The in vitro and in vivo effects of nuclear and cytosolic parafibromin expression on the aggressive phenotypes of colorectal cancer cells: a search of potential gene therapy target

// Hua-chuan Zheng 1 , Jia-jie Liu 2 , Jing Li 2 , Ji-cheng Wu 1 , Lei Yang 1 , Gui-feng Zhao 1 , Xin Zhao 1 , Hua-mao Jiang 2 , Ke-qiang Huang 2 , Zhi-jie Li 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China 2 Jinzhou Medical University, Jinzhou 121001, China Correspondence to: Hua-chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: colorectal cancer, parafibromin, pathobiological behaviors, aggressive phenotypes, gene therapy Received: December 16, 2016     Accepted: January 24, 2017     Published: February 16, 2017 ABSTRACT Down-regulated parafibromin is positively linked to the pathogenesis of parathyroid, lung, breast, ovarian, gastric and colorectal cancers. Here, we found that wild-type (WT) parafibromin overexpression suppressed proliferation, tumor growth, induced cell cycle arrest and apoptosis in colorectal cancer cells (p<0.05), but it was the converse for mutant-type (MT, mutation in nucleus localization sequence) parafibromin (p<0.05). Both WT and MT transfectants inhibited migration and invasion, and caused better differentiation (p<0.05) of cancer cells. WT parafibromin transfectants showed the overexpression of Cyclin B1, Cyclin D1, Cyclin E, p38, p53, and AIF in HCT-15 and HCT-116 cells, while MT parafibromin only up-regulated p38 expression. There was lower mRNA expression of bcl-2 in parafibromin transfectants than the control and mock, while higher expression of c-myc , Cyclin D1 , mTOR , and Raptor . According to transcriptomic analysis, WT parafibromin suppressed PI 3 K-Akt and FoxO signaling pathways, while MT one promoted PI 3 K-Akt pathway, focal adhesion, and regulation of actin cytoskeleton. Parafibromin was less expressed in colorectal cancer than paired mucosa (p<0.05), and inversely correlated with its differentiation at both mRNA and protein levels (p<0.05). These findings indicated that WT parafibromin might reverse the aggressive phenotypes of colorectal cancer cells and be employed as a target for gene therapy. Down-regulated parafibromin expression might be closely linked to colorectal carcinogenesis and cancer differentiation.