Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

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

Authors: Xiao-Peng Tian, Xiao-Han Jin, Mei Li, Wei-Juan Huang, Dan Xie, Jia-Xing Zhang

Published in: Molecular Cancer | Issue 1/2017

Login to get access

Abstract

Background

The telomerase/telomere interacting protein PinX1 has been suggested as a tumor suppressor. However, the clinical and biological significance of PinX1 in human non-small cell lung cancer (NSCLC) is unclear.

Methods

PinX1 gene/expression pattern and its association with NSCLC patient survival were analyzed in cBioportal Web resource and two cohorts of NSCLC samples. A series of in vivo and in vitro assays were performed to elucidate the function of PinX1 on NSCLC cells proliferation and underlying mechanisms.

Results

More frequency of gene PinX1 homozygous deletion and heterozygote deficiency was first retrieved from cBioportal Web resource. Low expression of PinX1 correlated with smoking condition, histological type, T stage, N stage, M stage and TNM stage, and was an independent predictor for overall survival in a learning cohort (n = 93) and a validation cohort (n = 51) of NSCLC patients. Furthermore, knockdown of PinX1 dramatically accelerated NSCLC cell proliferation and G1/S transition, whereas ectopic overexpression of PinX1 substantially inhibited cell viability and cell cycle transition in vitro and in vivo. p15/cyclin D1 pathway and BMP5 might contribute to PinX1-associated cell proliferation and cell cycle transition.

Conclusion

The cost-effective expression of PinX1 could constitute a novel molecular predictor/marker for NSCLC management.
Appendix
Available only for authorised users
Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMed
2.
Aarts MJ, van den Borne BE, Biesma B, Kloover JS, Aerts JG, Lemmens VE. Improvement in population-based survival of stage IV NSCLC due to increased use of chemotherapy. Int J Cancer. 2015;136:E387–95.CrossRefPubMed
3.
Patnaik SK, Kannisto E, Knudsen S, Yendamuri S. Evaluation of microRNA expression profiles that may predict recurrence of localized stage I non-small cell lung cancer after surgical resection. Cancer Res. 2010;70:36–45.CrossRefPubMed
4.
Warth A. Diagnosis, prognosis, and prediction of non-small cell lung cancer: Importance of morphology, immunohistochemistry and molecular pathology. Pathologe. 2015;36 Suppl 2:194–200.CrossRefPubMed
5.
Yu Y, He J. Molecular classification of non-small-cell lung cancer: diagnosis, individualized treatment, and prognosis. Front Med. 2013;7:157–71.CrossRefPubMed
6.
Banik SS, Counter CM. Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR. J Biol Chem. 2004;279:51745–8.CrossRefPubMed
7.
8.
9.
Zhou XZ, Huang P, Shi R, Lee TH, Lu G, Zhang Z, Bronson R, Lu KP. The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice. J Clin Invest. 2011;121:1266–82.CrossRefPubMedPubMedCentral
10.
Zhang B, Bai YX, Ma HH, Feng F, Jin R, Wang ZL, Lin J, Sun SP, Yang P, Wang XX, et al. Silencing PinX1 compromises telomere length maintenance as well as tumorigenicity in telomerase-positive human cancer cells. Cancer Res. 2009;69:75–83.CrossRefPubMed
11.
Zhang B, Qian D, Ma HH, Jin R, Yang PX, Cai MY, Liu YH, Liao YJ, Deng HX, Mai SJ, et al. Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation. Oncogene. 2012;31:1–12.CrossRefPubMed
12.
Zuo J, Wang DH, Zhang YJ, Liu L, Liu FL, Liu W. Expression and mechanism of PinX1 and telomerase activity in the carcinogenesis of esophageal epithelial cells. Oncol Rep. 2013;30:1823–31.PubMed
13.
Song H, Li Y, Chen G, Xing Z, Zhao J, Yokoyama KK, Li T, Zhao M. Human MCRS2, a cell-cycle-dependent protein, associates with LPTS/PinX1 and reduces the telomere length. Biochem Biophys Res Commun. 2004;316:1116–23.CrossRefPubMed
14.
Yuan K, Li N, Jiang K, Zhu T, Huo Y, Wang C, Lu J, Shaw A, Thomas K, Zhang J, et al. PinX1 is a novel microtubule-binding protein essential for accurate chromosome segregation. J Biol Chem. 2009;284:23072–82.CrossRefPubMedPubMedCentral
15.
16.
Qian D, Zhang B, He LR, Cai MY, Mai SJ, Liao YJ, Liu YH, Lin MC, Bian XW, Zeng YX, et al. The telomere/telomerase binding factor PinX1 is a new target to improve the radiotherapy effect of oesophageal squamous cell carcinomas. J Pathol. 2013;229:765–74.CrossRefPubMed
17.
Li JP, Zhu SW, Chen YH, Wang XL, Gao X. Suppression of PinX1 resulted in telomere dysfunction and enhanced radiosensitivity in osteosarcoma cell lines. Neoplasma. 2015;62:887–93.CrossRefPubMed
18.
Tian XP, Qian D, He LR, Huang H, Mai SJ, Li CP, Huang XX, Cai MY, Liao YJ, Kung HF, et al. The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas. Cancer Lett. 2014;353:104–14.CrossRefPubMed
19.
Shi R, Zhao Z, Zhou H, Wei M, Ma WL, Zhou JY, Tan WL. Reduced expression of PinX1 correlates to progressive features in patients with prostate cancer. Cancer Cell Int. 2014;14:46.CrossRefPubMedPubMedCentral
20.
Cai MY, Zhang B, He WP, Yang GF, Rao HL, Rao ZY, Wu QL, Guan XY, Kung HF, Zeng YX, Xie D. Decreased expression of PinX1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma. Cancer Sci. 2010;101:1543–9.CrossRefPubMed
21.
Ma Y, Wu L, Liu C, Xu L, Li D, Li JC. 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;135:431–7.CrossRefPubMed
22.
Li HL, Han L, Chen HR, Meng F, Liu QH, Pan ZQ, Bai J, Zheng JN. PinX1 serves as a potential prognostic indicator for clear cell renal cell carcinoma and inhibits its invasion and metastasis by suppressing MMP-2 via NF-kappaB-dependent transcription. Oncotarget. 2015;6:21406–20.CrossRefPubMedPubMedCentral
23.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:l1.CrossRef
24.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.CrossRefPubMed
25.
Shi R, Zhou JY, Zhou H, Zhao Z, Liang SH, Zheng WL, Ma WL. 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.PubMedPubMedCentral
26.
Kondo T, Oue N, Mitani Y, Kuniyasu H, Noguchi T, Kuraoka K, Nakayama H, Yasui W. Loss of heterozygosity and histone hypoacetylation of the PINX1 gene are associated with reduced expression in gastric carcinoma. Oncogene. 2005;24:157–64.CrossRefPubMed
27.
Akiyama Y, Maesawa C, Wada K, Fujisawa K, Itabashi T, Noda Y, Honda T, Sato N, Ishida K, Takagane A, Saito K, Masuda T. Human PinX1, a potent telomerase inhibitor, is not involved in human gastrointestinal tract carcinoma. Oncol Rep. 2004;11:871–4.PubMed
28.
Hawkins GA, Chang BL, Zheng SL, Isaacs SD, Wiley KE, Bleecker ER, Walsh PC, Meyers DA, Xu J, Isaacs WB. Mutational analysis of PINX1 in hereditary prostate cancer. Prostate. 2004;60:298–302.CrossRefPubMed
29.
Kim MS, Kim SS, Yoo NJ, Lee SH. Somatic mutation of PINX1 gene is rare in common solid cancers. APMIS. 2012;120:770–1.CrossRefPubMed
30.
Klonowska K, Czubak K, Wojciechowska M, Handschuh L, Zmienko A, Figlerowicz M, Dams-Kozlowska H, Kozlowski P. Oncogenomic portals for the visualization and analysis of genome-wide cancer data. Oncotarget. 2016;7:176–92.PubMed
31.
Baichuan L, Cao S, Liu Y. LPTS: A Novel Tumor Suppressor Gene and a Promising Drug Target for Cancer Intervention. Recent Pat Anticancer Drug Discov. 2015;10:170–5.CrossRefPubMed
32.
Mei PJ, Chen YS, Du Y, Bai J, Zheng JN. PinX1 inhibits cell proliferation, migration and invasion in glioma cells. Med Oncol. 2015;32:73.CrossRefPubMed
33.
Cheung DH, Kung HF, Huang JJ, Shaw PC. PinX1 is involved in telomerase recruitment and regulates telomerase function by mediating its localization. FEBS Lett. 2012;586:3166–71.CrossRefPubMed
34.
Shcherba M, Liang Y, Fernandes D, Perez-Soler R, Cheng H. Cell cycle inhibitors for the treatment of NSCLC. Expert Opin Pharmacother. 2014;15:991–1004.CrossRefPubMed
35.
Waite KA, Eng C. From developmental disorder to heritable cancer: it’s all in the BMP/TGF-beta family. Nat Rev Genet. 2003;4:763–73.CrossRefPubMed
36.
Shen Z, Kauttu T, Cao J, Seppanen H, Vainionpaa S, Ye Y, Wang S, Mustonen H, Puolakkainen P. Macrophage coculture enhanced invasion of gastric cancer cells via TGF-beta and BMP pathways. Scand J Gastroenterol. 2013;48:466–72.CrossRefPubMed
37.
Alarcon C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ, et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell. 2009;139:757–69.CrossRefPubMedPubMedCentral
38.
Deng T, Lin D, Zhang M, Zhao Q, Li W, Zhong B, Deng Y, Fu X. Differential expression of bone morphogenetic protein 5 in human lung squamous cell carcinoma and adenocarcinoma. Acta Biochim Biophys Sin (Shanghai). 2015;47:557–63.CrossRef
Metadata
Title
The depletion of PinX1 involved in the tumorigenesis of non-small cell lung cancer promotes cell proliferation via p15/cyclin D1 pathway
Authors
Xiao-Peng Tian
Xiao-Han Jin
Mei Li
Wei-Juan Huang
Dan Xie
Jia-Xing Zhang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0637-4

Other articles of this Issue 1/2017

Molecular Cancer 1/2017 Go to the issue

Research

SPAG6 and L1TD1 are transcriptionally regulated by DNA methylation in non-small cell lung cancers

Review

Linking long non-coding RNAs and SWI/SNF complexes to chromatin remodeling in cancer

Letter to the Editor

Dual role for p16 in the metastasis process of HPV positive head and neck cancers

Research

Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ

Erratum

Erratum to: Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p

Letter to the Editor

Profiling, clinicopathological correlation and functional validation of specific long non-coding RNAs for hepatocellular carcinoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits