PINX1

Gene Summary

Gene:PINX1; PIN2/TERF1 interacting, telomerase inhibitor 1
Aliases: LPTL, LPTS
Location:8p23
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:PIN2/TERF1-interacting telomerase inhibitor 1
HPRD
Source:NCBIAccessed: 08 August, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 08 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PINX1 (cancer-related)

Badrzadeh F, Akbarzadeh A, Zarghami N, et al.
Comparison between effects of free curcumin and curcumin loaded NIPAAm-MAA nanoparticles on telomerase and PinX1 gene expression in lung cancer cells.
Asian Pac J Cancer Prev. 2014; 15(20):8931-6 [PubMed] Related Publications
BACKGROUND: Herbal compounds such as curcumin which decrease telomerase and gene expression have been considered as beneficial tools for lung cancer treatment. In this article, we compared the effects of pure curcumin and curcumin-loaded NIPAAm-MAA nanoparticles on telomerase and PinX1 gene expression in a lung cancer cell line.
MATERIALS AND METHODS: A tetrazolium-based assay was used for determination of cytotoxic effects of curcumin on the Calu-6 lung cancer cell line and telomerase and pinX1 gene expression was measured with real-time PCR.
RESULTS: MTT assay showed that Curcumin-loaded NIPAAm-MAA inhibited the growth of the Calu-6 lung cancer cell line in a time and dose-dependent manner. Our q-PCR results showed that the expression of telomerase gene was effectively reduced as the concentration of curcumin-loaded NIPAAm-MAA increased while expression of the PinX1 gene became elevated.
CONCLUSIONS: The results showed that curcumin- loaded- NIPAAm-MAA exerted cytotoxic effects on the Calu-6 cell line through down-regulation of telomerase and stimulation of pinX1 gene expression. NIPPAm-MAA could be good carrier for such kinds of hydrophobic agent.

Shi R, Zhou JY, Zhou H, et al.
The role of PinX1 in growth control of breast cancer cells and its potential molecular mechanism by mRNA and lncRNA expression profiles screening.
Biomed Res Int. 2014; 2014:978984 [PubMed] Free Access to Full Article Related Publications
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.

Wu G, Liu D, Jiang K, et al.
PinX1, a novel target gene of p53, is suppressed by HPV16 E6 in cervical cancer cells.
Biochim Biophys Acta. 2014; 1839(2):88-96 [PubMed] Related Publications
The aberrant activation of telomerase is critical for the initiation and development of human cervical cancer, which is dependent on the activation of human telomerase reverse transcriptase (hTERT). Recently, Pin2/TRF1-interacting protein X1 (PinX1) has been identified as a suppressor of hTERT. It has been found that the telomerase is activated while the level of PinX1 is decreased in cervical cancer. However, the regulatory mechanism of PinX1 in cervical cancer cells remains unclear. In the present study, we demonstrated that the level of PinX1 is regulated by p53, and p53 functions as a transcriptional factor to directly activate the expression of PinX1 in cervical cancer cells. Moreover, we found that HPV16 E6 suppresses the expression of PinX1 via inhibiting p53 transcriptional activity, resulting in the enhancement of telomerase activity. This study not only for the first time shows that PinX1 is a novel target gene of p53 but also suggests that suppression of p53/PinX1 pathway may be a novel mechanism by which HPV16 E6 enhances the telomerase activity in cervical cancer cells.

Liu JY, Qian D, He LR, et al.
PinX1 suppresses bladder urothelial carcinoma cell proliferation via the inhibition of telomerase activity and p16/cyclin D1 pathway.
Mol Cancer. 2013; 12(1):148 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: PIN2/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.
METHODS: The 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.
RESULTS: PinX1 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.
CONCLUSIONS: These 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.

El Idrissi M, Hervieu V, Merle P, et al.
Cause-specific telomere factors deregulation in hepatocellular carcinoma.
J Exp Clin Cancer Res. 2013; 32:64 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Among the numerous genetic defects associated with hepatocarcinogenesis, telomere abnormalities appear to play a role both in tumor promotion and maintenance. Telomeres, the chromosome extremities, are protected by specific proteins, the shelterin complex and by additional factors. Besides telomerase dysregulation, expression changes of these telomere factors have been observed in cancers.
METHODS: Here, we tested the hypothesis that such dysregulation might occur in hepatocellular carcinoma (HCC) with specific patterns depending on the cause of HCC. We compared telomere length, telomerase activity (TA), hTERT and telomere genes expression using PCR and Western-blot analyses between non-cirrhotic liver, peritumoral cirrhotic tissue (40 samples) and cancerous tissue (40 samples) derived from 40 patients with HBV-, HCV-, or alcohol-related HCC.
RESULTS: Alterations in TA, hTERT expression and telomere length between non-cirrhotic, cirrhotic, and tumor samples were not significantly influenced by the cause of HCC. In contrast, the expression pattern of hTR, shelterin, and non-shelterin telomere protective factors clearly distinguished the 3 causes of cirrhosis and HCC. For patients with HBV diseased liver, when compared with non-cirrhotic liver, the cirrhotic tissue underexpressed all shelterin and all but HMRE11A and RAD50 non-shelterin telomere factors. For HCV the expression level of POT1, RAP1, Ku80, and RAD50 was higher in cirrhotic than in non-cirrhotic liver samples without evidence for significant transcriptional change for the remaining genes. For alcohol-related liver diseases, the expression level of POT1, RAP1, TIN2, hMRE11A, hMRE11B, Ku70, Ku80, RAD50, TANK1, and PINX1 was higher in cirrhotic than in non-cirrhotic liver samples. For the 3 causes of HCC, there was no significant change in shelterin and non-shelterin gene expression between cirrhosis and HCC samples.
CONCLUSIONS: These results validate our hypotheses and demonstrate that cirrhosis and HCC add-up numerous telomere dysfunctions including numerous cause-specific changes that appear to occur early during the course of the disease.

Ghaffari SH, Momeny M, Bashash D, et al.
Cytotoxic effect of arsenic trioxide on acute promyelocytic leukemia cells through suppression of NFkβ-dependent induction of hTERT due to down-regulation of Pin1 transcription.
Hematology. 2012; 17(4):198-206 [PubMed] Related Publications
Acute promyelocytic leukemia (APL) is characterized by specific t(15;17), distinct morphologic picture, and clinical coagulopathy that contributes to the morbidity and mortality of the disease. This study was purposed to dissect the molecular mechanisms underlying telomerase-dependent arsenic trioxide (ATO)-induced cytotoxic and anti-proliferative effects in NB4 cells. ATO exposure was associated with transcriptional repression of Pin1, survivin, c-Myc, hTERT, and PinX1 along with an expressive enhancement in p73 mRNA level. Moreover, ATO treatment suppressed cell growth, viability and metabolic activity, exerted apoptosis, hindered telomerase activity, shortened telomere length, and dampened NF-κB activation. On aggregate, these issues indicate that ATO might preempt cell growth and proliferation in NB4 cells through suppression of Pin1-mediated NF-κB-dependent stimulation of telomerase and survivin.

Shen J, Gammon MD, Terry MB, et al.
Genetic polymorphisms in telomere pathway genes, telomere length, and breast cancer survival.
Breast Cancer Res Treat. 2012; 134(1):393-400 [PubMed] Free Access to Full Article Related Publications
The impact of genetic variants in telomere pathway genes on telomere length and breast cancer survival remains unclear. We hypothesized that telomere length and genetic variants of telomere pathway genes are associated with survival among breast cancer patients. A population-based cohort study of 1,026 women diagnosed with a first primary breast cancer was conducted to examine telomere length and 52 genetic variants of 9 telomere pathway genes. Adjusted Cox regression analysis was employed to examine associations between telomere length, genetic variants and all-cause and breast cancer-specific mortality. Longer telomere length was significantly correlated with all-cause mortality in the subgroup with HER-2/neu negative tumors (HR=1.90, 95% CI: 1.12-3.22). Carrying the PINX1-33 (rs2277130) G-allele was significantly associated with increased all-cause mortality (HR=1.45, 95% CI: 1.06-1.98). Three SNPs (TERF2-03 rs35439397, TERT-14 rs2853677, and TERT-67 rs2853669) were significantly associated with reduced all-cause mortality. A similar reduced trend for breast cancer-specific mortality was observed for carrying the TERT-14 (rs2853677) T-allele (HR=0.57, 95% CI: 0.39-0.84), while carrying the POT1-18 (rs1034794) T-allele significantly increased breast cancer-specific mortality (HR=1.48, 95% CI: 1.00-2.19). However, none of the associations remained significant after correction for multiple tests. A significant dose-response effect was observed with increased number of unfavorable alleles/genotypes (PINX1-33 G-allele, POT1-18 T-allele, TERF2-03 GG, TERT-14 CC, and TERT-67 TT genotypes) and decreased survival. These data suggest that unfavorable genetic variants in telomere pathway genes may help to predict breast cancer survival.

Chang J, Dinney CP, Huang M, et al.
Genetic variants in telomere-maintenance genes and bladder cancer risk.
PLoS One. 2012; 7(2):e30665 [PubMed] Free Access to Full Article Related Publications
Telomeres are critical in maintaining genomic stability. Genetic variants in telomere pathway genes may affect telomere and telomerase function, and subsequently cancer risk. We evaluated 126 SNPs from 10 genes related to telomere regulation in relation to bladder cancer risk. Five SNPs, 4 from TEP1 gene and 1 from PINX1 gene, were found to be highly significant (P<0.01). Out of these, the most significant association was found in rs2228041 of TEP1 (OR 1.66, 95% CI 1.19-2.31) while rs1469557 of PINX1 had a protective effect (OR 0.75, 95% CI 0.61-0.93). Haplotype analysis showed that a TEP1 haplotype consisting of the variant alleles of 7 SNPs exhibited a 2.28 fold increased risk (95% CI 1.13-4.60). We then performed cumulative analysis of multiple risk variants, as well as Classification and Regression Tree (CART) to look for gene-gene interactions. In cumulative effect analysis, the group with 4-5 risk variants had an OR of 2.57 (95% CI = 1.62-4.09) versus the reference group with 0 risk variants. The CART analysis categorized individuals into five subgroups with different bladder cancer risk profiles based on their distinct genotype background. To our knowledge, this is one of the largest, most comprehensive studies on bladder cancer risk concerning telomere-regulating pathway gene SNPs and our results support that genetic variations of telomere maintenance modulate bladder cancer risk individually and jointly.

Lai XF, Shen CX, Wen Z, et al.
PinX1 regulation of telomerase activity and apoptosis in nasopharyngeal carcinoma cells.
J Exp Clin Cancer Res. 2012; 31:12 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human interacting protein X1 (PinX1) has been identified as a critical telomerase inhibitor and proposed to be a putative tumor suppressor gene. Loss of PinX1 has been found in a large variety of malignancies, however, its function in inhibiting telomerase activity of tumor cells is not well documented. Here we show that PinX1 is essential for down-regulation telomerase activity of nasopharyngeal carcinoma.
METHODS: Expression vectors of human PinX1 (pEGFP-C3-PinX1) and its small interfering RNA (PinX1-FAM-siRNA) were constructed and transfected into NPC. Their effects on mRNA of telomerase catalytic subunit (hTERT), telomerase activity, cell proliferation, cell migration, wound healing, cell cycles and apoptosis were examined using semi-quantitative RT-PCR, stretch PCR, MTT assay, Transwell, scratch assay and flow cytometry, respectively.
RESULTS: Transfection of pEGFP-C3-PinX1 and PinX1-FAM-siRNA increased and reduced PinX1 mRNA by 1.6-fold and 70%, respectively. Over-expression of PinX1 decreased hTERT mRNA by 21%, reduced telomerase activity, inhibited cell growth, migration and wound healing ability, arrested cells in G0/G1 phase, and increased apoptotic index. In contrast, down-regulation of PinX1 did not alter the above characteristics.
CONCLUSIONS: PinX1 may play important roles in NPC proliferation, migration and apoptosis and has application potential in tumor-targeted gene therapy.

Zhou XZ
PinX1: a sought-after major tumor suppressor at human chromosome 8p23.
Oncotarget. 2011; 2(10):810-9 [PubMed] Free Access to Full Article Related Publications
Human chromosome 8p23 is a region that has the most frequent heterozygosity in common human adult epithelial malignancies, but its major tumor suppressor gene(s) remain to be identified. Telomerase is activated in most human cancers and is critical for cancer cell growth. However, little is known about the significance of telomerase activation in chromosome instability and cancer initiation. The gene encoding the potent and highly conserved endogenous telomerase inhibitor PinX1 is located at human chromosome 8p23. However, the role of PinX1 in telomerase regulation and cancer development is not clear. Recent works from our group indicate that PinX1 is critical for maintaining telomere length at the optimal length. Furthermore, PinX1 is reduced in a large subset of human breast cancer tissues and cells. Significantly, PinX1 inhibition activates telomerase, and elongates telomeres, eventually leading to chromosome instability, all of which are abrogated by telomerase knockdown or knockout. Moreover, PinX1 allele loss causes majority of mice to develop a variety of epithelial cancers, which display chromosome instability and recapitulate to 8p23 allele loss in humans. These results indicate that PinX1 is a sought-after major tumor suppressor at human chromosome 8p23 that is essential for regulating telomerase activity and maintaining chromosome stability. These results suggest that inhibition of telomerase using PinX1 especially its telomerase inhibitory fragment or other methods might be used to treat cancers that have telomerase activation.

Wan SM, Tie J, Zhang YF, et al.
Silencing of the hPOT1 gene by RNA inference promotes apoptosis and inhibits proliferation and aggressive phenotype of gastric cancer cells, likely through up-regulating PinX1 expression.
J Clin Pathol. 2011; 64(12):1051-7 [PubMed] Related Publications
BACKGROUND: The human protection of telomeres 1 (hPOT1) protein, a single-strand telomeric DNA binding protein, plays an important role in telomere protection and telomere length regulation. However, its effect on invasion of gastric cancer remains unclear.
AIMS: To explore the role of hPOT1 in the proliferation and invasion of gastric cancer cells.
METHODS: The gastric expression of hPOT1 was examined in normal gastric mucosa (n=25), intestinal metaplasia (n=20), gastric dysplasia (n=20) and gastric cancer (n=150) by immunohistochemistry. The mean optical density (MOD) of the immunostaining was determined by semi-quantitative image analysis. The role of hPOT1 in the cell proliferation, apoptosis and invasion of gastric cancer 7901 cells was determined by means of the RNA interference (RNAi) of hPOT1 mRNA. The effects of hPOT1 RNAi on the expression of hPinX1 and hTERT were detected with western blotting.
RESULTS: The hPOT1 MOD was progressively increased from the normal mucosa to intestinal metaplasia, dysplasia, and gastric cancer. An increased hPOT1 expression significantly correlated with tumour serosal invasion, node metastasis and advanced stage. Transfection of hPOT1 siRNA into SGC-7901 cells led to a decrease in cell proliferation, colony formation and invasion, and also an increase of apoptosis. An up-regulation of hPinX1 and down-regulation of hTERT were found in gastric cancer cells with hPOT1 siRNA.
CONCLUSIONS: Increased hPOT1 expression is associated with an advanced tumour stage. hPOT1 RNAi inhibits proliferation and invasion, and induces apoptosis of gastric cancer cells. The effects of hPOT1 RNAi seem to be functionally linked to up-regulation of PinX1 and down-regulation of hTERT.

Wang HB, Wang WQ, Wang XW, et al.
PinX1 gene transfection enhances the sensitivity of gastric carcinoma cell line to 5-fluorouracil.
Hepatogastroenterology. 2011 Mar-Apr; 58(106):682-6 [PubMed] Related Publications
BACKGROUND/AIMS: Since telomeres and telomerase play crucial roles in maintaining cell immortalization and cancer progression, they may be targets for anticancer treatment. PinX1 is a potent telomerase inhibitor, and a putative tumor suppressor. The use of PinX1 to treat cancers has not been reported yet.
METHODOLOGY: In order to use PinX1 in gene therapy for gastric carcinoma, we transfected PinX1 gene into the gastric carcinoma line MKN28 using the eukaryotic expression vector pIRES2-EGFP. PinX1-expressing, drug-resistant clones were screened with G418 and used in the study.
RESULTS: MKN28 cells transfected with PinX1 gene grew more slowly than the cells not transfected or transfected with void vectors (p<0.05). The IC50 value decreased markedly in cells transfected with PinX1 gene. PinX1 gene transfection enhanced the sensitivity of MKN28 cells to 5-fluorouracil (p<0.05).
CONCLUSIONS: PinX1 may be used in gene therapy for gastric carcinoma.

Zhou XZ, Huang P, Shi R, et al.
The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice.
J Clin Invest. 2011; 121(4):1266-82 [PubMed] Free Access to Full Article Related Publications
Telomerase is activated in most human cancers and is critical for cancer cell growth. However, little is known about the significance of telomerase activation in chromosome instability and cancer initiation. The gene encoding the potent endogenous telomerase inhibitor PinX1 (PIN2/TRF1-interacting, telomerase inhibitor 1) is located at human chromosome 8p23, a region frequently exhibiting heterozygosity in many common human cancers, but the function or functions of PinX1 in development and tumorigenesis are unknown. Here we have shown that PinX1 is a haploinsufficient tumor suppressor essential for chromosome stability in mice. We found that PinX1 expression was reduced in most human breast cancer tissues and cell lines. Furthermore, PinX1 heterozygosity and PinX1 knockdown in mouse embryonic fibroblasts activated telomerase and led to concomitant telomerase-dependent chromosomal instability. Moreover, while PinX1-null mice were embryonic lethal, most PinX1+/- mice spontaneously developed malignant tumors with evidence of chromosome instability. Notably, most PinX1 mutant tumors were carcinomas and shared tissues of origin with human cancer types linked to 8p23. PinX1 knockout also shifted the tumor spectrum of p53 mutant mice from lymphoma toward epithelial carcinomas. Thus, PinX1 is a major haploinsufficient tumor suppressor essential for maintaining telomerase activity and chromosome stability. These findings uncover what we believe to be a novel role for PinX1 and telomerase in chromosome instability and cancer initiation and suggest that telomerase inhibition may be potentially used to treat cancers that overexpress telomerase.

Capraro V, Zane L, Poncet D, et al.
Telomere deregulations possess cytogenetic, phenotype, and prognostic specificities in acute leukemias.
Exp Hematol. 2011; 39(2):195-202.e2 [PubMed] Related Publications
OBJECTIVE: Telomeres are protected by tightly regulated factors and elongated by telomerase. Short and/or deprotected chromosomes are recombinogenic and thereby cancer prone.
MATERIALS AND METHODS: Together with the quantification of telomerase activity (TA), measuring telomere length (TL) and expression of the genes that govern telomere protection and elongation are useful for assessing telomere homeostasis.
RESULTS: By these means we demonstrate that TL, hTERT, and TA are in the order acute myelogenous leukemia (AML) > T-cell acute lymphoblastic leukemia (T-ALL) > B-cell acute lymphoblastic leukemia (B-ALL) > T-ALL > AML, and B-ALL > AML > T-ALL. AML0 and AML3 display the lowest amounts of hTERT transcripts, and ALL and AML cells with cytogenetic abnormalities possess the shortest telomeres. hTERT expression includes phenotype-specific RNA maturation and correlates with TA but not with TL. A wide ratio of TA to hTERT expression between leukemia subtypes suggests phenotype-specific hTERT post-transcriptional deregulations. B- and T-ALL overexpress Ku70 and Pinx1, T-ALL PTOP and RAP1, and B-ALL TRF2, the expression of which is significantly higher in cases with abnormal karyotype. hTERT transcription and TL correlate with response to intensive chemotherapy, and hTERT and RAD50 are independent prognostic factors for survival.
CONCLUSIONS: Each leukemia subtype possesses specific telomere dysregulations that rely on phenotype, karyotype, response to treatment, and survival.

Chen G, Da L, Wang H, et al.
HIV-Tat-mediated delivery of an LPTS functional fragment inhibits telomerase activity and tumorigenicity of hepatoma cells.
Gastroenterology. 2011; 140(1):332-43 [PubMed] Related Publications
BACKGROUND & AIMS: Human liver-related putative tumor suppressor (LPTS) is a gene that encodes a telomerase inhibitory protein that is similar to human Pin2/TRF1-interacting protein. The LPTS protein binds directly to the telomerase catalytic subunit (human telomerase reverse transcriptase) and suppresses telomerase activity. Telomere maintenance and telomerase activity are required for long-term proliferation of cancer cells, so LPTS might be used in anticancer strategies.
METHODS: The carboxy-terminal (functional) fragment of LPTS was fused to the transactivator of transcription of human immunodeficiency virus (Tat)-an 11-amino acid peptide that translocates across the cell membrane; the TAT-fused C-terminal of LPTS (TAT-LPTS-LC) was purified and transduced into cells. Telomerase activity was identified by using the telomeric repeat amplification protocol. The effects of the TAT-LPTS-LC protein on cell proliferation and death were evaluated by colorimetric tetrazolium salt and flow cytometry analyses. Tumor growth was analyzed in nude mice.
RESULTS: The purified TAT-LPTS-LC protein was efficiently delivered into the cells, where it suppressed telomerase activity and shortened telomere length. TAT-LPTS-LC inhibited proliferation of telomerase-positive hepatocellular carcinoma BEL-7404 and hepatoblastoma HepG2cells and induced their death; however, it had no effect on telomerase-negative liver cell line L02 and osteosarcoma cell line Saos-2. In mice, tumor formations by BEL-7404 cells were suppressed by TAT-LPTS-LC treatments.
CONCLUSIONS: Transduction of hepatoma cells with a fusion protein that contains the C-terminal, functional fragment of LPTS and human immunodeficiency virus Tat (TAT-LPTS-LC) causes telomere shortening, limits proliferation, and inhibits growth of tumors from these cells in mice. TAT-LPTS-LC inhibits telomerase activity and might be developed as an anticancer agent.

Wang HB, Wang XW, Zhou G, et al.
PinX1 inhibits telomerase activity in gastric cancer cells through Mad1/c-Myc pathway.
J Gastrointest Surg. 2010; 14(8):1227-34 [PubMed] Related Publications
INTRODUCTION: The aim of this study was to investigate the role of Mad1/c-Myc in telomerase regulation in gastric cancer cells in order to gain insight into telomerase activity and to evaluate PinX1 as a putative inhibitor of gastric cancer.
METHODS: PinX1 and PinX1siRNA eukaryotic expression vectors were constructed by recombinant technology and transfected into gastric carcinoma cells using Lipofectamine 2000. Telomerase activity was measured by the telomeric repeat amplification protocol. Apoptosis of gastric cancer cells was analyzed by flow cytometry and transmission electron microscopy. Reverse transcription-polymerase chain reaction and Western blotting were used to assess the expression levels of PinX1 and Mad1/c-Myc.
RESULTS: We found that PinX1-negative gastric cancer cells showed significantly higher telomerase activity than did the PinX1-postive cells. PinX1-transfection reduced telomerase activity in PinX1-negative gastric cancer cells and exhibited an upregulation of Mad1 and downregulation of c-Myc expression. Pinx1 RNAi treatment led to downregulation of Mad1 and upregulation of c-Myc.
CONCLUSION: Suppression of telomerase activity mediated by PinX1 is involved in the Mad1/c-Myc pathway.

Cai MY, Zhang B, He WP, et al.
Decreased expression of PinX1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma.
Cancer Sci. 2010; 101(6):1543-9 [PubMed] Related Publications
Human interacting protein X1 (PinX1) has been identified as a critical telomerase inhibitor and proposed to be a putative tumor suppressor gene. Loss of PinX1 has been found in a large variety of malignancies, but the expression status in epithelial ovarian tumors has not been investigated. In this study, immunohistochemistry for PinX1 protein was performed on a tissue microarray (TMA) of epithelial ovarian tumors (informatively containing 25 cystadenomas, 29 borderline tumors, and 157 invasive carcinomas) and 12 normal ovaries. Receiver-operator curve (ROC) analysis was used to determine cut-off scores for tumor positivity and to evaluate patients' survival status. The threshold for PinX1 positivity was determined to be above 60% (area under the curve = 0.856, P < 0.001) based on the area under the ROC. Positive expression of PinX1 was observed in 100% of normal ovarian tissues, in 84% of cystadenomas, in 75.9% borderline tumors, and 66.2% of ovarian carcinomas. Decreased expression of PinX1 was strongly related to patients with poor prognostic factors regarding presence of lymph node metastasis (P = 0.024), distant metastasis (P < 0.001), and late International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.001). In univariate survival analysis, a highly significant correlation between loss of PinX1 and shortened patient survival (mean, 48.2 months vs 99.2 months, P < 0.001) was displayed. Multivariate analysis demonstrated PinX1 expression (P = 0.027) was evaluated as an independent parameter. Our findings suggest that loss of PinX1 is an adverse independent molecular marker for epithelial ovarian carcinoma patients. PinX1 may be a novel target for telomerase-based anticancer therapy due to inhibiting telomerase activity.

Zhang B, Bai YX, Ma HH, et al.
Silencing PinX1 compromises telomere length maintenance as well as tumorigenicity in telomerase-positive human cancer cells.
Cancer Res. 2009; 69(1):75-83 [PubMed] Related Publications
The nucleolar protein PinX1 has been proposed to be a putative tumor suppressor due to its binding to and inhibition of the catalytic activity of telomerase, an enzyme that is highly expressed in most human cancers in which it counteracts telomere shortening-induced senescence to confer cancer cell immortalization. However, the role of PinX1 in telomere regulation, as well as in cancer, is still poorly understood. In this study, we showed that the PinX1 protein is constitutively expressed in various human cells regardless of their telomerase activity and malignant status. Most interestingly, we found that silencing PinX1 expression by a potent short hairpin RNA construct led to a robust telomere length shortening and growth inhibition in telomerase-positive but not in telomerase-negative human cancer cells. We further showed that silencing PinX1 significantly reduced the endogenous association of telomerase with the Pot1-containing telomeric protein complex, and therefore, could account for the phenotypic telomere shortening in the affected telomerase-positive cancer cells. Our results thus reveal a novel positive role for PinX1 in telomerase/telomere regulations and suggest that the constitutive expression of PinX1 attributes to telomere maintenance by telomerase and tumorigenicity in cancer cells.

Ma Y, Wu L, Liu C, et al.
The correlation of genetic instability of PINX1 gene to clinico-pathological features of gastric cancer in the Chinese population.
J Cancer Res Clin Oncol. 2009; 135(3):431-7 [PubMed] Related Publications
PURPOSE: This project explored the influence of loss of heterozygosity (LOH) and microsatellite instability (MSI) of locus D8S277 to PINX1 expression of gastric cancer in Chinese people.
METHODS: LOH and MSI of locus D8S277 in 90 paraffin-embedded gastric carcinoma specimens were detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Envision immunohistochemistry was used to assess the expression of PINX1.
RESULTS: The frequency of LOH was higher in cases with lymph node metastasis than those without (18.57 vs. 0.00%, P < 0.01), and was higher in the specimens that were at TNM stage III + IV than those at stage I + II (21.43 vs. 2.94%, P < 0.01). In terms of the frequency of MSI, it was lower in cases with lymph node metastasis than those without (10.00 vs. 30.00%,P < 0.05). The positive rate of PINX1 protein was higher in samples without lymph node metastasis than those with lymph node metastasis (80.00 vs. 50.00%, P < 0.01); and was higher in the cases at TNM stage I + II than those at stage III + IV; and was lower in the cases between 40 and 60 years old than those above 60 years old (43.75 vs. 65.52%, P < 0.05).
CONCLUSION: LOH and MSI of PINX1 may play major role in tumor development and regulate it through different pathways. Because LOH plays a major role in negative expression of PINX1, it can be regarded as a sign of gastric cancer development and MSI may affect the prognosis and tumor turnover.

Campbell LJ, Fidler C, Eagleton H, et al.
hTERT, the catalytic component of telomerase, is downregulated in the haematopoietic stem cells of patients with chronic myeloid leukaemia.
Leukemia. 2006; 20(4):671-9 [PubMed] Related Publications
Telomere shortening is associated with disease progression in chronic myeloid leukaemia (CML). To investigate the biology and regulation of telomerase in CML, we evaluated expression of the telomerase components, its regulators and several telomeric-associated proteins. Quantitative real-time-polymerase chain reaction (PCR) was used to compare gene expression in the CD34+/leukaemic blast cells of 22 CML patient samples to the CD34+ cell population of healthy individuals. hTERT, the catalytic component of telomerase, was downregulated in eight of 12 chronic phase (CP) patients (P = 0.0387). Furthermore, hTERT was significantly downregulated in two of three patients in accelerated phase (AP) and seven of seven patients in blast crisis (BC), P = 0.0017. Expression of hTR and telomeric-associated proteins TEP1, TRF1, TRF2, tankyrase and PinX1 was high in the majority of CP and AP patients. With the exceptions of TEP1 and hTR, expression of these factors was highest in CP and decreased during disease progression. Expression of c-Myc, a positive regulator of hTERT transcription, correlated with hTERT expression and decreased with disease progression, falling below control levels in BC. hTERT levels were increased in CP patients following successful treatment with imatinib, relative to untreated CP patients. We suggest that reduced hTERT expression directly causes the shortened telomeres observed in CML.

Sun J, Huang H, Zhu Y, et al.
The expression of telomeric proteins and their probable regulation of telomerase during the differentiation of all-trans-retinoic acid-responsive and -resistant acute promyelocytic leukemia cells.
Int J Hematol. 2005; 82(3):215-23 [PubMed] Related Publications
Telomerase activity has been linked to retinoid induction of tumor cell differentiation, and the patterns of telomerase expression are different in the 2 pathways of acute promyelocytic leukemia (APL) cell differentiation: the retinoic acid receptor 3 (RAR3)-dependent and the retinoic X receptor 3 (RXR3)-dependent pathways. Still, whether telomeric proteins respond to retinoid treatment is not clear. If they do, how they would respond and how they would interfere in telomerase regulation during differentiation are also unclear. Using all-trans-retinoic acid (ATRA)-sensitive and -resistant APL cell lines NB4, NB4-R1, and NB4-R2, we analyzed a panel of telomeric proteins, including TRF1, PINX1, TANK1, and TANK2, at the messenger RNA (mRNA) and protein expression levels during the differentiation of these cell lines in the 2 pathways. Our analyses showed that both mRNA and protein expression of TRF1 remained stable during NB4 and NB4-R1 cell differentiation but slightly increased in NB4-R2 cells, suggesting that TRF1 may have different functions in the RAR3- and RXR3-dependent pathways. The stable expression of TRF1 may be because telomere length remains unchanged. Pinx1 mRNA expression was tightly correlated with telomerase reverse transcriptase (hTERT) mRNA expression during differentiation. Variation in Pinx1 expression may be a reaction induced by hTERT expression variation. TANK1 mRNA expression and TANK1 protein levels were both down-regulated in all 3 APL cell lines at a later period of differentiation, suggesting that TANK1 may positively regulate telomerase activity and that both RAR3- and RXR3-dependent pathways may exert this regulation.TANK2 expression levels remained stable in all 3 APL cell lines during differentiation, showing that TANK2 may have little effect on telomerase. Thus, our studies provide an outline of the dynamics of telomeric protein expression and the probable regulatory effects of these proteins on telomerase during the differentiation of ATRA-responsive and -resistant APL cells.

Kondo T, Oue N, Mitani Y, et al.
Loss of heterozygosity and histone hypoacetylation of the PINX1 gene are associated with reduced expression in gastric carcinoma.
Oncogene. 2005; 24(1):157-64 [PubMed] Related Publications
The expression of PINX1, a possible telomerase inhibitor and a putative tumor suppressor, has not been studied in human cancers, including gastric cancer (GC). We examined expression of PINX1 by quantitative reverse transcription (RT)-PCR in 73 cases of GC, and 45 of these cases were further studied for loss of heterozygosity (LOH) by PCR with microsatellite marker D8S277. Reduced expression (tumor vs normal ratio<0.5) of PINX1 was detected in 50 (68.5%) of 73 cases of GC. GC tissues with reduced expression of PINX1 showed significantly higher telomerase activities as measured by telomeric repeat amplification protocol than those with normal expression of PINX1 (P=0.031). LOH of PINX1 locus was detected in 15 (33.3%) of 45 cases of GC and was correlated significantly with reduced expression of PINX1 (P=0.031). Expression of PINX1 in a GC cell line, MKN-74, was induced by treatment with trichostatin A (TSA) or nicotinamide (NAM). Chromatin immunoprecipitation assay of MKN-74 cells revealed that acetylation of histone H4 in the 5' untranslated region (UTR) of PINX1 was enhanced by treatment with TSA or NAM, whereas acetylation of histone H3 was not changed by TSA or NAM. In addition, TSA or NAM treatment led to inhibition of telomerase activity in MKN-74 cells. These results indicate that LOH of PINX1 locus and hypoacetylation of histone H4 in the 5' UTR of PINX1 are associated with reduced expression of PINX1 in GC.

Oh BK, Chae KJ, Park C, Park YN
Molecular analysis of PinX1 in human hepatocellular carcinoma.
Oncol Rep. 2004; 12(4):861-6 [PubMed] Related Publications
PinX1 is located at 8p23, a region with frequent loss of heterozygosity in hepatocellular carcinomas (HCCs). Overexpression of PinX1 is known to inhibit telomerase activity, shorten telomeres and induce crisis while its depletion increases tumorigenesis in nude mice. These results suggest that PinX1 might be critical for hepatocarcinogenesis. In this study, we assessed transcript expression of PinX1, the correlation between PinX1 mRNA level and telomere length and telomerase activity, as well as sequence alteration, in 24 HCCs and their adjacent non-HCC tissues from patients with B viral chronic hepatitis/cirrhosis. There was no significant difference between the levels of PinX1 mRNA in HCCs and those in non-HCCs. The PinX1 mRNA tended to increase as the telomere shortened in the HCCs (p=0.067, R(2)=0.166), but no correlation was found in non-HCCs. The PinX1 level revealed no significant relationship with telomerase activity in HCCs and non-HCCs. The missense mutations of PinX1, at the 254 and 265 residues, were found in 17% of the HCCs and their adjacent non-HCCs. The mutations were located in the non-conserved region and revealed no relation with PinX1 expression, telomere length and telomerase activity, suggesting that they are likely polymorphisms. Our findings suggest that PinX1 may not play a major role in hepatocarcinogenesis as a target tumor suppressor gene. PinX1, however, might be involved in the telomere length regulation of HCCs.

Hawkins GA, Chang BL, Zheng SL, et al.
Mutational analysis of PINX1 in hereditary prostate cancer.
Prostate. 2004; 60(4):298-302 [PubMed] Related Publications
BACKGROUND: Telomerase activity is increased in most tumors. PinX1 has recently been identified as a critical component in regulating telomerase activity. The PinX1 gene is located within chromosomal region 8p22-23, a region associated with LOH and potentially linked to increased prostate cancer risk.
METHODS: PINX1 was re-sequenced in 159 hereditary prostate cancer (HPC) probands. Four non-synonymous coding variants were genotyped in 159 HPC families.
RESULTS: Thirty-nine polymorphisms were identified in the HPC screening panel. Ten coding polymorphisms were identified, seven (Gln50His, Leu91Met, Gln206His, Arg215Ile, Thr220Ala, Ser254Cys, and Glu414Ala) of which were non-synonymous. The most common variants Thr220Ala and Ser254Cys were not significantly over-transmitted from affected parent to affected offspring.
CONCLUSIONS: Based on these results, we conclude that PINX1 is not a major factor for HPC risk.

Song H, Li Y, Chen G, et al.
Human MCRS2, a cell-cycle-dependent protein, associates with LPTS/PinX1 and reduces the telomere length.
Biochem Biophys Res Commun. 2004; 316(4):1116-23 [PubMed] Related Publications
Human LPTS/PinX1 is a telomerase-inhibitory protein, which binds to the telomere protein Pin2/TRF1 and the catalytic subunit hTERT of telomerase. To explore the proteins that might be involved in the telomerase pathway, we performed a yeast two-hybrid screening with LPTS/PinX1 as the bait. A novel gene, MCRS2, encoding for an isoform of MCRS1/p78 and MSP58 was isolated. The expression of MCRS2 protein is cell-cycle dependent, accumulating in the very early S phase. MCRS2 interacts with LPTS/PinX1 in vitro, in vivo and colocalizes with LPTS/PinX1 in cells. MCRS2 and its amino terminus inhibit telomerase activity in vitro and long-term overexpression of MCRS2 in SMMC-7721 cells results in a gradual and progressive shortening of telomeres. Our findings suggest that MCRS2 might be a linker between telomere maintenance and cell-cycle regulation.

Akiyama Y, Maesawa C, Wada K, et al.
Human PinX1, a potent telomerase inhibitor, is not involved in human gastrointestinal tract carcinoma.
Oncol Rep. 2004; 11(4):871-4 [PubMed] Related Publications
PinX1 was isolated as a Pin2/TRF1 binding protein that also binds to the telomerase catalytic subunit hTERT. The gene is a potent telomerase inhibitor and a putative tumor suppressor since it inhibits telomerase activity and affects tumorigenicity in nude mice. This study investigated aberrations of PinX1 gene in gastrointestinal tract carcinomas (GITCs). We examined mutations, mRNA expression and promoter methylation of PinX1 gene in 15 GITC cell lines, and 20 patients with primary GITC. We found a missense mutation at codon 254 (AGC/TGC) in a colon and an esophageal carcinoma cell line, and in cancerous and matching normal tissues of 2 patients with primary GITC (10%). It might be a benign polymorphism. No hyper-methylation was found in the promoter region and the treatment by 5-Aza-2'-deoxycytidine did not affect PinX1 mRNA expression level in any of the cell lines. It was concluded that the human PinX1 does not affect tumorigenesis of human GITC.

Chang Q, Pang JC, Li J, et al.
Molecular analysis of PinX1 in medulloblastomas.
Int J Cancer. 2004; 109(2):309-14 [PubMed] Related Publications
Our group has previously demonstrated a high frequency of allelic loss on the short arm of chromosome 8 and identified a region of homozygous deletion of 1.41 Mb, flanked by D8S520 and D8S1130, on 8p23.1 in medulloblastomas, suggesting the presence of a tumor suppressor gene in this critical deletion region. The aim of our study was to investigate whether PinX1, a newly identified gene whose product is a potent inhibitor of telomerase, is the target gene in the homozygous deletion region identified in medulloblastomas. We assessed for alterations in gene sequence and transcript expression of PinX1, as well as the correlation between PinX1 expression and telomerase activity in a series of 52 medulloblastomas, 3 medulloblastoma cell lines (D283, D341 and Daoy) and 4 primitive neuroectodermal tumors (PNETs). Direct sequence analysis of all 7 exons and splice junctions of the PinX1 gene revealed no somatic mutations but 11 genetic polymorphisms. Transcript expression of PinX1, as evaluated by reverse transcription-polymerase chain reaction, in microdissected tumors and normal cerebellum showed 2 transcript variants, corresponding to the full-length form and an alternative spliced variant lacking exon 6, in all samples. This result indicated that PinX1 expression was not suppressed in medulloblastomas. Using the telomeric repeat amplification protocol (TRAP) assay, 13 of 19 (68%) medulloblastomas, 1 of 2 PNETs and all 3 cell lines showed telomerase activity. There is no significant correlation between PinX1 transcript expression and telomerase activity, but our results showed that telomerase activation is involved in medulloblastomas. Taken together, our results suggest that PinX1 does not play a major role in the oncogenesis of medulloblastomas.

Liao C, Zhao MJ, Zhao J, et al.
Mutation analysis of novel human liver-related putative tumor suppressor gene in hepatocellular carcinoma.
World J Gastroenterol. 2003; 9(1):89-93 [PubMed] Related Publications
AIM: To find the point mutations meaningful for inactivation of liver-related putative tumor suppressor gene (LPTS) gene, a human novel liver-related putative tumor suppressor gene and telomerase inhibitor in hepatocellular carcinoma.
METHODS: The entire coding sequence of LPTS gene was examined for mutations by single strand conformation polymorphism (SSCP) assay and PCR products direct sequencing in 56 liver cancer cell lines, 7 ovarian cancer and 7 head neck tumor cell lines and 70 pairs of HCC tissues samples. The cDNA fragment coding for the most frequent mutant protein was subcloned into GST fusion expression vector. The product was expressed in E.coli and purified by glutathione-agarose column. Telomeric repeat amplification protocol (TRAP) assays were performed to study the effect of point mutation to telomerase inhibitory activity.
RESULTS: SSCP gels showed the abnormal shifting bands and DNA sequencing found that there were 5 different mutations and/or polymorphisms in 12 tumor cell lines located at exon2, exon5 and exon7. The main alterations were A(778)A/G and A(880)T in exon7. The change in site of 778 could not be found in HCC tissue samples, while the mutation in position 880 was seen in 7 (10 %) cases. The mutation in the site of 880 had no effect on telomerase inhibitory activity.
CONCLUSION: Alterations identified in this study are polymorphisms of LPTS gene. LPTS mutations occur in HCC but are infrequent and of little effect on the telomerase inhibitory function of the protein. Epigenetics, such as methylation, acetylation, may play the key role in inactivation of LPTS.

Liao C, Zhao MJ, Zhao J, et al.
Over-expression of LPTS-L in hepatocellular carcinoma cell line SMMC-7721 induces crisis.
World J Gastroenterol. 2002; 8(6):1050-2 [PubMed] Related Publications
AIM: To evaluate the function of the longer transcripts LPTS-L in hepatocellular carcinoma cell line SMMC-7721.
METHODS: SMMC-7721 cells were transfected with LPTS-L expression construct and stably transfected cells were selected by G418. Multiple single clones formed and were checked for their phenotype. In the study of the effect on telomerase activity of LPTS-L in vitro, GST-LPTS-L fusion protein was expressed in E.coli and purified by glutathione-agarose column. Telomeric repeat amplification protocol (TRAP) assays were performed to study the influence of telomerase activity in SMMC-7721 cells.
RESULTS: Over-expression of LPTS-L induced SMMC-7721 cells into crisis. LPTS-L could inhibit the telomerase activity in SMMC-7721 cells in vitro.
CONCLUSION: LPTS-L is a potent telomerase inhibitor. Over-expression of LPTS-L can induce hepatoma cells into crisis due to the reduction of telomerase activity.

Park WS, Lee JH, Park JY, et al.
Genetic analysis of the liver putative tumor suppressor (LPTS) gene in hepatocellular carcinomas.
Cancer Lett. 2002; 178(2):199-207 [PubMed] Related Publications
Recently, a novel liver-related putative tumor suppressor (LPTS), which has a growth inhibitory function in the hepatocellular carcinoma (HCC) cell line, has been identified at chromosome 8p23. To determine the relationship of the LPTS with the development or progression of HCC, we analyzed the genetic alterations and the expression pattern of the LPTS gene in a series of 80 HCCs, six dysplastic nodules, and eight large regenerating nodules, determining the genomic structures. We identified a total of seven exons, of which two were alternative, and three LPTS isoforms, short (LPTS-S), medium (LPTS-M), and long-sizes (LPTS-L). In the genetic alteration study of the LPTS gene, no mutation was detected in the large regenerating nodules, dysplastic nodules, and HCC, whereas ten (34.5%) of 29 informative cases at one or more intragenic polymorphic sites showed loss of heterozygosity (LOH). Interestingly, LOH was identified only in HCC samples with hepatitis B virus (HBV) infection and the frequency of LOH was not statistically related with histologic grade and clinical stage, suggesting that allelic loss of the LPTS gene may occur as an early event in the development of HCC, especially in the cases with HBV infection.

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