UTR-APA产生的p62不同转录本在人乳腺癌进展中的不同作用及其分子机制

p62通过多种途径参与肿瘤的发生发展，但其具体角色尚存在矛盾报道。基因非编码区的可变多聚腺苷酸化（UTR-APA）在人类肿瘤中广泛存在，其产生的不同转录本包括全长型 3’UTR（LU）和多种截短型3’UTR（SU），不同的转录本引起翻译效率和蛋白质定位等不同，进而导致所编码的蛋白生物学功能出现差异。前期通过测序及实验验证发现：乳腺癌中p62基因存在UTR-APA现象，3’UTR长度不同的p62-LU和p62-SU不仅翻译效率不同，而且生物学功能也不尽相同。通过Co-IP等实验，我们推测：不同于p62-SU，p62-LU编码的蛋白可通过蛋白质相互作用与特异性蛋白形成复合物，进而产生不同的生物学功能。为此，本项目拟在体内外以及临床样本中分别观察p62的不同转录本对乳腺癌生物学行为的影响和意义，探索p62基因UTR-APA的上游调控和下游功能执行的分子机制，为乳腺癌的诊治提供新的理论基础。

P62 is involved the development and progression of diverse human cancers through a variety of pathways, while its specific role is still controversial. Untranslated region alternative polyadenylation (UTR-APA) is widespread in human cancers. Different transcripts including the long 3’UTR isoform (LU) and the short 3’UTR isoform (SU) could be generated by UTR-APA processing. Among those transcripts, the translation efficiency, protein localization, etc are all differently regulated, which results in the differences in the biological functions of their encoded proteins. Our preliminary study demonstrated that there was UTR-APA of p62 in breast cancer cells. P62-SU and p62-LU with different lengths of 3’UTR not only had different translation efficiency, but also had different biological functions. Based on the preliminary results from protein-protein interaction experiments, we speculate that unlike p62-SU, p62-LU-encoded protein could form complexes with specific protein through protein-protein interactions, which in turn possesses the additional biological functions. Therefore, this project intends to identify the role and significance of different transcripts of p62 on the biological behavior of breast cancer in vitro and in vivo, and explores the molecular mechanisms involved upstream regulation and downstream function implementation of UTR-APA of p62 gene. The results might provide a new theoretical basis for the diagnosis and treatment of breast cancer.