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.
Highlights
IntroductionParafibromin is a protein encoded by oncosuppressor gene HRPT2 (hyperparathyroidism 2), whose mutation causes the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid cancer
Parafibromin is a protein encoded by oncosuppressor gene HRPT2, whose mutation causes the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid cancer
WT parafibromin overexpression resulted in a low proliferation and a high apoptosis in both transfectants, evidenced by CCK-8 and Annexin-V staining (p
Summary
Parafibromin is a protein encoded by oncosuppressor gene HRPT2 (hyperparathyroidism 2), whose mutation causes the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid cancer. Parafibromin might interact with the ring finger proteins RNF20 and RNF40 to maintain histone 2B monoubiquitination [3]. Parafibromin overexpression was demonstrated to induce G1 arrest by repressing cyclin D1 via histone H3K9 methylation [4, 5], and cause apoptosis by activating Caspase-3 and Caspase-9, and down-regulating the expression of bcl and survivin [6, 7]. In oral squamous carcinoma cells, oncogenic microRNA-155 down-regulated parafibromin and promoted cell proliferation [8]. WT1 overexpression decreased parafibromin level and promoted proliferation by binding to HRPT2 promoter. Parafibromin overexpression attenuated the protumorigenic activity of WT1 by apoptotic induction [9], promoted IFN-γ-triggered phosphorylation of STAT1 at Tyr (701) by JAKs, and subsequently cellular antiviral response by the interaction www.impactjournals.com/oncotarget with JAK1/2 and STAT1 [10]. Parafibromin could play an oncogenic role by binding to β-catenin, and thereby activate promitogenic/ Wnt signaling upon tyrosine dephosphorylation by SHP2 [11], which was supported by a positive relationship between parafibromin and ki-67 expression [12]
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