| BackgroundGastric cancer is one of the most common digestive system neoplasms,which ranks the fifth in the incidence of malignant tumors and the third in the tumor-related mortality.The new cases and deaths of Chinese gastric cancer patients accounted nearly half of the world.Moreover,80%gastric cancer patients are diagnosed in the advanced stages or have distant metastases in China and the 5-year overall survival of the total gastric cancer population is less than 30%.Liver is the most common site of hematogenous metastases and the treatment is limited.Therefore,the study of its mechanism and treatments are of great importance.ObjectiveTo analyze the expression of THBS2 in gastric cancer and preliminarily investigate its tumorigenesis mechanism.The role of THBS2 combining with PTEN subcellular translocation in regulating gastric cancer liver metastases(GCLM)was detected.Futhermore,we analyzed the chemotherapy sensitization of carmofur for trastuzumab in gastric cancer.And then we established the xenograft models to comfirm the tendency.Finally,we evaluated the efficacy of hepatectomy,RFA and TACE as local treatments for liver metastases from gastric cancer.And the compared the short-and long-term surgical outcomes of minimally invasive techniques(MIS)and conventional open surgery for GCLM in terms of safety,feasibility,and efficacy.MethodsUse sequencing and data analysisin to find differentially expressed genes.Immunohistochemical,cell culture and isolation of primary gastric tumor cells,tumorspheres formation and culture,construction of lentivirus and cell transfection,protein extraction and western blot,RNA extraction and quantitative real-time PCR,cell scratch test,immunofluorescence,herceptin susceptibility assays and apoptosis analysis were used to explore the mechanism of THBS-2 regulating the liver metastases of gastric cancer through altering subcellular location of PTEN and chemotherapy sensitization of carmofur for trastuzumab.Orthotopic and subcutaneous xenograft assay were set up to verify the tendency.Retrospective cohort studies were designed.Continuous variables for the two groups were checked for normality of distribution using the one-sample Kolmogorov-Smirnov test,and compared using analysis of variance(Student's t test or Mann-Whitney U test).Binomial and categorical data were evaluated by using cross-linked tables and the Pearson chi-squared test or the 2-tailed Fisher's exact test.Characteristics influencing survival were identified by means of univariate and multivariate analyses using the Cox proportional hazards model.Cumulative OS was analyzed using the Kaplan-Meier method,and the differences in survival curves among groups were compared using the log-rank test.Propensity score matching(PSM)analysis was performed to overcome possible bias in retrospectively observational study.Results(1)Not only THBS2 was significantly up-regulated in gastric tumors compared to matching normal tissues,but also had a potential function in distal metastasis.(2)Expression levels of THBS2 is significantly associated with prognosis in gastric cancer patients.(3)Expression levels of THBS2 is relatively high in primary gastric tumor cells and human gastric cancer cell line NCI-N87.(4)THBS2 downregulation induced mesenchymal-epithelial transition(MET)and combining with PTEN nuclear import prevented gastric tumor cells metastases.(5)Carmofur promoted PTEN nuclear translocation preventing metastases.(6)Carmofur can be used as sensitizer to improve the efficacy of trastuzumab.(7)The propensity model revealed that hepatectomy was associated with significantly longer OS compared with either or both RFA and TACE.(8)Hepatectomy is therefore the optimal local treatment for liver metastases when surgical RO resection is intended.(9)If patients are not appropriate for hepatectomy,palliative local treatments such as TACE and RFA are recommended.TACE is an acceptable method with relatively high cost-effectiveness.(10)MIS was associated with less estimated blood loss and faster postoperative recovery without increasing postoperative complication rates compared with open surgery.(11)Oncological outcomes were comparable between the MIS and open surgery groups.(12)For experienced surgeons,both laparoscopic and robotic methods of MIS are reasonable approaches for the management of highly selected GCLM patients.ConclusionTaken together,our study provides both genetic and biochemical evidence that THBS2 downregulation inhibited EMT though classic FAK signaling pathway and combining with PTEN subcellular translocation inhibited metastases of gastric cancer.THBS2 was overexpressed in gastric tumor tissues from gastric cancer patients with synchronous liver metastases and associated with poor prognosis.Furthermore,our study throws light on carmofur,a better chemo-sensitizer for trastuzumab via regulating PTEN.As THBS2 is a potential target for gastric cancer therapy,working with carmofur can be a new thought for treatment of late-stage gastric cancer with metastases.Hepatectomy is the optimal local treatment for GCLM when surgical RO resection is intended.TACE and RFA can work as alternatives for some patients who cannot achieve RO resection.MIS achieved superior short-term outcomes and comparable long-term outcomes compared with open surgery in GCLM patients. |
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