The Metastatic Mechanism of MicroRNA-148a and Its Target Gene 14-3-3β in Gastric Cancer
Date Issued
2011
Date
2011
Author(s)
Tseng, Chien-Wei
Abstract
Gastric cancer is the second leading cause of cancer deaths worldwide (WHO 2009 report). Patients diagnosed with advanced stages have a survival rate of less than 35% beyond 5 years. The poor prognosis is mainly related to tumor metastasis. In addition, some microRNAs (miRNAs) are reported as oncomirs which function as either oncogenes or tumor suppressors and involved in tumorigenesis and cancer progression. Here, we studied the mechanisms of gastric cancer metastasis and identified an antimetastatic miRNA, miR-148a, that was down-regulated in tumor tissues. Kaplan–Meier survival method revealed that patients with higher miR-148a expression levels had higher 5-year overall survival rates (71.4%) compared with patients with low miR-148a levels (32.1%, P = 0.03). Clinical data indicated that elevated miR-148a levels highly correlated with distant metastasis (P = 0.043), organ (P = 0.013) and peritoneal invasion (P = 0.04). Over-expression of miR-148a could decrease invasiveness, migration and adhesion of tumor cells. Moreover, Over-expression of miR-148a could repress cell growth and induce cell apoptosis. We further used isobaric tag for relative and absolute quantitation (iTRAQ) method to analyze miR-148a-regulated proteome. The results showed that miR-148a-regulated proteome was closely related with tumor progression, including cell movement, growth and proliferation as well as cell death. These results are consistent with our previous data that miR-148a suppresses metastasis-related functions of gastric cancer cells. On the other hand, we verified that miR-148a could directly regulate 14-3-3β expression using luciferase assay. 14-3-3β levels were elevated in tumor tissues (N = 40, P < 0.01), and serum 14-3-3β levels in cancer patients (N = 145) were also significantly higher than healthy controls (N = 63) (P < 0.0001). Patients with higher serum 14-3-3β levels had worse overall survival (P = 0.038). Over-expression of 14-3-3β enhanced the growth, invasiveness and migration of tumor cells. In conclusion, 14-3-3β is involved in metastasis of gastric cancer. miR-148a may function as a tumor suppressor in gastric cancer, suppressing cell metastasis through targeting 14-3-3β, a potential detective and prognostic marker in gastric cancer.
Subjects
miR-148a
gastric cancer
metastasis
biomarker
SDGs
Type
thesis
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