PinX1 suppresses bladder urothelial carcinoma cell proliferation via the inhibition of telomerase activity and p16/cyclin D1 pathway

Abstract

BackgroundPIN2/TRF1-interacting telomerase inhibitor1 (PinX1) was recently suggested as a putative tumor suppressor in several types of human cancer, based on its binding to and inhibition of telomerase. Moreover, loss of PinX1 has been detected in many human malignancies. However, the possible involvement of PinX1 and its clinical/prognostic significance in urothelial carcinoma of the bladder (UCB) are unclear.MethodsThe PinX1 expression profile was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC) in UCB tissues and adjacent normal urothelial bladder epithelial tissues. PinX1 was overexpressed and silenced in UCB cell lines to determine its role in tumorigenesis, development of UCB, and the possible mechanism.ResultsPinX1 expression in UCB was significantly down-regulated at both mRNA and protein level as compared with that in normal urothelial bladder epithelial tissues. PinX1 levels were inversely correlated with tumor multiplicity, advanced N classification, high proliferation index (Ki-67), and poor survival (P < 0.05). Moreover, overexpression of PinX1 in UCB cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing PinX1 dramatically enhanced cell proliferation. Overexpression of PinX1 resulted in G1/S phase arrest and cell growth/proliferation inhibition, while silencing PinX1 led to acceleration of G1/S transition, and cell growth/proliferation promotion by inhibiting/enhancing telomerase activity and via the p16/cyclin D1 pathway.ConclusionsThese findings suggest that down-regulation of PinX1 play an important role in the tumorigenesis and development of UCB and that the expression of PinX1 as detected by IHC is an independent molecular marker in patients with UCB.

MicroRNA-576-3p Inhibits Proliferation in Bladder Cancer Cells by Targeting Cyclin D1

“…In bladder cancers, the overexpression of CCND1 has already been identified (Kopparapu et al, 2013), and our experiments also revealed the same up-regulation of CCND1 in T24 and UM-UC-3 cell lines. Furthermore, numerous evidences have proved that the variation of CCND1 expression could remarkably affect the proliferation of bladder cancer cells (Fang et al, 2013;Liu et al, 2013). And microRNAs, on the other hand, such as miR-15b, miR-34a and miR-193a have also been reported to inhibit proliferation through down-regulation of CCND1 expression in various cancers (Chen et al, 2010;Sun et al, 2008;Xia et al, 2009).…”

PinX1 inhibits cell proliferation, migration and invasion in glioma cells

“…Accumulated studies have showed that PinX1 overexpression in some types of cancer cells can suppress proliferation [16,17]; however, the precise roles of PinX1 in gliomas cell proliferation are still not explored. In order to test the role of PinX1 expression in gliomas cell growth, we over-expressed PinX1 in U87 and U251 cells (Fig.…”

“…2a-d, P \ 0.05 in these two cell lines). Studies have indicated that PinX1 controls the expression of hTERT and cyclin-CDK complexes in the process of suppressing cell growth [17,19,20]. Therefore, Western blot was used to explore the expressions of hTERT and the cell cycle-relative biomarkers.…”

“…Moreover, series of studies about PinX1 in cancers have demonstrated that the expression of PinX1 in cancer tissues is frequently down-regulated when compared to the normal tissues, and reduced PinX1 expression is associated with increased tumor cell metastasis and poor prognosis in some cancers, including gastric cancer [12,13], prostate cancer [14] and ovarian cancer [15]. PinX1 over-expression in some cancer cells induces apoptosis and suppresses cell proliferation [16,17]. However, the precise role of PinX1 in gliomas cell is still unclear so far.…”

Immune Checkpoint Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 is Upregulated and Independently Predicts Unfavorable Prognosis in Bladder Urothelial Carcinoma

“…Approximately 90% of BCa cases belong to bladder urothelial carcinoma (BUC) [5]. Most BCa patients undergo transurethral resection of the bladder tumor at the initial diagnosis [6]. Nevertheless, 50-70% of patients with non-muscle invasive BUC recur after the transurethral resection of the bladder tumor, and 15-25% of the recurrent patients progress into a higher cancer grade and stage [7].…”