Studies On Colorectal And Gastric Cancer Detection Using Serum And CTSD Enhancing Gastric Cancer Cells Sensitivity To Cisplatin

Colorectal cancer (CRC) is the third most common cancer in the world. It accounts for nearly500,000deaths each year and is the second leading cause of cancer-related death. It was estimated that, every year, one and half million new CRC cases would be diagnosed worldwide. Prognosis of patients with colorectal cancer (CRC) is generally poor because of the lack of simple, convenient, and noninvasive tools for CRC detection at the early stage. Although qualified care and screening programs play important roles in the survival of patients with CRC, surgical resection in the early stage is the most effective treatment and prolongs the survival of patients. Unfortunately, early-stage CRCs are difficult to detect because of fewer symptoms. The discovery of microRNAs (miRNAs) and their different expression profiles among different kinds of diseases has opened a new avenue for tumor diagnosis. We built a serum microRNA expression profile signature and tested its specificity and sensitivity as a biomarker in the diagnosis of CRC. We also studied its possible role in monitoring the progression of CRC. We conducted a two phase case-control test to identify serum miRNAs as biomarkers for CRC diagnosis. Using quantitative reverse transcription polymerase chain reactions, we tested ten candidate miRNAs in a training set (30CRCs vs30controls). Risk score analysis was used to evaluate the diagnostic value of the serum miRNA profiling system. Other independent samples, including83CRCs and59controls, were used to validate the diagnostic model. In the training set, six serum miRNAs (miR-21, let-7g, miR-31, miR-92a, miR-181b, and miR-203) had significantly different expression levels between the CRCs and healthy controls. Risk score analysis demonstrated that the six-miRNA-based biomarker signature had high sensitivity and specificity for distinguishing the CRC samples from cancer-free controls. The areas under the receiver operating characteristic (ROC) curve of the six-miRNA signature profiles were0.900and0.923for the two sets of serum samples, respectively. However, for the same serum samples, the areas under the ROC curve used by the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen19-9(CA19-9) were only0.649and0.598, respectively.Many studies have shown that the miRNA expression level are not only changed in the colorectal cancer, but also changed in the gastric cancer. In order to validate the diagnostic efficiency of this six serum miRNAs in the GC cases,92gastric cancer patients were recruited from the Cancer Institute and Hospital, Chinese Academy of Medical Sciences between2010and2012. Compared with normal controls, there are five serum miRNAs changed in the gastric cancer, including miR-21, miR-31, miR-92, miR-181b, miR-203. Risk score analysis demonstrated that the five-miRNA-based biomarker signature had high sensitivity and specificity for distinguishing the GC samples from cancer-free controls. The areas under the receiver operating characteristic (ROC) curve of the five-miRNA signature profiles were0.933and0.919for the two sets of serum samples, respectively.Now cisplatin (DDP) is one of the most common chemotherapeutics in clinical application because of the obvious effectiveness for anti-tumor function and cheap price. Recently, it has indicated that several tumor cells’curative effect of cisplatin decreased if it was given cisplatin for a long time. Cathepsin D (CTSD) as a functional regulator of programme cell death (PCD), can mediate apoptosis induced by many apoptotic agents, such as IFN-gamma, FAS/APO, TNF-alpha. In order to induce apoptosis in tumor cell, reconstruct and enhance the sensitivity of tumor cells to chemotherapy drugs, we will explore if CTSD combined cisplatin could enhance the inhibitory effect to gastric cancer cells in vitro and vivo experiments, so that it could apply an available way to treat gastric carcinoma in clinic. Our results indicated that compared with cisplatin, CTSD and/or D231N, a mutant that the enzymatic activity was inactivated, combined cisplatin made more important effect in inhibition the survival rate, induction the apoptosis and suppression the tumor growth. Knocked down the CTSD expression, the sensitivity of the cells to cisplatin decreased significantly. Furthermore, CTSD and/or D23IN enhanced the effect of cisplatin to cells through the mitochondrial pathways.