub 2020 Sep 24.

Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Spain; Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. Electronic address:

Background & Aims: Compared with drugs plus endoscopy, placement of transjugular portosystemic shunt within 72 hours of admission to the hospital (early or preventive transjugular intrahepatic portosystemic shunt [TIPS], also called preemptive TIPS) increases the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survive for 1 year. However, the benefit of preemptive TIPS is less clear for patients with a Child-Pugh score of B and active bleeding (CP-B+AB). We performed an individual data meta-analysis to assess the efficacy of preemptive TIPS in these patients and identify factors associated with reduced survival of patients receiving preemptive TIPS.

Methods: We searched publication databases for randomized controlled trials and observational studies comparing the effects of preemptive TIPS versus endoscopy plus nonselective beta-blockers in the specific population of high-risk patients with cirrhosis and acute variceal bleeding (CP-B+AB or Child-Pugh C, below 14 points), through December 31, 2019. We performed a meta-analysis of data from 7 studies (3 randomized controlled trials and 4 observational studies), comprising 1327 patients (310 received preemptive TIPS and 1017 received drugs plus endoscopy). We built adjusted models to evaluate risk using propensity score for baseline covariates. Multivariate Cox regression models were used to assess the factors associated with survival time. The primary endpoint was effects of preemptive TIPS versus drugs plus endoscopy on 1-year survival in the overall population as well as CP-B+AB and Child-Pugh C patients.

Results: Overall, preemptive TIPS significantly increased the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survived for 1 year, compared with drugs plus endoscopy (hazard ratio [HR] 0.443; 95% CI 0.323-0.607; P < .001). This effect was observed in CP-B+AB patients (HR 0.524; 95% CI 0.307-0.896; P = .018) and in patients with Child-Pugh C scores below 14 points (HR 0.374; 95% CI 0.253-0.553; P < .001). Preemptive TIPS significantly improved control of bleeding and ascites without increasing risk of hepatic encephalopathy in Child-Pugh C and CP-B+AB patients, compared with drugs plus endoscopy. Cox analysis of patients who received preemptive TIPS showed that patients could be classified into 3 categories for risk of death, based on age, serum level of creatinine, and Child-Pugh score. In each of these risk categories, preemptive TIPS increased the proportion of patients who survived for 1 year, compared with drugs plus endoscopy.

Conclusions: In a meta-analysis of data from 1327 patients with cirrhosis, acute variceal bleeding, and Child-Pugh score between 10 and 13 points or CP-B+AB, preemptive TIPS increased the proportion who survived for 1 year, in both subgroups separately, compared with drugs plus endoscopy.
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http://dx.doi.org/10.1053/j.gastro.2020.09.026DOI Listing
January 2021

EI24 Inhibits Cell Proliferation and Drug Resistance of Esophageal Squamous Cell Carcinoma.

Front Oncol 2020 21;10:1570. Epub 2020 Aug 21.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, China.

Drug resistance, whether intrinsic or acquired, often leads to treatment failure in esophageal squamous cell carcinoma (ESCC). Clarifying the mechanism of drug resistance in ESCC has great significance for reversing drug resistance, as well as improving the prognosis of patients. Previously, we demonstrated that etoposide-induced 2.4-kb mRNA (EI24) is the target of miR-483-3p, which promoted the growth, migration, and drug resistance in ESCC, suggesting that EI24 participates in repressing the tumorigenesis and progression of ESCC. Here, we observed that EI24 was remarkably decreased in ESCC tissues. Moreover, its expression was directly linked to the prognosis of patients. We then confirmed that the forced overexpression of EI24 repressed cell growth and sensitized ESCC cells to chemotherapeutic agents, whereas EI24 silencing had the opposite effect. Furthermore, gene microarray and ingenuity pathway analysis (IPA) were performed to establish the potential mechanisms and indicated that EI24 exerts a tumor-suppressive role via suppressing the acute phase response signaling pathway or IL-1 signaling pathway in ESCC. Collectively, our data reveal that EI24 overexpression attenuates malignant phenotypes of ESCC and that it is a novel possible ESCC therapeutic target.
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http://dx.doi.org/10.3389/fonc.2020.01570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471874PMC
August 2020

Molecular mechanisms and clinical implications of miRNAs in drug resistance of colorectal cancer.

Ther Adv Med Oncol 2020 25;12:1758835920947342. Epub 2020 Aug 25.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Systemic chemotherapy is identified as a curative approach to prolong the survival time of patients with colorectal cancer (CRC). Although great progress in therapeutic approaches has been achieved during the last decades, drug resistance still extensively persists and serves as a major hurdle to effective anticancer therapy for CRC. The mechanism of multidrug resistance remains unclear. Recently, mounting evidence suggests that a great number of microRNAs (miRNAs) may contribute to drug resistance in CRC. Certain of these miRNAs may thus be used as promising biomarkers for predicting drug response to chemotherapy or serve as potential targets to develop personalized therapy for patients with CRC. This review mainly summarizes recent advances in miRNAs and the molecular mechanisms underlying miRNA-mediated chemoresistance in CRC. We also discuss the potential role of drug resistance-related miRNAs as potential biomarkers (diagnostic and prognostic value) and envisage the future orientation and challenges in translating the findings on miRNA-mediated chemoresistance of CRC into clinical applications.
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http://dx.doi.org/10.1177/1758835920947342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450467PMC
August 2020

Long-term survival prediction for transjugular intrahepatic portosystemic shunt in severe cirrhotic ascites: assessment of ten prognostic models.

Eur J Gastroenterol Hepatol 2020 Aug 28. Epub 2020 Aug 28.

Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an.

Objectives: Patients with severe cirrhotic ascites have poor prognosis, yet individual patient survival varies greatly. Therefore, suitable prognostic models can be helpful in clinical decision making. The aim of this study was to evaluate and compare the performance of 10 scores in predicting transplant-free survival (TFS) after transjugular intrahepatic portosystemic shunt (TIPS) in severe cirrhotic ascites.

Methods: Two hundred eighty consecutive cirrhotic patients with severe ascites undergoing TIPS between March 2006 and December 2017 were retrospectively screened and included from nine tertiary Chinese centers, consisting of 123 patients with refractory ascites and 157 with recurrent ascites. Discriminatory ability of these models was further assessed in the whole cohort and subgroups.

Results: TFS rates of all 280 patients were 75.4, 65.7, and 53.6% at 6-month, 1-year, and 2-year follow-up, respectively. Compared with other prognostic systems, the integrated model for end-stage liver disease (iMELD, incorporating serum sodium and age) showed optimal performance in predicting 6-month, 1-year, and 2-year TFS. Cutoffs were determined according to c-index and were used to stratify patients into three strata presenting significantly different TFS for short-term and long-term: iMELD < 32, ≥32 but <38 and ≥38 (log-rank P < 0.001).

Conclusions: The iMELD score proved to be the best prognostic model in predicting TFS in patients with severe cirrhotic ascites receiving TIPS. Meanwhile, the model could stratify patients in three strata to help guiding clinical practice.
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http://dx.doi.org/10.1097/MEG.0000000000001890DOI Listing
August 2020

O-GlcNAcylation of SIX1 enhances its stability and promotes Hepatocellular Carcinoma Proliferation.

Theranostics 2020 2;10(21):9830-9842. Epub 2020 Aug 2.

State key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.

It is universally accepted that aberrant metabolism facilitates tumor growth. However, how cancer cells coordinate glucose metabolism and tumor proliferation is largely unknown. Sine oculis homeobox homolog 1 (SIX1) is a transcription factor that belongs to the SIX family and is believed to play an important role in the regulation of the Warburg effect in tumors. However, whether the role of SIX1 and the molecular mechanisms that regulate its activity are similar in hepatocellular carcinoma (HCC) still needs further investigation. Western blotting was performed to determine the levels of SIX1 and O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) in HCC tissues. Cell Counting Kit 8 (CCK8), colony formation and mouse tumor model assays were used to establish the role of SIX1 and O-GlcNAcylation in HCC processes. Mass spectrometry, immunoprecipitation and site-directed mutagenesis were performed to confirm the O-GlcNAcylation of SIX1. Here, we demonstrated that SIX1, the key transcription factor regulating the Warburg effect in cancer, promotes HCC growth and . Furthermore, we revealed that SIX1 could also enhance the levels of a posttranslational modification called O-GlcNAcylation. Importantly, we found that SIX1 was also highly modified by O-GlcNAcylation and that O-GlcNAcylation inhibited the ubiquitination degradation of SIX1. In addition, site-directed mutagenesis at position 276 (T276A) decreased the O-GlcNAcylation level and reversed the protumor effect of SIX1. We conclude that O-GlcNAcylation of SIX1 enhances its stability and promotes HCC proliferation. Our findings illustrate a novel feedback loop of SIX1 and O-GlcNAcylation and show that O-GlcNAcylation of SIX1 is an important way to coordinate glucose metabolism and tumor progression.
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http://dx.doi.org/10.7150/thno.45161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449927PMC
May 2021

Risk Stratification Based on Chronic Liver Failure Consortium Acute Decompensation Score in Patients With Child-Pugh B Cirrhosis and Acute Variceal Bleeding.

Hepatology 2021 Apr 23;73(4):1478-1493. Epub 2021 Jan 23.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Background And Aims: Optimal candidates for early transjugular intrahepatic portosystemic shunt (TIPS) in patients with Child-Pugh B cirrhosis and acute variceal bleeding (AVB) remain unclear. This study aimed to test the hypothesis that risk stratification using the Chronic Liver Failure Consortium Acute Decompensation score (CLIF-C ADs) may be useful to identify a subgroup at high risk of mortality or further bleeding that may benefit from early TIPS in patients with Child-Pugh B cirrhosis and AVB.

Approach And Results: We analyzed the pooled individual data from two previous studies of 608 patients with Child-Pugh B cirrhosis and AVB who received standard treatment between 2010 and 2017 in China. The concordance index values of CLIF-C ADs for 6-week and 1-year mortality (0.715 and 0.708) were significantly better than those of active bleeding at endoscopy (0.633 [P < 0.001] and 0.556 [P < 0.001]) and other prognostic models. With X-tile software identifying an optimal cutoff value, patients were categorized as low risk (CLIF-C ADs <48), intermediate risk (CLIF-C ADs 48-56), and high risk (CLIF-C ADs >56), with a 5.6%, 16.8%, and 25.4% risk of 6-week death, respectively. Nevertheless, the performance of CLIF-C ADs for predicting a composite endpoint of 6-week death or further bleeding was not satisfactory (area under the receiver operating characteristics curve [AUC], 0.588). A nomogram incorporating components of CLIF-C ADs and albumin, platelet, active bleeding, and ascites significantly improved the prediction accuracy (AUC, 0.725).

Conclusions: In patients with Child-Pugh B cirrhosis and AVB, risk stratification using CLIF-C ADs identifies a subgroup with high risk of death that may derive survival benefit from early TIPS. With improved prediction accuracy for 6-week death or further bleeding, the data-driven nomogram may help to stratify patients in randomized trials. Future external validation of these findings in patients with different etiologies is required.
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http://dx.doi.org/10.1002/hep.31478DOI Listing
April 2021

Exploratory Analysis to Identify Candidates Benefitting from Combination Therapy of Transarterial Chemoembolization and Sorafenib for First-Line Treatment of Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Observational Study.

Liver Cancer 2020 Jun 19;9(3):308-325. Epub 2020 Feb 19.

Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Introduction: The benefits of combining transarterial chemoembolization (TACE) and sorafenib (TACE-S) over TACE alone for treatment of unresectable hepatocellular carcinoma (HCC) remain controversial. Yet, such populations are heterogeneous in terms of baseline characteristics.

Objective: To investigate the predictors of survival benefits from added sorafenib and identify the potential candidates for TACE-S.

Methods: This multicenter observational study was conducted in 17 Chinese tertiary hospitals for patients with unresectable, liver-confined HCC. Eligible patients with performance status score of ≤1 and Child-Pugh score of ≤7 were treated with TACE or TACE-S. Interactions between treatment and baseline variables were evaluated to find indicators for survival benefits, based on which the patients were stratified. Multivariate models adjusted for baseline characteristics or propensity score were used to compare overall survival (OS) and time to tumor progression (TTP).

Results: From January 2009 to December 2015, 1,719 consecutive patients received TACE ( = 1,406) or TACE-S ( = 313). Although TACE-S compared with TACE improved TTP (adjusted hazard ratio [HR] 0.75, = 0.008), no difference in OS was observed (adjusted HR 0.87, = 0.090). Nevertheless, the tumor burden (sum of maximum diameter of largest tumor [cm] and tumor number) and albumin-bilirubin (ALBI) score independently predicted the survival benefits from added sorafenib (interaction < 0.001). For patients with either moderate tumor burden (7-13) or low ALBI score (no more than -2.8) defined as candidates, TACE-S prolonged OS (adjusted HR 0.73, = 0.003) and TTP (adjusted HR 0.72, = 0.014) compared to TACE alone, whereas its superiority disappeared in non-candidates.

Conclusions: Not all unresectable HCC patients but those with moderate tumor burden or low ALBI score achieve survival benefits from TACE-S compared with TACE alone. Future randomized controlled trials focusing on the subset are warranted.
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http://dx.doi.org/10.1159/000505692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325128PMC
June 2020

KRAS Mutation-Responsive miR-139-5p inhibits Colorectal Cancer Progression and is repressed by Wnt Signaling.

Theranostics 2020 5;10(16):7335-7350. Epub 2020 Jun 5.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Colorectal cancer (CRC) frequently harbors KRAS mutations that result in chemoresistance and metastasis. MicroRNAs (miRNAs) are usually dysregulated and play important regulatory roles in tumor progression. However, the KRAS mutation-responsive miRNA profile in CRC remains uninvestigated. miR-139-5p was identified and evaluated by small RNA sequencing, qRT-PCR and hybridization. The roles of miR-139-5p in CRC cells with and without KRAS mutation were determined by Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry and transwell assays and by tumorigenesis and metastasis assays . Microarrays followed by bioinformatic analyses, luciferase reporter assays and Western blotting were applied for mechanistic studies. miR-139-5p was significantly downregulated in KRAS-mutated CRC cells and tissues compared with their wild-type counterparts. Low miR-139-5p expression was associated with aggressive phenotypes and poor prognosis in CRC patients. miR-139-5p overexpression inhibited CRC cell proliferation, migration and invasion , sensitized tumors to chemotherapy, and impaired tumor growth and metastasis . Transcriptomic profiling identified multiple modulators in the Ras (JUN and FOS) and Wnt (CTNNB1 and DVL1) signaling pathways and the epithelial-to-mesenchymal transition (EMT) process (ZEB1) as direct targets of miR-139-5p, and inverse correlations were confirmed in CRC clinical tissues. Aberrantly activated Wnt signaling in KRAS-mutant cells was demonstrated to transcriptionally repress miR-139-5p through TCF4, forming a miR-139-5p/Wnt signaling double-negative feedback loop. We identified miR-139-5p as a KRAS-responsive miRNA and demonstrated its involvement in CRC progression. KRAS mutation disrupted the miR-139-5p/Wnt signaling reciprocal negative feedback mechanism, which might cause miR-139-5p downregulation and derepression of oncogenic signaling pathways and EMT. These results reveal a transcriptional regulatory mode of KRAS-driven malignant transformation and highlight miR-139-5p as a novel regulator of crosstalk between the Ras and Wnt signaling pathways in CRC.
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http://dx.doi.org/10.7150/thno.45971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330859PMC
May 2021

SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7.

Oncogene 2020 08 2;39(33):5536-5552. Epub 2020 Jul 2.

Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.

The therapeutic strategies for advanced gastric cancer (GC) remain unsatisfying and limited. Therefore, it is still imperative to fully elucidate the mechanisms underlying GC metastasis. Here, we report a novel role of SRY-box transcription factor 18 (SOX18), a member of the SOX family, in promoting GC metastasis. The elevated expression of SOX18 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in human GC. SOX18 expression was an independent and significant risk factor for the recurrence and survival in GC patients. Up-regulation of SOX18 promoted GC invasion and metastasis, whereas down-regulation of SOX18 decreased GC invasion and metastasis. Melanoma cell adhesion molecule (MCAM) and C-C motif chemokine ligand 7 (CCL7) are direct transcriptional targets of SOX18. Knockdown of MCAM and CCL7 significantly decreased SOX18-mediated GC invasion and metastasis, while the stable overexpression of MCAM and CCL7 reversed the decrease in cell invasion and metastasis that was induced by the inhibition of SOX18. A mechanistic investigation indicated that the upregulation of SOX18 that was mediated by the CCL7-CCR1 pathway relied on the ERK/ELK1 pathway. SOX18 knockdown significantly reduced CCL7-enhanced GC invasion and metastasis. Furthermore, BX471, a specific CCR1 inhibitor, significantly reduced the SOX18-mediated GC invasion and metastasis. In human GC tissues, SOX18 expression was positively correlated with CCL7 and MCAM expression, and patients with positive coexpression of SOX18/CCL7 or SOX18/MCAM had the worst prognosis. In conclusion, we defined a CCL7-CCR1-SOX18 positive feedback loop that played a pivotal role in GC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of GC.
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http://dx.doi.org/10.1038/s41388-020-1378-1DOI Listing
August 2020

Prognostic value of circulating tumor cells detected with the CellSearch system in esophageal cancer patients: a systematic review and meta-analysis.

BMC Cancer 2020 Jun 22;20(1):581. Epub 2020 Jun 22.

State key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 Changle West Road, Xi'an, Shaanxi Province, 710032, PR China.

Background: Esophageal carcinoma (EC) is the seventh-most prevalent tumor in the world, which is still one of the primary causes of tumor-related death. Identifying noteworthy biomarkers for EC is particularly significant in guiding effective treatment. Recently, circulating tumor cells (CTCs) in peripheral blood (PB) were intensively discussed as prognostic markers in patients with EC. However, an ongoing controversy still exists regarding the prognostic significance of CTCs determined by the CellSearch system in EC sufferers. This meta-analysis was designed to approach this topic.

Methods: We systematically conducted searches using PubMed, Medline, Web of Science and the Cochrane Library for relevant studies, which were published through February 20, 2020. Using the random-effects model, our study was performed in Review Manager software, with odds ratios (ORs), risk ratios (RRs), hazard ratios (HRs) and 95% confidence intervals (CIs) as the effect values.

Results: Totally 7 articles were finally included in this study. For clinicopathological characteristics, the pooled results on TNM stage indicated that the III/IV group had higher rate of CTCs compared with the I/II group (OR = 1.36, 95% CI: 0.68-2.71, I = 0%). Incidence of CTCs was higher in patients with T3/T4 stage (OR = 2.92, 95% CI: 1.31-6.51, I = 0%) and distant metastasis group (OR = 5.18, 95% CI: 2.38-11.25, I = 0%) compared to patients with T1/T2 stage or non-metastatic group. The pooled analysis revealed that CTC positivity detected in EC patients was correlated with poor overall survival (OS) (HR = 2.83, 95% CI:1.99-4.03, I = 0%) and relapse-free survival (RFS) (HR = 4.71, 95% CI:2.73-8.13, I = 0%). When pooling the estimated RR, a poor therapeutic response to chemoradiotherapy was discovered in patients with CTC positivity (RR = 1.99, 95% CI:1.73-2.29, I = 60%).

Conclusions: In summary, our meta-analysis demonstrated that CTCs positivity determined by the CellSearch system are correlated with the prognosis of EC patients and might indicate a poor therapeutic response to chemotherapy in EC patients.
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http://dx.doi.org/10.1186/s12885-020-07059-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310134PMC
June 2020

Biological properties and clinical applications of berberine.

Front Med 2020 Oct 25;14(5):564-582. Epub 2020 Apr 25.

Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.

Berberine, an isoquinoline alkaloid isolated from the Chinese herb Coptis chinensis and other Berberis plants, has a wide range of pharmacological properties. Berberine can be used to treat many diseases, such as cancer and digestive, metabolic, cardiovascular, and neurological diseases. Berberine has protective capacities in digestive diseases. It can inhibit toxins and bacteria, including Helicobacter pylori, protect the intestinal epithelial barrier from injury, and ameliorate liver injury. Berberine also inhibits the proliferation of various types of cancer cells and impedes invasion and metastasis. Recent evidence has confirmed that berberine improves the efficacy and safety of chemoradiotherapies. In addition, berberine regulates glycometabolism and lipid metabolism, improves energy expenditure, reduces body weight, and alleviates nonalcoholic fatty liver disease. Berberine also improves cardiovascular hemodynamics, suppresses ischemic arrhythmias, attenuates the development of atherosclerosis, and reduces hypertension. Berberine shows potent neuroprotective effects, including antioxidative, antiapoptotic, and anti-ischemic. Furthermore, berberine exerts protective effects against other diseases. The mechanisms of its functions have been extensively explored, but much remains to be clarified. This article summarizes the main pharmacological actions of berberine and its mechanisms in cancer and digestive, metabolic, cardiovascular, and neurological diseases.
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http://dx.doi.org/10.1007/s11684-019-0724-6DOI Listing
October 2020

Secular trend analysis of antibiotic utilisation in China's hospitals 2011-2018, a retrospective analysis of procurement data.

Antimicrob Resist Infect Control 2020 04 15;9(1):53. Epub 2020 Apr 15.

International Research Center for Medicinal Administration (IRCMA), Peking University, No.38 Xueyuan Road, Haidian District, Beijing, 100191, China.

Background: This study was aimed to explore the secular trends of antibiotic utilisation in China's hospitals over an 8-year period.

Methods: We retrospectively analysed aggregated monthly antibiotic procurement data of 586 hospitals from 28 provinces in China from January 2011 to December 2018. Information including generic name, procurement amount, dosage form, strength, the route of administration, and geographical data were collected. Population weighted antibiotic utilisation were expressed in DDD per 1000 inhabitants per day (DID). WHO's 'Access, Watch, Reserve' categorization was also adopted to analyse antibiotic utilisation.

Results: Between 2011 and 2018, total antibiotic utlisation in China's hospitals increased by 39.6% (from 4.8 DID in 2010 to 6.7 DID in 2018). Antibiotic utilisation was stable or had moderately decreased in 13 provinces, while in the other 15 provinces they had substantially increased. Cephalosporins were the most consumed antibiotics, accounting for 26.9% of the total antibiotic utilisation (1.8 DID/6.7 DID). In 2018, antibiotics in the Access category comprised 19.4% of the total utilisation (1.3 DID/6.7 DID), where antibiotics in the Watch category comprised the largest proportion of 71.6% (4.8 DID/6.7 DID). Population-weighted antibiotic utlisation was greater in secondary hospitals than in tertiary hospitals (7.3 DID vs 6.6 DID). The utilisation of oral forms was almost two times the amount of parenteral forms in secondary hospitals, whereas in tertiary hospitals the amounts were about the same.

Conclusions: Despite efforts have been made towards restricting antibiotic use by the Chinese government, antibiotic utilisation demonstrated an upward trend after the medical reform. The increase of last-resort antibiotics raises serious concern for public health. Current patterns of antibiotic utilisation demonstrated that gaps are existed towards the global target set up by the WHO. To better facilitate proper antibiotic use, more efforts are needed to explore the appropriateness of antibiotic use at the individual level.
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http://dx.doi.org/10.1186/s13756-020-00709-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160954PMC
April 2020

Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer.

Front Oncol 2020 13;10:308. Epub 2020 Mar 13.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Chemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms are still unclear. Here, we found that integrin subunit alpha 2 (ITGA2) is upregulated in chemoresistant GC cells and that increased ITGA2 levels correlated with the poor prognosis of GC patients who received chemotherapy. ITGA2 overexpression led to elevated chemotherapy resistance and drug-induced apoptosis inhibition in GC cells. ITGA2 knockdown resulted in restored chemosensitivity and increased apoptosis in chemoresistant GC cells both and . NanoString analysis revealed a unique signature of deregulated pathway expression in GC cells after ITGA2 silencing. The MAPK/ERK pathway and epithelial-mesenchymal transition (EMT) were found to be downregulated after ITGA2 knockdown. miR-135b-5p was identified as a direct upstream regulator of ITGA2. miR-135b-5p overexpression reduced chemoresistance and induced apoptosis in GC cells and attenuated ITGA2-induced chemoresistance and antiapoptotic effects by inhibiting MAPK signaling and EMT. In conclusion, this study underscored the role and mechanism of ITGA2 in GC and suggested the novel miR-135b-5p/ITGA2 axis as an epigenetic cause of chemoresistance with diagnostic and therapeutic implications.
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http://dx.doi.org/10.3389/fonc.2020.00308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082357PMC
March 2020

Regulation of the small GTPase Ran by miR-802 modulates proliferation and metastasis in colorectal cancer cells.

Br J Cancer 2020 05 25;122(11):1695-1706. Epub 2020 Mar 25.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, China.

Background: The small GTPase Ran is upregulated in multiple cancers and fundamental for cancer cell survival and progression, but its significance and molecular mechanisms in colorectal cancer (CRC) remain elusive.

Methods: Ran expression was detected in CRC cell lines and tumour tissues. In vitro and in vivo functional assays were performed to examine the effects of Ran on cell proliferation and metastasis. The pathways and effectors regulated by Ran were explored by an unbiased screening. Bioinformatics prediction and experimental validation were used to identify the miRNA regulator for Ran.

Results: Ran expression was frequently increased in metastatic CRC cells and tissues, especially in metastatic tissues. The upregulation of Ran correlated with poor CRC patient prognosis. Ran silencing reduced proliferation and metastasis of CRC cells both in vitro and in vivo. Ran regulated the expression of EGFR and activation of ERK and AKT signalling pathways. miR-802 was identified as an upstream regulator of Ran and miR-802 overexpression resulted in antiproliferative and antimetastatic activities.

Conclusion: Our study demonstrates the oncogenic roles and underlying mechanisms of Ran in CRC and the novel miR-802/Ran/EGFR regulatory axis may provide potential biomarkers for the treatment of CRC.
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http://dx.doi.org/10.1038/s41416-020-0809-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250854PMC
May 2020
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