Publications by authors named "Jinglei Qu"

41 Publications

Complete Pathologic Response of Multiple Liver Metastases and Clinical Complete Response of Rectal Cancer in a Patient with Ataxia-Telangiectasia Mutated Gene Mutations After XELOXIRI Plus Bevacizumab: A Case Report.

Onco Targets Ther 2021 15;14:4201-4209. Epub 2021 Jul 15.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, People's Republic of China.

Background: Doublet or triplet chemotherapy plus or minus targeted drugs can achieve a high objective response rate (ORR) and are currently considered to be the backbone of conventional therapy for liver metastatic colorectal cancer (mCRC). However, current biomarkers (such as UGT1A1 and DPYD) are limited to the prediction of toxicity and there are no effective biomarkers to predict chemotherapy response. Therefore, personalized cancer chemotherapy underpinned by genomic alterations in mCRC has received increasing attention.

Case Presentation: We present a case of a 28-year-old female rectal cancer patient with multiple liver metastases (clinical risk score, CRS = 5 points). The patient underwent XELOXIRI plus bevacizumab regimen that consisted of irinotecan (150 mg/m2), oxaliplatin (100 mg/m2) on day 1, capecitabine (1700 mg/m2 per day from day 2 to 15), bevacizumab (7.5 mg/kg) on day 1 (on the second cycle), given every three weeks for eight cycles. After multi-disciplinary team (MDT) discussion, the patient underwent right hemihepatectomy, partial liver resection of segment IV and cholecystectomy. Surprisingly, the patient achieved a complete pathologic response (pCR) of the hepatic metastasis and clinical complete response (cCR) of the primary rectal lesion. A paired tumor molecular profile revealed somatic mutations in ataxia-telangiectasia mutated (ATM) genes that may explain why the patient achieved such a dramatic tumor response. Treatment was discontinued after eight cycles of a single oral dose of capecitabine and the patient started a follow-up program of physical and radiological examinations. To monitor the signs of recurrence, we also obtained blood samples to analyze circulating tumor DNA (ctDNA). To date, the patient has remained disease-free.

Conclusion: The XELOXIRI-bevacizumab regimen is a feasible and effective regimen for patients with mCRC. Mutations in the ATM genes may characterize a subset of patients with a better prognosis who are more sensitive to chemotherapy plus biological agents.
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http://dx.doi.org/10.2147/OTT.S320477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289441PMC
July 2021

A Prognostic Nomogram of Colon Cancer With Liver Metastasis: A Study of the US SEER Database and a Chinese Cohort.

Front Oncol 2021 26;11:591009. Epub 2021 Feb 26.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.

Background: Among colon cancer patients, liver metastasis is a commonly deadly phenomenon, but there are few prognostic models for these patients.

Methods: The clinicopathologic data of colon cancer with liver metastasis (CCLM) patients were downloaded from the Surveillance, Epidemiology and End Results (SEER) database. All patients were randomly divided into training and internal validation sets based on the ratio of 7:3. A prognostic nomogram was established with Cox analysis in the training set, which was validated by two independent validation sets.

Results: A total of 5,700 CCLM patients were included. Age, race, tumor size, tumor site, histological type, grade, AJCC N status, carcinoembryonic antigen (CEA), lung metastasis, bone metastasis, surgery, and chemotherapy were independently associated with the overall survival (OS) of CCLM in the training set, which were used to establish a nomogram. The AUCs of 1-, 2- and 3-year were higher than or equal to 0.700 in the training, internal validation, and external validation sets, indicating the favorable effects of our nomogram. Besides, whether in overall or subgroup analysis, the risk score calculated by this nomogram can divide CCLM patients into high-, middle- and low-risk groups, which suggested that the nomogram can significantly determine patients with different prognosis and is suitable for different patients.

Conclusion: Higher age, the race of black, larger tumor size, higher grade, histological type of mucinous adenocarcinoma and signet ring cell carcinoma, higher N stage, RCC, lung metastasis, bone metastasis, without surgery, without chemotherapy, and elevated CEA were independently associated with poor prognosis of CCLM patients. A nomogram incorporating the above variables could accurately predict the prognosis of CCLM.
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http://dx.doi.org/10.3389/fonc.2021.591009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962604PMC
February 2021

Prediction of KRAS, NRAS and BRAF status in colorectal cancer patients with liver metastasis using a deep artificial neural network based on radiomics and semantic features.

Am J Cancer Res 2020 1;10(12):4513-4526. Epub 2020 Dec 1.

Department of Medical Oncology, The First Hospital of China Medical University 110001, Liaoning, China.

There is a critical need for development of improved methods capable of accurately predicting the RAS (KRAS and NRAS) and BRAF gene mutation status in patients with advanced colorectal cancer (CRC). The purpose of this study was to investigate whether radiomics and/or semantic features could improve the detection accuracy of RAS/BRAF gene mutation status in patients with colorectal liver metastasis (CRLM). In this retrospective study, 159 patients who had been diagnosed with CRLM in two hospitals were enrolled. All patients received lung and abdominal contrast-enhanced CT (CECT) scans prior to radiation therapy and chemotherapy. Semantic features were independently assessed by two radiologists. Radiomics features were extracted from the portal venous phase (PVP) of the CT scan for each patient. Seven machine learning algorithms were used to establish three scores based on the semantic, radiomics and the combination of both features. Two semantic and 851 radiomics features were used to predict the mutation status of RAS and BRAF using an artificial neural network method (ANN). This approach performed best out of the seven tested algorithms. We constructed three scores which were based on radiomics, semantic features and the combined scores. The combined score could distinguish between wild-type and mutant patients with an AUC of 0.95 in the primary cohort and 0.79 in the validation cohort. This study proved that the application of radiomics together with semantic features can improve non-invasive assessment of the gene mutation status of RAS (KRAS and NRAS) and BRAF in CRLM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783758PMC
December 2020

Clinical outcomes of capecitabine-based versus S-1-based regimens as first-line chemotherapy in patients with unresectable or metastatic gastric cancer: a propensity score matched single-center comparison.

J Gastrointest Oncol 2020 Aug;11(4):674-684

Department of Medical Oncology, Ministry of Education, the First Hospital of China Medical University, Shenyang, China.

Background: Fluoropyrimidine-based regimens are the cornerstone of first-line chemotherapy for metastatic gastric cancer (GC). Capecitabine or S-1 might be used as an alternative to infusional 5-fluorouracil, especially in pan-Asian. This study aimed to compare the clinical outcomes of capecitabine-based and S-1-based regimens as first-line chemotherapy in Chinese patients with unresectable or metastatic GC.

Methods: We conducted a retrospective study including unresectable or metastatic GC patients treated with the capecitabine-based or S-1-based regimen as first-line chemotherapy at the First Hospital of China Medical University. Propensity score matching (PSM) analysis was performed to reduce selection bias. Overall survival (OS) outcomes were compared using the Kaplan-Meier method and log-rank test. Prognostic significance was determined using multivariate Cox regression analysis. In addition, subgroup analyses were conducted to determine the effectiveness of capecitabine-based and S-1-based regimens in clinically relevant patient subsets.

Results: The clinical data of 469 patients included between October 2005 and September 2018. PSM analysis identified 187 patients receiving capecitabine-based or S-1-based regimen. No significant difference in OS (10.7 11.1 months, P=0.523) was detected between the two groups after PSM. In the subgroup analysis, the median OS (12.2 9.3 months, P=0.013) was longer for patients with peritoneum metastasis who received the capecitabine-based regimen compared to those who received the S-1-based regimen.

Conclusions: No significant difference in clinical outcomes was observed between the capecitabine and S-1-based regimen as first-line chemotherapy for metastatic or unresectable GC patients in China. The capecitabine-based regimen should be considered in the treatment of the GC patients with peritoneum metastasis.
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http://dx.doi.org/10.21037/jgo-20-52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475324PMC
August 2020

Nomogram-based prediction of survival in unresectable or metastatic gastric cancer patients with good performance status who received first-line chemotherapy.

Ann Transl Med 2020 Mar;8(6):311

Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.

Background: Good performance status (PS) is widely acknowledged to have a high prognostic ability, although the prognostic parameters of cancer patients with good PS are still uncertain. This study was conducted to establish and validate a point-based nomogram to assist with predicting prognosis in unresectable or metastatic gastric cancer (GC) patients who had good PS and underwent first-line chemotherapy.

Methods: At random, a total of 309 patients with GC were split into 2 cohorts: a training cohort (n=259) and an internal validation cohort (n=50). An independent external validation cohort comprising 147 patients was also recruited. Both univariate and multivariate Cox regression analyses were used to evaluate patients based on the overall survival (OS) to develop the nomogram, which was subsequently validated using the concordance index (c-index), calibration curve, and decision curve analysis (DCA).

Results: The nomogram contained 3 independent prognostic variables in the training cohort: the number of distant metastatic sites (P<0.001), carbohydrate antigen 199 (CA199) level (P=0.002), and fibrinogen (P=0.020). The nomogram predicted an OS with a c-index of 0.623 (95% CI, 0.58-0.67) in the training cohort. The internal validation showed that the nomogram had a c-index of 0.614 (95% CI, 0.51-0.72). For external validation, the c-index was 0.638 (95% CI, 0.58-0.70).

Conclusions: A reliable point-based nomogram for predicting the prognosis of patients who had unresectable or metastatic GC and good PS who underwent first-line chemotherapy was developed and validated.

Keywords: Nomogram-based prediction; overall survival; unresectable gastric cancer; metastatic gastric cancer; good performance status; first-line chemotherapy.
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http://dx.doi.org/10.21037/atm.2020.02.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186730PMC
March 2020

Exosomal PD-L1 Retains Immunosuppressive Activity and is Associated with Gastric Cancer Prognosis.

Ann Surg Oncol 2019 Oct 13;26(11):3745-3755. Epub 2019 May 13.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.

Background: A recent study showed that circulating exosomal PD-L1 is an effective predictor for anti-PD-1 therapy in melanomas. Exosomal PD-L1 induced immunosuppression microenvironments in cancer patients. However, its prognostic value and immunosuppressive effect in gastric cancer (GC) were poorly understood.

Methods: We retrospectively evaluated the prognostic value of exosomal PD-L1 and soluble PD-L1 in preoperative plasma of 69 GC patients. The correlation between exosomal PD-L1 and the T cell counts or cytokine in the plasma was evaluated in 31 metastatic GC patients before chemotherapy.

Results: Overall survival (OS) was significantly lower in the high exosomal PD-L1 group compared with the low exosomal PD-L1 group (P = 0.004). Exosomal PD-L1 was an independent prognostic factor in GC (n = 69, 95% confidence interval = 1.142-7.669, P = 0.026). However, soluble PD-L1 showed no correlation with OS (P = 0.139). Additionally, exosomal PD-L1 in the plasma samples of 31 metastatic GC patients was negatively associated with CD4+ T cell count (P = 0.001, R = - 0.549), CD8+ T-cell count (P = 0.054, R = - 0.349), and granzyme B (P = 0.002, R = - 0.537), indicating that exosomal PD-L1 was associated with immunosuppressive status of GC patients. GC cells also secreted exosomal PD-L1 and were positively associated with the amount of PD-L1 in corresponding GC cell lines. Besides, exosomal PD-L1 significantly decreased T-cell surface CD69 and PD-1 expressions compared with soluble PD-L1 due to its stable and MHC-I expression.

Conclusions: Overall, exosomal PD-L1 predicts the worse survival and reflects the immune status in GC patients, resulting from a stronger T-cell dysfunction due to its stable and MHC-I expression.
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http://dx.doi.org/10.1245/s10434-019-07431-7DOI Listing
October 2019

The dynamic monitoring of CEA in response to chemotherapy and prognosis of mCRC patients.

BMC Cancer 2018 Nov 7;18(1):1076. Epub 2018 Nov 7.

Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning Province, People's Republic of China.

Background: The role of carcinoembryonic antigen (CEA) change patterns in tumor response and long-term outcome is unclear. This study aimed to investigate the correlation between changes in CEA levels and tumor response as a potential prognostic model.

Methods: CEA levels were determined from baseline to progression. A χ test was used to assess the correlation between CEA changes and tumor response. Univariate and multivariate COX models were used to explore the correlation of CEA changes to progression-free survival (PFS) and overall survival (OS).

Results: All 114 patients were divided into five groups according to CEA change pattern (A: patients had an initial fast CEA decrease that then turned into a slow increase; B: patients had an initial slow CEA decrease that then turned to a slow increase; C: patients had a continually slow CEA increase; D: patients had a continually fast CEA increase; E: patients had an initial fast CEA decrease that then turned into a fast increase). Patients in Group A had the longest OS and PFS while Group E patients had the shortest OS. Baseline to week 12 and week 12 to week 18 change rates were consistent with tumor response and progression, respectively. An increase in CEA level by ≥2.7% from week 12 to 18 was an independent negative prognostic factor of OS.

Conclusions: CEA changes mirror the tumor response to first-line chemotherapy and are associated with prognosis. CEA monitoring may be a substitute for computed tomography during the CEA stable period of treatment.
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http://dx.doi.org/10.1186/s12885-018-4987-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223053PMC
November 2018

Caveolin‑1 enhances RANKL‑induced gastric cancer cell migration.

Oncol Rep 2018 Sep 5;40(3):1287-1296. Epub 2018 Jul 5.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

The classical pathway involving receptor activator of nuclear factor‑κB (RANK) and its ligand (RANKL) induces the activation of osteoclasts and the migration of a variety of tumor cells, including breast and lung cancer. In our previous study, the expression of RANK was identified on the surface of gastric cancer cells, however, whether the RANKL/RANK pathway is involved in the regulation of gastric cancer cell migration remains to be fully elucidated. Lipid rafts represent a major platform for the regulation of cancer signaling; however, their involvement in RANKL‑induced migration remains to be elucidated. To investigate the potential roles and mechanism of RANKL/RANK in gastric cancer migration and metastasis, the present study examined the expression of RANK by western blot analysis and the expression of caveolin‑1 (Cav‑1) in gastric cancer tissues by immunohistochemistry, in addition to cell migration which is measured by Transwell migration assay. The aggregation of lipid reft was observed by fluorescence microscopy and western blotting was used to measure signaling changes in associated pathways. The results showed that RANKL induced gastric cancer cell migration, accompanied by the activation of Cav‑1 and aggregation of lipid rafts. Nystatin, a lipid raft inhibitor, inhibited the activation of Cav‑1 and markedly reversed RANKL‑induced gastric cancer cell migration. The RANKL‑induced activation of Cav‑1 has been shown to occur with the activation of proto‑oncogene tyrosine‑protein kinase Src (c‑Src). The c‑Src inhibitor, PP2, inhibited the activation of Cav‑1 and lipid raft aggregation, and reversed RANKL‑induced gastric cancer cell migration. Furthermore, it was demonstrated that Cav‑1 was involved in RANKL‑induced cell migration in lung, renal and breast cancer cells. These results suggested that RANKL induced gastric cancer cell migration, likely through mechanisms involving the c‑Src/Cav‑1 pathway and lipid raft aggregation.
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http://dx.doi.org/10.3892/or.2018.6550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072394PMC
September 2018

MicroRNA-29b-2-5p inhibits cell proliferation by directly targeting Cbl-b in pancreatic ductal adenocarcinoma.

BMC Cancer 2018 Jun 25;18(1):681. Epub 2018 Jun 25.

Department of Medical Oncology, the First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang City, 110001, China.

Background: MicroRNAs can be used in the prognosis of malignancies; however, their regulatory mechanisms are unknown, especially in pancreatic ductal adenocarcinoma (PDAC).

Methods: In 120 PDAC specimens, miRNA levels were assessed by quantitative real time polymerase chain reaction (qRT-PCR). Then, the role of miR-29b-2-5p in cell proliferation was evaluated both in vitro (Trypan blue staining and cell cycle analysis in the two PDAC cell lines SW1990 and Capan-2) and in vivo using a xenograft mouse model. Next, bioinformatics methods, a luciferase reporter assay, Western blot, and immunohistochemistry (IHC) were applied to assess the biological effects of Cbl-b inhibition by miR-29b-2-5p. Moreover, the relationship between Cbl-b and p53 was evaluated by immunoprecipitation (IP), Western blot, and immunofluorescence.

Results: From the 120 PDAC patients who underwent surgical resection, ten patients with longest survival and ten with shortest survival were selected. We found that high miR-29b-2-5p expression was associated with good prognosis (p = 0.02). The validation cohort confirmed miR-29b-2-5p as an independent prognostic factor in PDAC (n = 100, 95% CI = 0.305-0.756, p = 0.002). Furthermore, miR-29b-2-5p inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis both in vivo and in vitro. Interestingly, miR-29b-2-5p directly bound the Cbl-b gene, down-regulating its expression and reducing Cbl-b-mediated degradation of p53. Meanwhile, miR-29b-2-5p expression was negatively correlated with Cbl-b in PDAC tissues (r = - 0.33, p = 0.001).

Conclusions: Taken together, these findings indicated that miR-29b-2-5p improves prognosis in PDAC by targeting Cbl-b to promote p53 expression, and would constitute an important prognostic factor in PDAC.
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http://dx.doi.org/10.1186/s12885-018-4526-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019739PMC
June 2018

The Chemokine Receptor CXCR4 and c-MET Cooperatively Promote Epithelial-Mesenchymal Transition in Gastric Cancer Cells.

Transl Oncol 2018 Apr 27;11(2):487-497. Epub 2018 Feb 27.

Department of Medical Oncology, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City 110001, PR China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City 110001, PR China. Electronic address:

The C-X-C motif chemokine receptor 4 (CXCR4) pathway can promote tumor metastasis but is dependent on cross talk with other signaling pathways. The MET proto-oncogene (c-MET) participates in metastasis and is highly expressed in gastric cancer. However, the relationship between CXCR4 and c-MET signaling and their mechanisms of action in gastric cancer metastasis remain unclear. In this study, in vitro experiments demonstrated that C-X-C motif chemokine ligand 12 (CXCL12)/CXCR4 induces epithelial-mesenchymal transition (EMT) and promotes migration in gastric cancer cells, which is accompanied by c-MET activation. These phenomena were reversed by c-MET inhibition. Further investigation revealed that c-MET activation correlated with its interaction with caveolin 1 in lipid rafts, induced by CXCL12. In clinical samples, we observed a significant positive association between CXCR4 expression and c-MET phosphorylation (r = 0.259, P = .005). Moreover, samples expressing both receptors were found to indicate significantly poorer patient prognosis (P < .001). These results suggest that CXCL12 induces EMT at least partially through cross talk between CXCR4 and c-MET signaling. In addition, changes in these pathways could have clinical importance for the treatment of gastric cancer.
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http://dx.doi.org/10.1016/j.tranon.2018.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884220PMC
April 2018

Combination of platelet count and neutrophil-lymphocyte ratio as a prognostic marker to predict chemotherapeutic response and survival in metastatic advanced gastric cancer.

Biomark Med 2017 Oct 26. Epub 2017 Oct 26.

Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, PR China.

Aim: The study evaluated the prognostic impact of combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR) for first-line chemotherapeutic response and survival outcomes in metastatic advanced gastric cancer patients.

Methods: Two hundred and seventy-three patients were categorized into three COP-NLR groups (COP-NLR 0, 1, 2) according to their platelet count and neutrophil-lymphocyte ratio.

Results: The COP-NLR 0 had a significantly higher disease control rate (93%) than the other two groups (p = 0.011). A logistic regression model showed that COP-NLR was an independent risk factor for response to chemotherapy (odds ratio: 2.247; 95% CI: 1.303-3.874; p = 0.044). The median overall survival for COP-NLR 0, 1 and 2 was 14.8, 10.3 and 9.1 months, respectively (p = 0.001).

Conclusion: COP-NLR is a useful predictor of survival outcomes and chemotherapeutic response in patients with metastatic advanced gastric cancer.
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http://dx.doi.org/10.2217/bmm-2016-0288DOI Listing
October 2017

Efficacy of Thalidomide in Preventing Delayed Nausea and Vomiting Induced by Highly Emetogenic Chemotherapy: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase III Trial (CLOG1302 study).

J Clin Oncol 2017 Nov 30;35(31):3558-3565. Epub 2017 Aug 30.

Lingyun Zhang, Xiujuan Qu, Yuee Teng, Jing Shi, Ping Yu, Mingfang Zhao, Jing Liu, Bo Jin, Ying Luo, Zan Teng, Ying Chen, Jinglei Qu, Feng Jin, Lingyu Fu, and Yunpeng Liu, First Hospital of China Medical University, Shenyang; Tao Sun and Jingdong Zhang, Cancer Hospital of China Medical University; Xiaodong Xie, General Hospital of Shenyang Military Region, Shenyang; Jingyan Wang, Liaoyang Petrochemical General Hospital; Jian Zhang, Liaoyang Central Hospital; Jun Wang, The Third People's Hospital of Liaoyang City, Liaoyang; Zhitu Zhu, Yuzhi An, Caijun Yuan, Lizhong Zhou, and Zhenghua Wang, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou; Xiuna Zhang, Yuyang Dong, Fugang Wen, Xiuhua Jin, and Li Man, Anshan Cancer Hospital, Anshan; and Tiejun Chen, Benxi Central Hospital, Benxi, People's Republic of China.

Purpose We examined the efficacy and safety of thalidomide (THD) for the prevention of delayed nausea and vomiting in patients who received highly emetogenic chemotherapy (HEC). Patients and Methods In a randomized, double-blind, active-controlled, phase III trial, chemotherapy-naive patients with cancer who were scheduled to receive HEC that contained cisplatin or cyclophosphamide-doxorubicin/epirubincin ≥ 50 mg/m regimens were randomly assigned to a THD group (100 mg twice daily on days 1 to 5) or placebo group, both with palonosetron (0.25 mg on day 1) and dexamethasone (12 mg on day 1; 8 mg on days 2 to 4). Primary end point was complete response to vomiting-no emesis or use of rescue medication-in the delayed phase (25 to 120 h). Nausea and anorexia on days 1 to 5 were evaluated by the 4-point Likert scale (0, no symptoms; 3, severe). Quality of life was assessed by the European Organization for Research and Treatment of Cancer QLQ-C30 version 3 questionnaire on days -1 and 6. Results Of 656 patients, 638 were evaluable: 317 in the THD group and 321 in the control group. Compared with placebo, delayed and overall (0 to 120 h) complete response rates to vomiting were significantly higher with THD: 76.9% versus 61.7% ( P < .001) and 66.1% versus 53.3% ( P = .001), respectively. Rates of no nausea were also higher in the THD group (delayed: 47.3% v 33.3%; P < .001; overall: 41% v 29.6%; P = .003), and mean scores of anorexia were lower overall (0.44 ± 0.717 v 0.64 ± 0.844; P = .003). Adverse effects were mild to moderate. The THD group had increased sedation, dizziness, constipation, and dry mouth, but experienced better quality of life after chemotherapy. Conclusion Thalidomide combined with palonosetron and dexamethasone significantly improved HEC-induced delayed nausea and vomiting prevention in chemotherapy-naive patients.
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http://dx.doi.org/10.1200/JCO.2017.72.2538DOI Listing
November 2017

Dual inhibition of MET and SRC kinase activity as a combined targeting strategy for colon cancer.

Exp Ther Med 2017 Aug 27;14(2):1357-1366. Epub 2017 Jun 27.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Hepatocyte growth factor (HGF)/MET signaling is implicated in the development of colorectal cancer (CRC) and possesses therapeutic value for various types of cancer. However, inhibition of MET alone has been demonstrated to have limited efficacy. The present study examined the combined inhibition of MET and SRC kinase activity in colon cancer cells. Furthermore, the role of the HGF/MET pathway in ligand-dependent and -independent activation was demonstrated. The single inhibition of MET by knockdown small interfering RNA or inhibitor indicated a limited anti-viability effects without inhibiting the basal phosphorylation levels of SRC, protein kinase B (AKT) or extracellular signal-regulated kinase (ERK). In view of the strong association between MET and SRC identified by direct regulation, growth factor-induced MET activation was suppressed by pretreatment with the SRC inhibitor, dasatinib, and downstream phosphorylation of AKT and ERK partially decreased, which suggested that SRC activation was essential for ligand-dependent and -independent activation of MET. Considering that both the activation of MET and SRC was required in ligand-dependent and -independent MET activation, the antitumor effect of concurrent inhibition of MET and SRC was examined, and it was demonstrated that combination treatment exerted increased viability inhibition and apoptosis enhancement in mutant and wild type RAS colon cancer cells. Therefore, combinational inhibition of MET and SRC may be a promising strategy for the treatment of CRC.
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http://dx.doi.org/10.3892/etm.2017.4692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526150PMC
August 2017

CXCL12/SDF-1α induces migration via SRC-mediated CXCR4-EGFR cross-talk in gastric cancer cells.

Oncol Lett 2017 Aug 15;14(2):2103-2110. Epub 2017 Jun 15.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Metastasis is the primary cause of mortality in patients with advanced gastric carcinoma, and multiple signaling pathways promote the development of this condition. Stromal cell-derived factor-1 (SDF-1α/CXCL12), the main ligand for CXC chemokine receptor-4 (CXCR4), serves an important role in gastric cancer cell migration. Previous studies have demonstrated that CXCL12 could also stimulate the secretion of epidermal growth factor receptor (EGFR) ligands, including amphiregulin and heparin-binding epidermal growth factor-like growth factor, from gastric cancer cells, resulting in an increase in the ability of migration. However, it remains to be elucidated whether CXCL12 activates EGFR intracellular signaling and therefore stimulates migration in gastric cancer. The present study demonstrated that three gastric cancer cell lines, SGC-7901, MGC-803 and BGC-823, all expressed CXCR4. The increased chemotactic migratory ability stimulated by CXCL12 was effectively abrogated by the CXCR4 antagonist, AMD3100. Furthermore, a rapid phosphorylation of Akt/extracellular signal-regulated kinase (ERK)/EGFR was demonstrated to be involved in CXCL12/CXCR4-induced gastric cancer cell migration. Knockdown of EGFR gene or the use of a monoclonal antibody against EGFR (C225) blocked the activation of ERK/Akt and partially prevented the ability of migration induced by CXCL12, which indicated that EGFR signaling is located downstream of CXCL12. In addition, it was also revealed that the activation of non-receptor tyrosine kinase c-steroid receptor co-activator (SRC) and the formation of the SRC/EGFR heterodimer are promoted by CXCL12, whereas the SRC inhibitor, PP2, blocks the SRC/EGFR heterodimer and the activation of EGFR, as well as CXCR4-meditated migration induced by CXCL12. The present results indicated that SRC mediates a potential CXCR4-EGFR cross-talk, and thereby utilizes the EGFR-Akt/ERK axis to promote cellular migration. The present study provided a novel insight into the underlying regulatory mechanisms of the CXCL12/CXCR4 pathway in gastric cancer cell migration.
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http://dx.doi.org/10.3892/ol.2017.6389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530148PMC
August 2017

Gastric cancer-derived exosomes promote peritoneal metastasis by destroying the mesothelial barrier.

FEBS Lett 2017 07 10;591(14):2167-2179. Epub 2017 Jul 10.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China.

An intact mesothelium serves as a protective barrier to inhibit peritoneal carcinomatosis. Cancer-derived exosomes can mediate directional tumor metastasis; however, little is known about whether gastric cancer-derived exosomes will destroy the mesothelial barrier and promote peritoneal dissemination. Here, we demonstrate that gastric cancer-derived exosomes facilitate peritoneal metastasis by causing mesothelial barrier disruption and peritoneal fibrosis. Injury of peritoneal mesothelial cells elicited by gastric cancer-derived exosomes is through concurrent apoptosis and mesothelial-to-mesenchymal transition (MMT). Additionally, upregulation of p-ERK in peritoneal mesothelial cells is primarily responsible for the MMT while contributing little to apoptosis. Together, these data support the concept that exosomes play a crucial role in remodeling the premetastatic microenvironment and identify a novel mechanism for peritoneal metastasis of gastric carcinoma.
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http://dx.doi.org/10.1002/1873-3468.12722DOI Listing
July 2017

A Four-Factor Immunoscore System That Predicts Clinical Outcome for Stage II/III Gastric Cancer.

Cancer Immunol Res 2017 07 15;5(7):524-534. Epub 2017 Jun 15.

The First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang 110001, China.

The American Joint Committee on Cancer (AJCC) staging system is insufficiently prognostic for operable gastric cancer patients; therefore, complementary factors are under intense investigation. Although the focus is on immune markers, the prognostic impact of a single immune factor is minimal, due to complex antitumor immune responses. A more comprehensive evaluation may engender more accurate predictions. We analyzed immune factors by immunohistochemical staining in two independent cohorts. The association with patients' survival was analyzed by the Kaplan-Meier method. Our immunoscore system was constructed using Cox proportional hazard analysis. PD-L1 immune cells (IC), PD-L1 tumor cells (TC), PD-1, and CD8 were found among 33.33%, 31.37%, 33.33%, and 49%, respectively, of patients from the discovery cohort, and 41.74%, 17.4%, 38.26%, and 30.43% from the validation cohort. PD-L1 ICs and PD-1 ICs correlated with poorer overall survival (OS), but PD-L1 TCs correlated with better OS and clinical outcomes and infiltration of more CD8 T cells. These four factors were independently prognostic after tumor/lymph nodes/metastasis (TNM) stage adjustment. An immunoscore system based on hazard ratios of the four factors further separated gastric cancer patients with similar TNM staging into low-, medium-, or high-risk groups, with significantly different survival. Our prognostic model yielded an area under the receiver operating characteristic curve (AUC) of 0.856 for prediction of mortality at 5 years, superior to that of TNM staging (AUC of 0.676). Thus, this more comprehensive immunoscore system can provide more accurate prognoses and is an essential complement to the AJCC staging system for operable gastric cancer patients. .
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http://dx.doi.org/10.1158/2326-6066.CIR-16-0381DOI Listing
July 2017

Role of patient-, tumor- and systemic inflammatory response-related factors in predicting survival of patients with node-negative gastric cancer.

Tumour Biol 2017 Jun;39(6):1010428317698374

1 Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.

It is currently unclear as to which patients with node-negative gastric cancer can benefit from adjuvant chemotherapy. This study aimed to develop a prognostic model based on patient-, tumor-, and host-related factors to stratify high-risk patients eligible for adjuvant therapy. Correlations of clinicopathological and hematological features with overall survival were analyzed using a Cox model. A score to identify risk classes was derived from hazard ratios in multivariate analysis. In all, 436 patients with node-negative gastric cancer (stage pT1-4aN0M0) were analyzed in this study. Multivariate analysis showed that age, depth of invasion, and neutrophil-lymphocyte ratio were independent prognostic indicators of overall survival, and a prognostic model was developed using these significant factors. Patients were stratified into three risk groups with significant differences in the 3-year survival rates (98.5%, 91.6%, and 70.7%, respectively; p < 0.001) according to their scores. The prognostic model improved the predictive accuracy of postoperative 3-year survival rate by 7% when compared with the pathological T stage. A model based on age, depth of invasion, and neutrophil-lymphocyte ratio is more effective than traditional staging systems in predicting the prognosis of node-negative gastric cancer. High-risk patients could be considered for adjuvant therapy.
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http://dx.doi.org/10.1177/1010428317698374DOI Listing
June 2017

A novel function of hepatocyte growth factor in the activation of checkpoint kinase 1 phosphorylation in colon cancer cells.

Mol Cell Biochem 2017 Dec 1;436(1-2):29-38. Epub 2017 Jun 1.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China.

The ATR/checkpoint kinase 1 (Chk1) pathway plays an essential role in modulating the DNA damage response and homologous recombination. Particularly, Chk1 phosphorylation is related to cancer prognosis and therapeutic resistance. Some receptor tyrosine kinases participate in the regulation of Chk1 phosphorylation; however, the effect of hepatocyte growth factor (HGF) on Chk1 phosphorylation is unknown. In the present study, we demonstrated that HGF moderately activated Chk1 phosphorylation in colon cancer cells by upregulating TopBP1 and RAD51, and promoting TopBP1-ATR complex formation. Furthermore, AKT activity, which was promoted by HGF, served as an important mediator linking HGF/MET signaling and Chk1 phosphorylation. Depleting AKT activity attenuated basal expression of p-Chk1 and HGF-induced Chk1 activation. Moreover, AKT activity directly regulated TopBP1 and RAD51 expression. AKT inhibition suppressed HGF-induced upregulation of TopBP1 and RAD51, and enhanced TopBP1/ATR complex formation. Our results show that HGF was involved in regulating Chk1 phosphorylation, and further demonstrate that AKT activity was responsible for this HGF-induced Chk1 phosphorylation. These findings might potentially result in management of prognosis and therapeutic sensitivity in cancer therapy.
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http://dx.doi.org/10.1007/s11010-017-3075-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674134PMC
December 2017

Pretreatment platelet-to-lymphocyte ratio is associated with the response to first-line chemotherapy and survival in patients with metastatic gastric cancer.

J Clin Lab Anal 2018 Jan 26;32(1). Epub 2017 Feb 26.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.

Background: Several studies have shown that platelet-to-lymphocyte ratio (PLR) is a prognostic factor for various cancers. However, there is no study about the role of PLR in predicting response to first-line chemotherapy of metastatic gastric cancer. Therefore, this study aimed to establish whether PLR is associated with the response to first-line chemotherapy and survival in patients with metastatic gastric cancer.

Methods: We enrolled 273 patients diagnosed with metastatic gastric cancer. The best cut-off value of PLR to predict chemotherapeutic response was chosen by receiver operating characteristic (ROC) curve analysis. Prognostic significance was determined using the log-rank test and multivariate Cox regression analysis.

Results: Based on the cut-off value of PLR, patients were divided into a low PLR group and high PLR group. In logistic regression analysis, the low PLR group had a significantly higher disease control rate than the high PLR group had (91.3 vs 76.1%, P=.002), and PLR was an independent risk factor for response to first-line chemotherapy (odds ratio [OR]: 3.256; 95% confidence interval [CI]: 1.521-6.969; P=.002). The low PLR group had significantly longer overall survival (OS) than the high PLR group had (13.4 vs 9.2 months; P=.020). Multivariate survival analysis showed that PLR was significantly associated with OS [hazard ratio (HR): 1.002; 95% CI: 1.000-1.003; P=.020].

Conclusions: Pre-treatment PLR is associated with the response rate to first-line chemotherapy and survival outcomes in patients with metastatic gastric cancer.
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http://dx.doi.org/10.1002/jcla.22185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817026PMC
January 2018

Efficacy of Bevacizumab in the First-Line Treatment of Patients with RAS Mutations Metastatic Colorectal Cancer: a Systematic Review and Network Meta-Analysis.

Cell Physiol Biochem 2016 21;40(1-2):361-369. Epub 2016 Nov 21.

Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, PR China.

Background/aims: Whether patients with RAS mutation metastatic colorectal cancer (mCRC) obtain benefits from bevacizumab added to first-line chemotherapy remains unclear.

Methods: PubMed, Cochrane Systematic Reviews, the Cochrane Collaboration Central Register of Controlled Clinical Trials, ClinicalTrials.gov, and the American Society of Clinical Oncology and European Society for Medical Oncology databases were searched to identify abstracts for randomized controlled trials (RCTs) evaluating the efficacy of bevacizumab for the first-line treatment of patients with RAS mutations mCRC from inception to the end of April 2016. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were estimated.

Results: Ten eligible papers reporting six RCTs were included. In the network meta-analysis of patients with RAS mutations, bevacizumab + chemotherapy prolonged PFS compared with chemotherapy alone (HR 0.75, 95% CI 0.51-1.10), but the difference was not statistically significant. Bevacizumab + chemotherapy did not prolong OS compared with chemotherapy alone (HR 1.10, 95% CI 0.73-1.66).

Conclusion: There was insufficient evidence to definitively state that patients with RAS mutations mCRC could benefit from bevacizumab combined with chemotherapy as first-line treatment.
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http://dx.doi.org/10.1159/000452551DOI Listing
February 2017

MicroRNA-891b is an independent prognostic factor of pancreatic cancer by targeting Cbl-b to suppress the growth of pancreatic cancer cells.

Oncotarget 2016 Dec;7(50):82338-82353

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, China.

Growing evidence has revealed that microRNAs could regulate the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells and predict the prognosis of PDAC. Here the comparative microRNA expression profiles of the good and poor prognosis groups were performed by microRNA microarray. MicroRNA-891b (miR-891b) was screened and validated to be a prognostic predictor of PDAC in the initial group and further evaluated to be an independent predictor for the overall survival of resectable PDACs in an independent cohort. By a series of cellular and animal experiments, as well as clinical specimen analyses, miR-891b was confirmed to target the Cbl-b gene, promot the expression of tumor suppressor p21 protein and inhibit the proliferation of PDAC cells. The results provide a theoretical basis for the study of miR-891b as an independent prognostic predictor of PDAC and the role of miR-891b/Cbl-b pathway in this prediction, as well as the identification of new targets for PDAC.
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http://dx.doi.org/10.18632/oncotarget.11001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347695PMC
December 2016

Effect of RAS status on anti-EGFR monoclonal antibodies + 5-FU infusion-based chemotherapy in first-line treatment of metastatic colorectal cancer: A meta-analysis.

Meta Gene 2016 Sep 9;9:110-9. Epub 2016 May 9.

Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, PR China.

Purpose: To investigate the effect of RAS on anti-EGFR moAb + 5-FU infusion based chemotherapy in first-line treatment of mCRC.

Methods: The MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane databases and ClinicalTrials.gov databases were independently reviewed. Primary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities. Correlation between RAS status and PFS, OS, ORR or toxicities was expressed as a hazard ratio (HR) or relative risk (RR).

Results: KRAS exon 2 wild-type (-wt) mCRC benefited from adding anti-EGFR moAb (compared with chemotherapy alone: OS: HR 0.88, P = 0.008; PFS: HR 0.74, P < 0.001; ORR: RR 1.34, P = 0.003. Compared with Bevacizumab: OS: HR 0.83, P = 0.003). KRAS exon 2-wt but other RAS mutations mCRC did not benefit from adding anti-EGFR moAb. RAS-wt mCRC benefited from adding anti-EGFR moAb (compared with chemotherapy alone: OS: HR: 0.75, P < 0.001; PFS: HR 0.65, P < 0.001; ORR: RR 1.51, P = 0.020. Compared with Bevacizumab: OS: HR 0.79, P = 0.002). KRAS exon 2-wt but BRAF mutation mCRC did not benefit from adding anti-EGFR moAb. Subgroup analysis suggested that anti-EGFR moAb prolonged PFS for male, liver metastasis-only, ECOG 0-1, and colon primary site groups. Anti-EGFR moAb increased controllable grade 3-4 toxicities including rash, diarrhea, and anemia.

Conclusions: Adding anti-EGFR moAb as first-line treatment in RAS-wt mCRC prolonged OS. Whether BRAF mutation is a predictive marker to anti-EGFR moAb is not clear.
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http://dx.doi.org/10.1016/j.mgene.2016.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908286PMC
September 2016

A Prognostic Model in Metastatic or Recurrent Gastric Cancer Patients with Good Performance Status Who Received First-Line Chemotherapy.

Transl Oncol 2016 Jun;9(3):256-61

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China. Electronic address:

Purpose: Good performance status is widely known as a superior prognostic predictor. However, some patients have large survival differences despite having good performance status that are influenced by certain prognostic factors. The purpose of this study was to explore baseline host- or tumor-related factors and to establish a prognostic model for metastatic or recurrent gastric cancer patients with good performance status who received first-line chemotherapy.

Methods: A total of 310 metastatic or recurrent gastric cancer patients with good performance status who received first-line chemotherapy were enrolled. Prognostic significance was determined using multivariate Cox regression analysis. Incorporating all pretreatment indicators, a prognostic model was established. Overall survival outcomes were compared with different risk groups using the Kaplan-Meier method and log-rank test.

Results: In multivariate analysis, no previous gastrectomy [hazard ratio (HR) = 1.42; 95% confidence interval (CI) = 1.08-1.85], number of distant metastatic sites (HR = 1.47; 95% CI = 1.11-1.96), bone metastasis (HR = 2.20; 95% CI = 1.16-4.18), liver metastasis (HR = 1.77; 95% CI = 1.31-2.39), and an elevated neutrophil lymphocyte ratio (HR = 1.37; 95% CI = 1.04-1.79) were independent prognostic factors of overall survival. Patients were categorized into three risk groups according to their risk scores. Median survival times for the low-risk (0 point), intermediate-risk (1-3 points), and high-risk (≥4 points) groups were 19.7, 10.7 and 5.1 months, respectively (P < .001).

Conclusions: A prognostic model was developed that could facilitate risk stratification for metastatic or recurrent gastric cancer patients with good performance status who received first-line chemotherapy to help clinicians choose an applicable treatment based on the estimated prognosis.
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http://dx.doi.org/10.1016/j.tranon.2016.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907898PMC
June 2016

Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells.

Cancer Chemother Pharmacol 2015 Sep 25;76(3):575-86. Epub 2015 Jul 25.

Department of Pharmacology, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang City, 110122, People's Republic of China.

Purpose: 5-Fluorouracil (5-FU) is the basic chemotherapeutic agent used to treat colon cancer. However, the sensitivity of colon cancer cells to 5-FU is limited. Gossypol is a polyphenolic extract of cottonseeds. The purpose of this study was to investigate the activities and related mechanism of gossypol alone or in combination with 5-FU against human colon carcinoma cells.

Methods: The IC50 of gossypol or/and 5-FU in vitro was tested by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the drug interaction was analyzed using the CalcuSyn method. Cell apoptosis was determined using presidium iodide staining and flow cytometric analysis. Western blotting was used to determine the expression of proteins. Transient transfection method was used to silence protein.

Results: The IC₅₀ at 48 h of gossypol in colon cancer cells was 26.11 ± 1.04 μmol/L in HT-29 cells, 14.11 ± 1.08 μmol/L in HCT116 cells, and 21.83 ± 1.05 μmol/L in RKO cells. When gossypol was combined with 5-FU, a synergistic cytotoxic effect was observed in HT-29 cells, HCT116 cells, and RKO cells compared with treatment with gossypol or 5-FU alone. The Western blotting results indicated that gossypol down-regulated thymidylate synthase (TS) rather than thymidine phosphorylase protein expression. Furthermore, the mTOR/p70S6K1 signaling pathway was inhibited in gossypol-treated colon cancer cells, and consequently, cyclin D1 expression was decreased, suggesting an additional mechanism of the observed antiproliferative synergistic interactions. All the observation was confirmed by silencing TS and inactivating the mTOR/p70S6K1 signaling pathway by rapamycin, both of which increased the chemo-sensitizing efficacy of 5-FU.

Conclusions: These findings suggest that gossypol-mediated down-regulation of TS, cyclin D1, and the mTOR/p70S6K1 signaling pathways enhances the anti-tumor effect of 5-FU. Ultimately, our data exposed a new action for gossypol as an enhancer of 5-FU-induced cell growth suppression.
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http://dx.doi.org/10.1007/s00280-015-2749-0DOI Listing
September 2015

Secreted protein acidic and rich in cysteine antagonizes bufalin-induced apoptosis in gastric cancer cells.

Mol Med Rep 2015 Aug 24;12(2):2926-32. Epub 2015 Apr 24.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Bufalin is an active compound in the traditional Chinese medicine Chan Su, which has been shown to induce apoptosis in a range of cancer cell types. However, certain gastric cancer cells are known to be resistant to bufalin. Intracellular secreted protein acidic and rich in cysteine (SPARC) regulates proliferation and apoptosis. This study aimed to evaluate the role of SPARC in bufalin-induced apoptosis in SGC7901 and MGC803 gastric cancer cells. SGC7901 cells with high SPARC expression were more resistant to bufalin than MGC803 cells with low SPARC expression. This resistance was significantly reversed by small interfering (si)RNA-mediated knockdown of SPARC. Furthermore, it was shown that SPARC negatively regulated bufalin-induced intrinsic apoptosis by protecting mitochondrial integrity, decreasing the release of cytoplasmic cytochrome c and increasing the ratio of Bcl-2/Bax. In addition, SPARC overcame bufalin-induced G2/M phase arrest by increasing levels of Cyclin B1 and Cyclin A protein expression. SPARC also activated cellular survival signals, including Src and Akt, but not extracellular signal-regulated kinase. This study demonstrated that SPARC antagonizes bufalin-induced apoptosis via inhibition of the intrinsic apoptosis pathway, inhibition of cell cycle arrest and activation of certain pathways involved in proliferation. This provides novel evidence for SPARC as a potential target by which to sensitize gastric cancer cells to bufalin.
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http://dx.doi.org/10.3892/mmr.2015.3676DOI Listing
August 2015

Celecoxib sensitizes gastric cancer to rapamycin via inhibition of the Cbl-b-regulated PI3K/Akt pathway.

Tumour Biol 2015 Jul 21;36(7):5607-15. Epub 2015 Feb 21.

Department of Medical Oncology, The First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang, 110001, People's Republic of China.

Mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. However, a phase III clinical trial found that monotherapy with the mTOR inhibitor everolimus did not significantly improve the overall survival of patients with advanced gastric cancer. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of mTOR inhibitors. Here, we demonstrate that Akt phosphorylation is increased in the rapamycin-resistant gastric cancer cell lines MGC803 and SGC7901. We further show that combined treatment with celecoxib and rapamycin results in an additive inhibitory effect on the growth of gastric cancer cells through suppression of rapamycin-induced Akt activation. Moreover, celecoxib upregulated the expression of the ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b). Knockdown of Cbl-b significantly attenuated celecoxib-mediated inhibition of Akt phosphorylation and impaired the additive anticancer effect of celecoxib and rapamycin. Our results suggest that celecoxib-mediated upregulation of Cbl-b is responsible, at least in part, for the additive antitumor effect of celecoxib and rapamycin via inhibition of rapamycin-induced Akt activation.
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http://dx.doi.org/10.1007/s13277-015-3232-6DOI Listing
July 2015

Cbl-b accelerates trypsin-induced cell detachment through ubiquitination and degradation of proline-rich tyrosine kinase 2.

Tumour Biol 2014 Nov 7;35(11):11129-35. Epub 2014 Aug 7.

Department of Medical Oncology, The First Hospital of China Medical University, No.155, North Nanjing Street, Heping District, Shenyang, 110001, China.

Trypsin is a digestive enzyme that is widely used for cell detachment, which is the first stage of tumor metastasis. Recent studies show that adhesion-related kinases are involved in cell detachment. Proline-rich tyrosine kinase 2 (Pyk2) is a crucial kinase in the regulation of cell adhesion and detachment. However, the effect of Pyk2 on cell detachment is controversial. In the present study, we found that Pyk2 expression was rapidly decreased after trypsin treatment in gastric cancer, breast cancer, colon cancer, lung cancer, and human gastric epithelial cells. Knockdown of Pyk2 accelerated cell detachment. Furthermore, lysosome inhibitor NH4CL suppressed cell detachment and increased ubiquitination of Pyk2. Cbl-b is a type of E3 ubiquitin ligase that interacted with Pyk2, reduced the expression of Pyk2, and promoted trypsin-induced degradation of Pyk2. These findings suggest that Cbl-b promoted cell detachment through mono-ubiquitination of Pyk2. Our data provide a new insight into the role of Cbl-b in cell detachment.
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http://dx.doi.org/10.1007/s13277-014-2296-zDOI Listing
November 2014

Cbl-b enhances sensitivity to 5-fluorouracil via EGFR- and mitochondria-mediated pathways in gastric cancer cells.

Int J Mol Sci 2013 Dec 16;14(12):24399-411. Epub 2013 Dec 16.

Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.

5-Fluorouracil (5-FU) is an essential component of anticancer chemotherapy against gastric cancer. However, the response rate of single drug is still limited. The ubiquitin ligase Cbl-b is a negative regulator of growth factor receptor signaling and is involved in the suppression of cancer cell proliferation. However, whether Cbl-b could affect 5-FU sensitivity remains unclear. The present study showed that Cbl-b knockdown caused higher proliferation concomitant with the decrease of apoptosis induced by 5-FU treatment in gastric cancer cell. Further mechanism investigation demonstrated that Cbl-b knockdown caused significant increase of phosphorylation of EGFR, ERK and Akt, decrease of mitochondrial membrane potential, and increase of expression ratio of Bcl-2/Bax. These results suggest that Cbl-b enhances sensitivity to 5-FU via EGFR- and mitochondria-mediated pathways in gastric cancer cells.
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http://dx.doi.org/10.3390/ijms141224399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876118PMC
December 2013

Trastuzumab and oxaliplatin exhibit a synergistic antitumor effect in HER2-postive gastric cancer cells.

Anticancer Drugs 2014 Mar;25(3):315-22

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.

Trastuzumab has recently been recommended for the treatment of epidermal growth factor receptor-2 (HER2)-positive advanced gastric cancer in combination with the capecitabine/cisplatin (XP) versus continuous infusion of 5-fluorouracil/cisplatin (FP) regimen. However, it is unclear whether it is rational to combine trastuzumab with other chemotherapy regimens in clinical practice. Our study demonstrates that adding trastuzumab to oxaliplatin, a commonly used third-generation platinum derivative, increases the antitumor effect in vitro. In MTT assays, combination treatment with oxaliplatin and trastuzumab significantly decreased the concentration of oxaliplatin required to induce 50% growth inhibition in HER2-positive gastric cancer cells. Further investigation revealed that the trastuzumab-oxaliplatin combination induced cell cycle arrest and decreased expression of both p-AKT and p-ERK. Notably, this treatment combination induced downregulation of the excision repair cross-complementation group 1 (ERCC1) protein, which is involved in the key repair process of the oxaliplatin-DNA platinum adduct at the protein level. Similar changes were also observed in HER2-positive breast cancer cells. These findings suggest that trastuzumab synergizes the cytotoxic effect of oxaliplatin on HER2-positive gastric and breast cancer cells. Our study provides preclinical evidence for the optimization of this combination regimen in the treatment of HER2-positive gastric cancer patients.
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http://dx.doi.org/10.1097/CAD.0000000000000048DOI Listing
March 2014

Cbl-b-dependent degradation of FLIP(L) is involved in ATO-induced autophagy in leukemic K562 and gastric cancer cells.

FEBS Lett 2012 Sep 1;586(19):3104-10. Epub 2012 Aug 1.

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China.

Various molecular mechanisms are involved in the efficacy of arsenic trioxide (ATO) against malignant hematologic and some solid tumors. FLICE-like inhibitory protein (FLIP) is an inhibitor of apoptosis mediated by death receptors. In this study, we identified a new link between the down-regulation of cellular FLIP(L) and ATO-induced autophagy. ATO induced the degradation of FLIP(L) in K562 and MGC803 cells, which was mediated by the ubiquitin-proteasome pathway. Moreover, the casitas B-lineage lymphoma-b (Cbl-b) was involved in this process, which interacted with FLIP(L) and promoted proteasomal degradation of FLIP(L). Our findings lead to a better understanding of the mechanism of action of ATO, and suggest that a novel signaling pathway is required for ATO-induced autophagy in K562 and MGC803 cells.
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http://dx.doi.org/10.1016/j.febslet.2012.07.067DOI Listing
September 2012
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