| Background Gastric cancer is one of the most common digestive tract malignant tumors worldwide. The incidence still ranks fifth in the incidence of malignant tumor, and mortality rate ranks third. The new cases and deaths of China accounted for 42% and 35% of the world, respectively. High heterogeneity, late TNM stage, limited efficacy of comprehensive treatment leads poor overall survival of gastric cancer patients. The successful application of HER2 targeted therapy is a great progress in diagnosis and treatment of gastric cancer. However, response rate to HER2 targeted therapy is limited and it lacks simple monitoring method. Investigation of the molecular mechanisms of HER2 targeted therapy, exploration of the right monitoring means, and discovery of new intervention measures will benefit the overall survival of gastric cancer patients, which is one of research hotspots of stomach cancer currently.Objective To analysis the correlation between telomerase activity and HER2 expression in gastric cancer cells, determining whether telomerase activity influence the efficacy of HER2 targeted therapy. Through the forward and reverse intervention, analysis how telomerase activity and HER2 regulating each other in different types of cells. Observation of cell proliferation, apoptosis, autophagy and cell cycle aiming to further understand the internal mechanism of HER2 targeted therapy. To explore new means of detection of HER2 positive gastric patients to provide new choice for the application of HER2 targeed therapy.Methods The gastric cancer cell lines with different HER2 expression levels were selected as cell models, Lapatinib was the main measures to target HER2. WB, rtPCR and the TRAP method were performed to detect the levels and correlation of HER2, hTERT and telomerase activity in gastric cancer. SiRNA interference, drug treatment, stable transfection was used to adjust HER2 expression or telomerase activity, followed by observation of the changes between each other. CCK8 experiment was performed for the analysis whether telomerase activity influence the effect of HER2 targeting therapy. Application of flow cytometry was to observe combination lapatinib with chemotherapy promote cell cycle arrest, apoptosis, autophagy etc. By means of systematic review and meta-analysis, we analyzed the accuracy that serum HER2 diagnosed HER2 positive patients with gastric cancer and the feasibility that it served as a guide for HER2 targeted therapy.Results (1) There were positive correlation between telomerase activity and the level of HER2 expression in gastric cancer cells. And Lapatinib can reduce TA by interfering with hTERT transcription activation. Telomerase activity affected the sensitivity of NCI-N87 cells to lapatinib and telomerase inhibitor BIBR1532 sensitized NCI-N87 and SGC7901 to lapatinib. (2) Overexpression of hTERT induced immortalization can raise HER2 expression level in 2BS cells. In HepG2 cells, hTERT SiRNA, BIBR1532 and stable transfection of telomerase inhibitors can inhibit the expression of HER2 protein. (3) Lapatinib can increase the rate of cell apoptosis and S phase arrest induced by oxaliplatin in gastric cancer cells.(4) During the exposure of lapatinib〠we observed autophagy, increased CD44 expression and telomerase activity in NCI-N87 cells, which would contribute to drug resistance.(5) Meta analysis showed, for the serum HER2, the pooled sensitivity is 0.39 (95% CI:0.210.61), and pooled specificity is 0.98 (95% CI:0.87-1.00, figure 3).Pooled PLR and NLR were 16.6 (95% CI:4.5-61.5) and 0.62 (95% CI: 0.46-0.85). AUSROC was 0.77 (95% CI:0.73-0.80) and DOR was 27 (95% CI:9-81).Conclusions (1) During tumorigenesis and tumor treatment process, there is a certain correlation between telomerase activity and expression of HER2. Combination of telomerase inhibitors and HER2 targeted therapy is expected to further improve the overall survival of patients with gastric cancer. (2) During the exposure of lapatinib, autophagy, increased CD44 expression and telomerase activity was thought to contribute to drug resistance.(3) Serum HER2 is expected to become a kind of screening method for gastric cancer with HER2 overexpression and a guide for HER2 targeted therapy. |
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