Role of DSB repair protein, MRE11, in hepatocellular carcinoma

• Main Authors: Ren-Jie Wei, 魏仁傑
• Other Authors: Yao-Tsung Yeh
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/45942097525160903256

碩士 === 輔英科技大學 === 醫學檢驗生物技術系碩士班 === 101 === Hepatocellular carcinoma (HCC) is generally one of the most resistant tumors to chemotherapy/radiotherapy. Unfortunately, there are no evidence-based guidelines to allow a rational choice in systemic chemotherapy, hormonal therapy or transcatheter embolization with or without chemotherapy/local irradiation. Therefore, the discovery of critical biomarkers associated with the response rate of the received treatments and patient survival may provide new strategies to improve patient outcome. The maintenance of genomic integrity is essential for cell survival and normal function, while genomic instability has been demonstrated in the development and progression of multistep cancers including HCC. Forming MRN complex with NBS1 and RAD50, nuclease MRE11 is dispensable for sensing DNA lesions, arresting cell cycle and repairing double-strand breaks (DSBs). Controversially, MRE11 signaling also promotes a PI3K-independent AKT phosphorylation following ionizing radiation (IR). Besides, elevated MRE11 levels are also observed and frequently associated with the resistance to chemotherapy/radiotherapy in certain cancers. Although little is known, altered MRE11 signaling such as the crosstalk between MRE11 and AKT signaling may play roles in HCC. The results showed that cytoplasmic MRE11 expression was positively correlated with the age at diagnosis greater than 50 years old, vascular invasion and cirrhosis (P=0.029, 0.046 and 0.019). In addition, when the MRE11 increasingly expressed in the nucleus, patients presented with larger tumor size over 5 cm (P= 0.019). The Kaplan-Meier survival curve analysis revealed that MRE11 expression was not significantly correlated with the overall survival rate of patients. Our results suggested that MRE11 might contribute to HCC development, although MRE11 could not independently predict patient survival in HCC. Intriguingly, ectopic MRE11 overexpression increased migration and invasion ability, while knockdown of MRE11 expression using MRE11-specific shRNA reduced both abilities in hepatocellular carcinoma cell line. Indict immunofluorescent staining further showed ectopic overexpression of MRE11 protein increased BrdU-positive cells of hepatocellular carcinoma cell line. Accordingly, knockdown of MRE11 expression reversed these growth-stimulatory effects. We also found that ectopic overexpression of MRE11 proteins promoted the formation ofH2AX foci as DSB agent, bleomycin, implying that increased MRE11 might trigger DNA DSB. Intriguingly, MRE11 overexpression also increased AKT activation and subsequently induced the expression of MMP-2 and CDK4. Meanwhile, the expression of mTOR and p-mTOR were concomitantly increased. In contrast, the specific phosphatase for AKT, PP2AA, was reduced at the same time. The results implicated that MRE11 might suppress the expression of PP2AA through uncertain mechanisms and further increased AKT and mTOR signaling. In conclusion, our results suggested that MRE11 may play some critical roles for prognosis in HCC. Further investigations are required. Hopefully, the study will provide a better understanding of the carcinogenesis and progression of HCC.