Identification of Protocadherin 10 as a tumor suppressor and its molecular mechanisms in colorectal cancer

• Main Authors: Tzu-Ming Jao, 饒梓明
• Other Authors: Ya-Chien Yang
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/03630783527979501814

博士 === 國立臺灣大學 === 醫學檢驗暨生物技術學研究所 === 102 === Colorectal cancer (CRC) is the third leading cause of cancer deaths in Taiwan and United States. Seventy-five percent of CRC is sporadic and 85% of them suffered chromosomal instability (CIN). Loss-of-function of tumor suppressor gene or gain-of-function of oncogene is a hallmark during tumor development. CIN results in frequent allelic loss and then loss of tumor suppressor genes. Our previous study showed that Protocadherin 10 (PCDH10), a novel tumor suppressor gene in human cancers, is located in one common deleted region at chromosome 4q28 in CRC. The genetic loss of PCDH10 was significantly associated with tumor progression and distant metastasis, as well as was an independent predictor of poor survival for CRC patients. This study aimed to explore the tumor suppressor function and molecular mechanisms of PCDH10. Expression of PCDH10 gene was silenced or markedly down-regulated in all of 12 CRC cell lines and 41 of 53 colorectal carcinomas compared with their matched normal mucosae. In addition, tumor suppressor activity of PCDH10 was identified by in vitro cell models and mouse xenograft tumor models. Ectopic expression of PCDH10 reduced cancer cell proliferation, anchorage-independent growth, migration, and invasion in vitro. Subcutaneous injection of PCDH10-expressing CRC cells in SCID mice showed alleviated tumor growth when compared with mock-inoculated mice. More importantly, via intrasplenic implantation, re-expression of PCDH10 in silenced cells restrained liver metastasis, and also improved survival in SCID mice. PCDH10 blockades epithelial-to-mesenchymal transition through inhibition of AKT phosphorylation and nuclear translocation of beta-catenin. In addition, PCDH10 suppresses cancer proliferation through up-regulation of p53 signaling and retardation of cell cycle progression.