Oncoprotein MCT-1 regulates microRNAs expression in triple negative breast cancer cells.

• Main Authors: Liu, Yi-Hong, 劉奕宏
• Other Authors: Hsu, Hsin-Ling
• Format: Others
• Language: zh-TW
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/53769185008581425666

碩士 === 國立清華大學 === 生物科技研究所 === 102 === The oncoprotein MCT-1 (Multiple copies in T-cell malignancies) was firstly identified in a human lymphoma cell line. MCT-1 is a RNA binding protein that is able to interact with DENR at 5 ' cap mRNA. Our researchs have discovered that MCT-1 is also overexpressed in both human lung and breast carcinomas. Overexpression MCT-1 plays multiple cellular functions such as cell survival, mitotic regulation, cell proliferation, genomic instability, tumor growth and translation regulation. Recent studies indicate that MCT-1 can regulate gene transcription and protein translation of the tumor suppressors and the oncogenic kinases, suggesting that MCT-1 may influence the stability of certain messenger RNA through modulating the biosynthesis of key microRNAs. Therefore, my main project is study: 1) Whether MCT-1 deregulates microRNAs expression in the tumor and the cancer cells? 2) Whether knockdown of MCT-1 decreases the oncomicroRNA expression level but increased the tumor suppressor microRNA presention? 3) Whether overexpression of MCT-1 can upregulate the oncomicroRNA but downregulate the tumor suppressor microRNA? 4) Is it possible that reduced MCT-1 activity can decrease one of RISC (RNA induced silencing complex) components Argonaute 2 (Ago2) that lead to downregulate the microRNAs and Ago2 endo-nuclease activity? The conclusion is that MCT-1 influences the expression levels of certain microRNAs in both TNBC cells and TNBC xenograft tumor. Because of increased activation of EGFR can interact with Ago2 and induce its phosphorylation that influences the maturation procedure of microRNAs in hypoxia condition. Similarly, I discovered that MCT-1 status can influence the activity of EGFR and the association between EGFR and Ago2, thus depleting MCT-1 inhibits the oncomicroRNA expression but elevates the tumor-suppressor microRNA presentation, probablely acting through its disruption on the formation of EGFR-Ago2 (RISC) complex. In summary, MCT-1 oncoprotein deregulates the transcription of specific genes persumbably through modulating the microRNA biosysthesis or by alterating their stabilities. The molecular mechanism and the potential of anti-metastaticity via controlling the maturation of miRNAs upon targeting the MCT-1 oncogenicity will be further investigated.