The Role of PinX1 in Growth Control of Breast Cancer Cells and Its Potential Molecular Mechanism by mRNA and lncRNA Expression Profiles Screening

Abstract

As a major tumor suppressor gene, the role of PinX1 in breast cancer and its molecular mechanism remain unclear. In this study, overexpression of PinX1 was generated in 3 breast cancer cell lines, and knockdown of PinX1 was performed in a nontumorigenic breast cell line. The regulation of PinX1 on cell proliferation and cell cycle was observed. A microarray-based lncRNA and mRNA expression profile screening was also performed. We found a lower growth rate, G0/G1 phase arrest, and S phase inhibition in the PinX1 overexpressed breast cancer cells, while a higher growth rate, decreased G0/G1 phase, and increased S phase rate in the PinX1 knocked-down nontumorigenic breast cell. A total of 977 mRNAs and 631 lncRNAs were identified as differentially expressed transcripts between PinX1 overexpressed and control MCF-7 cells. Further analysis identified the involvement of these mRNAs in 52 cancer related pathways and various other biological processes. 11 enhancer-like lncRNAs and 25 lincRNAs with their adjacent mRNA pairs were identified as coregulated transcripts. Our results confirmed the role of PinX1 as a major tumor suppressor gene in breast cancer cell lines and provided information for further research on the molecular mechanisms of PinX1 in tumorigenesis.

Novel role for PINX1 as a coregulator of nuclear hormone receptors

“…In this work, we carried out cellular viability assays where we observed that knockdown of PINX1 in MCF7 cells promotes estrogen dependent proliferation while overexpression of PINX1 has the opposite effect. This is supported by recent evidence published by Shi et al (2014a) where they show that overexpression of PINX1 inhibits growth and clonogenicity (Shi et al, 2014a). Additionally, PINX1 knockdown also promotes colony formation of these cells, suggesting that expression of PINX1 may be a marker for lower breast tumor aggressiveness and malignity.…”

“…In this study, we have identified a novel function for PINX1 as a corepressor of ERa. As a protein that has been previously characterized as a telomerase inhibitor (Banik and Counter, 2004;Cheung et al, 2012), PINX1 has been proposed as tumor suppressor in a number of epithelial tumors, including hepatic (Liao et al, 2000), breast (Shi et al, 2014a), esophagus (Zuo et al, 2013), prostate (Shi et al, 2014b), etc.…”

“…PINX1 was initially isolated as a liver related putative tumor suppressor (LPTS) by positional candidate cloning on the 8p23 chromosomal region; a region frequently associated with loss of heterozygosity in cancer, and was shown to inhibit proliferation in liver cancer cell lines (Liao et al, 2000). Later, it was found to have strong telomerase inhibitory activity both in vivo and in vitro (Banik and Counter, 2004;Zhou and Lu, 2001) and has been found to be downregulated in a number of cancers, including breast (Shi et al, 2014a), bladder , cervical (Wu et al, 2014), and prostate (Shi et al, 2014b). In this work, we demonstrate a novel activity for PINX1 as a corepressor of ERa.…”

The depletion of PinX1 involved in the tumorigenesis of non-small cell lung cancer promotes cell proliferation via p15/cyclin D1 pathway

“…The fold change (14.54) of BMP5 was significantly increased in microarray analysis and was expressed at the highest levels [25]. Therefore, BMP5 was involved in PinX1-slienced A549 cells and PinX1-overexpressed SK-MES-1 cells to understand the possible molecules of PinX1 act on P15/cyclinD1 pathway.…”

8p deletion is strongly linked to poor prognosis in breast cancer

“…68,69 It will thus be interesting to see if breast cancers with 8p-loss might respond better to neoadjuvant chemotherapy as compared to those lacking this alteration. The fact that 8p deletions were markedly associated with rapid cell proliferation is potentially caused by deletion-dependent down-regulation of several wellknown cell-cycle control genes located at 8p21, 8p22 and 8p23, including for example LZTS1, an inhibitor of the Cdk1/cyclin B1 complex, 23 PINX1, which prolongs G0/S1 phase, 70 DLC1, an inducer of apoptosis, 71 and MTUS1, which delays progression of mitosis by prolonging metaphase. 21 Further steps for identification of putative tumor suppressor genes would include comparison between expression and copy numbers of 8p genes followed by functional studies.…”