title: The in vitro and vivo effects of nuclear and cytosolic parafibromin expression on the aggressive phenotypes of colorectal cancer cells: a search of potential gene therapy target.
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 PI3K-Akt and FoxO signaling pathways, while MT one promoted PI3K-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.
authors.affiliation: Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China.
authors.forename: Hua-Chuan
authors.initials: HC
authors.lastname: Zheng
authors.affiliation: Jinzhou Medical University, Jinzhou 121001, China.
authors.forename: Jia-Jie
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Jinzhou Medical University, Jinzhou 121001, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China.
authors.forename: Ji-Cheng
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China.
authors.forename: Gui-Feng
authors.initials: GF
authors.lastname: Zhao
authors.affiliation: Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Jinzhou Medical University, Jinzhou 121001, China.
authors.forename: Hua-Mao
authors.initials: HM
authors.lastname: Jiang
authors.affiliation: Jinzhou Medical University, Jinzhou 121001, China.
authors.forename: Ke-Qiang
authors.initials: KQ
authors.lastname: Huang
authors.affiliation: Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China.
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C454900:CDC73 protein, human; D025521:Tumor Suppressor Proteins
keywords: aggressive phenotypes; colorectal cancer; gene therapy; parafibromin; pathobiological behaviors