Skip to main content
Top
Published in: Journal of Translational Medicine 1/2015

Open Access 01-12-2015 | Research

PIWIL2 promotes progression of non-small cell lung cancer by inducing CDK2 and Cyclin A expression

Authors: Xiaohan Qu, Jinlu Liu, Xinwen Zhong, Xi Li, Qigang Zhang

Published in: Journal of Translational Medicine | Issue 1/2015

Login to get access

Abstract

Background

PIWI proteins have important roles in tumorigenesis due to their interaction with piRNAs. Recent studies suggest that PIWI proteins affect prognosis of various cancers.

Methods

In the present study, PIWI genes expression was assayed in non-small cell lung cancer (NSCLC). To determine the effects of PIWIL2 on NSCLC cells, overexpression and interference assays were performed using the A549 and H460 cell lines. The tumor formation model was performed to demonstrate the effects of PIWIL2 on tumor formation in vivo.

Results

PIWIL2 was increased both at the RNA and protein level in malignant cancer tissues compared with adjacent normal tissue. Moreover, increased PIWIL2 gene expression was negatively correlated with prognosis in NSCLC patients. Overexpression and interference of PIWIL2 promoted and depressed cell proliferation, respectively. Meanwhile, PIWIL2 interference arrested cells at the G2/M stage. In addition, we found that CDK2 and Cyclin A expression were correlated with PIWIL2 expression. Moreover, transfection of PIWIL2 promoted tumor growth in nude mice.

Conclusion

Our findings shed light on the function of PIWIL2 in NSCLC and suggest potential prognostic and therapeutic value.
Literature
1.
2.
go back to reference Chang A. Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer. 2011;71:3–10.CrossRefPubMed Chang A. Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer. 2011;71:3–10.CrossRefPubMed
3.
go back to reference Wroblewski JM, Bixby DL, Borowski C, Yannelli JR. Characterization of human non-small cell lung cancer (NSCLC) cell lines for expression of MHC, co-stimulatory molecules and tumor-associated antigens. Lung Cancer. 2001;33:181–94.CrossRefPubMed Wroblewski JM, Bixby DL, Borowski C, Yannelli JR. Characterization of human non-small cell lung cancer (NSCLC) cell lines for expression of MHC, co-stimulatory molecules and tumor-associated antigens. Lung Cancer. 2001;33:181–94.CrossRefPubMed
4.
go back to reference Rivera MP. Multimodality therapy in the treatment of lung cancer. Semin Respir Crit Care Med. 2004;25 Suppl 1:3–10.CrossRefPubMed Rivera MP. Multimodality therapy in the treatment of lung cancer. Semin Respir Crit Care Med. 2004;25 Suppl 1:3–10.CrossRefPubMed
5.
go back to reference Weinstein IB, Joe AK. Mechanisms of disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. 2006;3:448–57.CrossRefPubMed Weinstein IB, Joe AK. Mechanisms of disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. 2006;3:448–57.CrossRefPubMed
6.
go back to reference Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S. Highly tumorigenic lung cancer CD133 + cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci USA. 2009;106:16281–6.CrossRefPubMedPubMedCentral Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S. Highly tumorigenic lung cancer CD133 + cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci USA. 2009;106:16281–6.CrossRefPubMedPubMedCentral
8.
go back to reference Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, Sebree R, Rodgers K, Hooker CM, Franco N. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1:598–607.CrossRefPubMedPubMedCentral Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, Sebree R, Rodgers K, Hooker CM, Franco N. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1:598–607.CrossRefPubMedPubMedCentral
9.
go back to reference Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27–40.CrossRefPubMedPubMedCentral Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27–40.CrossRefPubMedPubMedCentral
12.
go back to reference Chénais B. Transposable elements and human cancer: a causal relationship? Biochim Biophys Acta. 2013;1835:28–35.PubMed Chénais B. Transposable elements and human cancer: a causal relationship? Biochim Biophys Acta. 2013;1835:28–35.PubMed
13.
go back to reference Laird PW, Jaenisch R. The role of DNA methylation in cancer genetics and epigenetics. Annu Rev Genet. 1996;30:441–64.CrossRefPubMed Laird PW, Jaenisch R. The role of DNA methylation in cancer genetics and epigenetics. Annu Rev Genet. 1996;30:441–64.CrossRefPubMed
14.
go back to reference Esteller M, Herman JG. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J Pathol. 2002;196:1–7.CrossRefPubMed Esteller M, Herman JG. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J Pathol. 2002;196:1–7.CrossRefPubMed
15.
go back to reference Aravin AA, Hannon GJ, Brennecke J. The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science. 2007;318:761–4.CrossRefPubMed Aravin AA, Hannon GJ, Brennecke J. The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science. 2007;318:761–4.CrossRefPubMed
16.
go back to reference Slotkin RK, Martienssen R. Transposable elements and the epigenetic regulation of the genome. Nat Rev Genet. 2007;8:272–85.CrossRefPubMed Slotkin RK, Martienssen R. Transposable elements and the epigenetic regulation of the genome. Nat Rev Genet. 2007;8:272–85.CrossRefPubMed
17.
go back to reference Siomi MC, Sato K, Pezic D, Aravin AA. PIWI-interacting small RNAs: the vanguard of genome defence. Nat Rev Mol Cell Biol. 2011;12:246–58.CrossRefPubMed Siomi MC, Sato K, Pezic D, Aravin AA. PIWI-interacting small RNAs: the vanguard of genome defence. Nat Rev Mol Cell Biol. 2011;12:246–58.CrossRefPubMed
19.
go back to reference Wang D-W, Wang Z-H, Wang L-L, Song Y, Zhang G-Z. Overexpression of hiwi promotes growth of human breast cancer cells. Asian Pac J Cancer Prev. 2013;15:7553–8.CrossRef Wang D-W, Wang Z-H, Wang L-L, Song Y, Zhang G-Z. Overexpression of hiwi promotes growth of human breast cancer cells. Asian Pac J Cancer Prev. 2013;15:7553–8.CrossRef
20.
go back to reference Wang Y, Liu Y, Shen X, Zhang X, Chen X, Yang C, Gao H. The PIWI protein acts as a predictive marker for human gastric cancer. Int J Clin Exp Pathol. 2012;5:315.PubMedPubMedCentral Wang Y, Liu Y, Shen X, Zhang X, Chen X, Yang C, Gao H. The PIWI protein acts as a predictive marker for human gastric cancer. Int J Clin Exp Pathol. 2012;5:315.PubMedPubMedCentral
21.
go back to reference Cui L, Lou Y, Zhang X, Zhou H, Deng H, Song H, Yu X, Xiao B, Wang W, Guo J. Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using piRNAs as markers. Clin Biochem. 2011;44:1050–7.CrossRefPubMed Cui L, Lou Y, Zhang X, Zhou H, Deng H, Song H, Yu X, Xiao B, Wang W, Guo J. Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using piRNAs as markers. Clin Biochem. 2011;44:1050–7.CrossRefPubMed
22.
go back to reference Girard A, Sachidanandam R, Hannon GJ, Carmell MA. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature. 2006;442:199–202.PubMed Girard A, Sachidanandam R, Hannon GJ, Carmell MA. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature. 2006;442:199–202.PubMed
23.
go back to reference Qiao D, Zeeman A-M, Deng W, Looijenga L, Lin H. Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas. Oncogene. 2002;21:3988–99.CrossRefPubMed Qiao D, Zeeman A-M, Deng W, Looijenga L, Lin H. Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas. Oncogene. 2002;21:3988–99.CrossRefPubMed
24.
go back to reference Sasaki T, Shiohama A, Minoshima S, Shimizu N. Identification of eight members of the Argonaute family in the human genome. Genomics. 2003;82:323–30.CrossRefPubMed Sasaki T, Shiohama A, Minoshima S, Shimizu N. Identification of eight members of the Argonaute family in the human genome. Genomics. 2003;82:323–30.CrossRefPubMed
25.
go back to reference Liu W, Jiang X, Zhang Z. Expression of PSCA, PIWIL1, and TBX2 in endometrial adenocarcinoma. Onkologie. 2010;33:241–5.CrossRefPubMed Liu W, Jiang X, Zhang Z. Expression of PSCA, PIWIL1, and TBX2 in endometrial adenocarcinoma. Onkologie. 2010;33:241–5.CrossRefPubMed
26.
go back to reference Lee JH, Jung C, Javadian-Elyaderani P, Schweyer S, Schütte D, Shoukier M, Karimi-Busheri F, Weinfeld M, Rasouli-Nia A, Hengstler JG. Pathways of proliferation and antiapoptosis driven in breast cancer stem cells by stem cell protein piwil2. Cancer Res. 2010;70:4569–79.CrossRefPubMed Lee JH, Jung C, Javadian-Elyaderani P, Schweyer S, Schütte D, Shoukier M, Karimi-Busheri F, Weinfeld M, Rasouli-Nia A, Hengstler JG. Pathways of proliferation and antiapoptosis driven in breast cancer stem cells by stem cell protein piwil2. Cancer Res. 2010;70:4569–79.CrossRefPubMed
27.
go back to reference Liu JJ, Shen R, Chen L, Ye Y, He G, Hua K, Jarjoura D, Nakano T, Ramesh GK, Shapiro CL. Piwil2 is expressed in various stages of breast cancers and has the potential to be used as a novel biomarker. Int J Clin Exp Pathol. 2010;3:328.PubMedPubMedCentral Liu JJ, Shen R, Chen L, Ye Y, He G, Hua K, Jarjoura D, Nakano T, Ramesh GK, Shapiro CL. Piwil2 is expressed in various stages of breast cancers and has the potential to be used as a novel biomarker. Int J Clin Exp Pathol. 2010;3:328.PubMedPubMedCentral
28.
go back to reference He G, Chen L, Ye Y, Xiao Y, Hua K, Jarjoura D, Nakano T, Barsky SH, Shen R, Gao J-X. Piwil2 expressed in various stages of cervical neoplasia is a potential complementary marker for p16INK4a. Am J Transl Res. 2010;2:156.PubMedPubMedCentral He G, Chen L, Ye Y, Xiao Y, Hua K, Jarjoura D, Nakano T, Barsky SH, Shen R, Gao J-X. Piwil2 expressed in various stages of cervical neoplasia is a potential complementary marker for p16INK4a. Am J Transl Res. 2010;2:156.PubMedPubMedCentral
30.
go back to reference Yao Y, Li C, Zhou X, Zhang Y, Lu Y, Chen J, Zheng X, Tao D, Liu Y, Ma Y. PIWIL2 induces c-Myc expression by interacting with NME2 and regulates c-Myc-mediated tumor cell proliferation. Oncotarget. 2014;5:8466.PubMedPubMedCentral Yao Y, Li C, Zhou X, Zhang Y, Lu Y, Chen J, Zheng X, Tao D, Liu Y, Ma Y. PIWIL2 induces c-Myc expression by interacting with NME2 and regulates c-Myc-mediated tumor cell proliferation. Oncotarget. 2014;5:8466.PubMedPubMedCentral
31.
go back to reference Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982;6:655–64.CrossRefPubMed Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982;6:655–64.CrossRefPubMed
32.
go back to reference Chapman EJ, Carrington JC. Specialization and evolution of endogenous small RNA pathways. Nat Rev Genet. 2007;8:884–96.CrossRefPubMed Chapman EJ, Carrington JC. Specialization and evolution of endogenous small RNA pathways. Nat Rev Genet. 2007;8:884–96.CrossRefPubMed
33.
34.
go back to reference Aravin A, Gaidatzis D, Pfeffer S, Lagos-Quintana M, Landgraf P, Iovino N, Morris P, Brownstein MJ, Kuramochi-Miyagawa S, Nakano T. A novel class of small RNAs bind to MILI protein in mouse testes. Nature. 2006;442:203–7.PubMed Aravin A, Gaidatzis D, Pfeffer S, Lagos-Quintana M, Landgraf P, Iovino N, Morris P, Brownstein MJ, Kuramochi-Miyagawa S, Nakano T. A novel class of small RNAs bind to MILI protein in mouse testes. Nature. 2006;442:203–7.PubMed
35.
go back to reference Cardoso MC, Leonhardt H, Nadal-Ginard B. Reversal of terminal differentiation and control of DNA replication: cyclin A and Cdk2 specifically localize at subnuclear sites of DNA replication. Cell. 1993;74:979–92.CrossRefPubMed Cardoso MC, Leonhardt H, Nadal-Ginard B. Reversal of terminal differentiation and control of DNA replication: cyclin A and Cdk2 specifically localize at subnuclear sites of DNA replication. Cell. 1993;74:979–92.CrossRefPubMed
36.
go back to reference Katayose Y, Kim M, Rakkar AN, Li Z, Cowan KH, Seth P. Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res. 1997;57:5441–5.PubMed Katayose Y, Kim M, Rakkar AN, Li Z, Cowan KH, Seth P. Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res. 1997;57:5441–5.PubMed
37.
go back to reference Zhang K, Lu Y, Yang P, Li C, Sun H, Tao D, Liu Y, Zhang S, Ma Y. HILI inhibits TGF-β signaling by interacting with Hsp90 and promoting TβR degradation. PLoS One. 2012;7:e41973.CrossRefPubMedPubMedCentral Zhang K, Lu Y, Yang P, Li C, Sun H, Tao D, Liu Y, Zhang S, Ma Y. HILI inhibits TGF-β signaling by interacting with Hsp90 and promoting TβR degradation. PLoS One. 2012;7:e41973.CrossRefPubMedPubMedCentral
39.
go back to reference Lim SL, Ricciardelli C, Oehler MK, Tan IMDA, Russell D, Grützner F. Overexpression of piRNA pathway genes in epithelial ovarian cancer. PLoS One. 2014;9:e99687.CrossRefPubMedPubMedCentral Lim SL, Ricciardelli C, Oehler MK, Tan IMDA, Russell D, Grützner F. Overexpression of piRNA pathway genes in epithelial ovarian cancer. PLoS One. 2014;9:e99687.CrossRefPubMedPubMedCentral
40.
go back to reference Reeves ME, Firek M, Chen S-T, Amaar YG. Evidence that RASSF1C stimulation of lung cancer cell proliferation depends on IGFBP-5 and PIWIL1 Expression levels. PLoS One. 2014;9:e101679.CrossRefPubMedPubMedCentral Reeves ME, Firek M, Chen S-T, Amaar YG. Evidence that RASSF1C stimulation of lung cancer cell proliferation depends on IGFBP-5 and PIWIL1 Expression levels. PLoS One. 2014;9:e101679.CrossRefPubMedPubMedCentral
41.
go back to reference Pan Y, Hu M, Liang H. Wang J-j, Tang L-j: The expression of the PIWI family members miwi and mili in mice testis is negatively affected by estrogen. Cell Tissue Res. 2012;350:177–81.CrossRefPubMed Pan Y, Hu M, Liang H. Wang J-j, Tang L-j: The expression of the PIWI family members miwi and mili in mice testis is negatively affected by estrogen. Cell Tissue Res. 2012;350:177–81.CrossRefPubMed
42.
go back to reference Houwing S, Kamminga LM, Berezikov E, Cronembold D, Girard A, van den Elst H, Filippov DV, Blaser H, Raz E, Moens CB, et al. A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in Zebrafish. Cell. 2007;129:69–82.CrossRefPubMed Houwing S, Kamminga LM, Berezikov E, Cronembold D, Girard A, van den Elst H, Filippov DV, Blaser H, Raz E, Moens CB, et al. A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in Zebrafish. Cell. 2007;129:69–82.CrossRefPubMed
43.
go back to reference Houwing S, Kamminga L, Berezikov E, Cronembold D, Girard A, Elst H, Filippov D, Blaser H, Raz E, Moens C, et al. A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in Zebrafish. Cell. 2007;129:69–82.CrossRefPubMed Houwing S, Kamminga L, Berezikov E, Cronembold D, Girard A, Elst H, Filippov D, Blaser H, Raz E, Moens C, et al. A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in Zebrafish. Cell. 2007;129:69–82.CrossRefPubMed
44.
go back to reference Kuramochi-Miyagawa S, Kimura T, Ijiri TW, Isobe T, Asada N, Fujita Y, Ikawa M, Iwai N, Okabe M, Deng W. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development. 2004;131:839–49.CrossRefPubMed Kuramochi-Miyagawa S, Kimura T, Ijiri TW, Isobe T, Asada N, Fujita Y, Ikawa M, Iwai N, Okabe M, Deng W. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development. 2004;131:839–49.CrossRefPubMed
45.
go back to reference Zhou Y, Zhong H, Liu S, Yu F, Hu J, Zhang C, Tao M, Liu Y. Elevated expression of Piwi and piRNAs in ovaries of triploid crucian carp. Mol Cell Endocrinol. 2014;383:1–9.CrossRefPubMed Zhou Y, Zhong H, Liu S, Yu F, Hu J, Zhang C, Tao M, Liu Y. Elevated expression of Piwi and piRNAs in ovaries of triploid crucian carp. Mol Cell Endocrinol. 2014;383:1–9.CrossRefPubMed
46.
go back to reference Lau NC, Ohsumi T, Borowsky M, Kingston RE, Blower MD. Systematic and single cell analysis of Xenopus Piwi-interacting RNAs and Xiwi. EMBO J. 2009;28:2945–58.CrossRefPubMedPubMedCentral Lau NC, Ohsumi T, Borowsky M, Kingston RE, Blower MD. Systematic and single cell analysis of Xenopus Piwi-interacting RNAs and Xiwi. EMBO J. 2009;28:2945–58.CrossRefPubMedPubMedCentral
Metadata
Title
PIWIL2 promotes progression of non-small cell lung cancer by inducing CDK2 and Cyclin A expression
Authors
Xiaohan Qu
Jinlu Liu
Xinwen Zhong
Xi Li
Qigang Zhang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2015
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-015-0666-y

Other articles of this Issue 1/2015

Journal of Translational Medicine 1/2015 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.