ETS2 Mediated Tumor Suppressive Function and MET Oncogene Inhibition in Human Non-small Cell Lung Cancer

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2013 May 11

PMID 23659968

Citations 84

Authors

Mohamed Kabbout

Melinda M Garcia

Junya Fujimoto

Diane D Liu

Denise Woods

Chi-Wan Chow

Gabriela Mendoza

Amin A Momin

Brian P James

Luisa Solis

Carmen Behrens

J Jack Lee

Ignacio I Wistuba

Humam Kadara

Affiliations

Soon will be listed here.

Abstract

Purpose: The ETS2 transcription factor is an evolutionarily conserved gene that is deregulated in cancer. We analyzed the transcriptome of lung adenocarcinomas and normal lung tissue by expression profiling and found that ETS2 was significantly downregulated in adenocarcinomas. In this study, we probed the yet unknown functional role of ETS2 in lung cancer pathogenesis.

Experimental Design: Lung adenocarcinomas (n = 80) and normal lung tissues (n = 30) were profiled using the Affymetrix Human Gene 1.0 ST platform. Immunohistochemical (IHC) analysis was conducted to determine ETS2 protein expression in non-small cell lung cancer (NSCLC) histologic tissue specimens (n = 201). Patient clinical outcome, based on ETS2 IHC expression, was statistically assessed using the log-rank and Kaplan-Meier tests. RNA interference and overexpression strategies were used to assess the effects of ETS2 expression on the transcriptome and on various malignant phenotypes.

Results: ETS2 expression was significantly reduced in lung adenocarcinomas compared with normal lung (P < 0.001). Low ETS2 IHC expression was a significant predictor of shorter time to recurrence in NSCLC (P = 0.009, HR = 1.89) and adenocarcinoma (P = 0.03, HR = 1.86). Moreover, ETS2 was found to significantly inhibit lung cancer cell growth, migration, and invasion (P < 0.05), and microarray and pathways analysis revealed significant (P < 0.001) activation of the HGF pathway following ETS2 knockdown. In addition, ETS2 was found to suppress MET phosphorylation and knockdown of MET expression significantly attenuated (P < 0.05) cell invasion mediated by ETS2-specific siRNA. Furthermore, knockdown of ETS2 augmented HGF-induced MET phosphorylation, cell migration, and invasion.

Conclusion(s): Our findings point to a tumor suppressor role for ETS2 in human NSCLC pathogenesis through inhibition of the MET proto-oncogene.

Citing Articles

CENPF (+) cancer cells promote malignant progression of early-stage TP53 mutant lung adenocarcinoma.

Xiong Y, Lei J, Wen M, Ma Y, Zhao J, Tian Y Oncogenesis. 2025; 14(1):5.

PMID: 40044674 PMC: 11882812. DOI: 10.1038/s41389-025-00546-5.

Identification of the EBF1/ETS2/KLF2-miR-126-Gene Feed-Forward Loop in Breast Carcinogenesis and Stemness.

Gambacurta A, Tullio V, Savini I, Mauriello A, Catani M, Gasperi V Int J Mol Sci. 2025; 26(1.

PMID: 39796183 PMC: 11719960. DOI: 10.3390/ijms26010328.

Unveiling the shared genes between systemic sclerosis and lung cancer.

Pan P, Liu X, Wang Y, Wang H, Xu C, Lu J Front Med (Lausanne). 2025; 11:1431642.

PMID: 39744538 PMC: 11688373. DOI: 10.3389/fmed.2024.1431642.

Rab3B Proteins: Cellular Functions, Regulatory Mechanisms, and Potential as a Cancer Therapy Target.

Xu J, Zhang H, Yang L Cell Biochem Biophys. 2024; 83(1):263-277.

PMID: 39320613 DOI: 10.1007/s12013-024-01549-6.

Molecular pathway of anticancer effect of next-generation HSP90 inhibitors XL-888 and Debio0932 in neuroblastoma cell line.

Kaplan O, Tosun N Med Oncol. 2024; 41(8):194.

PMID: 38958814 PMC: 11222184. DOI: 10.1007/s12032-024-02428-z.

References

Ekerot M, Stavridis M, Delavaine L, Mitchell M, Staples C, Owens D . Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J. 2008; 412(2):287-98. PMC: 2474557. DOI: 10.1042/BJ20071512. View

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

Arriola E, Canadas I, Arumi-Uria M, Domine M, Lopez-Vilarino J, Arpi O . MET phosphorylation predicts poor outcome in small cell lung carcinoma and its inhibition blocks HGF-induced effects in MET mutant cell lines. Br J Cancer. 2011; 105(6):814-23. PMC: 3171012. DOI: 10.1038/bjc.2011.298. View

Bottaro D, Rubin J, Faletto D, Chan A, Kmiecik T, Woude G . Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991; 251(4995):802-4. DOI: 10.1126/science.1846706. View

Christensen J, Schreck R, Burrows J, Kuruganti P, Chan E, Le P . A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 2003; 63(21):7345-55. View

Yamamoto Y, Nishimura N, Morimoto S, Kitamura H, Manabe S, Kanayama H . Distinct roles of Rab3B and Rab13 in the polarized transport of apical, basolateral, and tight junctional membrane proteins to the plasma membrane. Biochem Biophys Res Commun. 2003; 308(2):270-5. DOI: 10.1016/s0006-291x(03)01358-5. View

Song L, Webb N, Song Y, Tuan R . Identification and functional analysis of candidate genes regulating mesenchymal stem cell self-renewal and multipotency. Stem Cells. 2006; 24(7):1707-18. DOI: 10.1634/stemcells.2005-0604. View

Landi M, Dracheva T, Rotunno M, Figueroa J, Liu H, Dasgupta A . Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival. PLoS One. 2008; 3(2):e1651. PMC: 2249927. DOI: 10.1371/journal.pone.0001651. View

Munera J, Cecena G, Jedlicka P, Wankell M, Oshima R . Ets2 regulates colonic stem cells and sensitivity to tumorigenesis. Stem Cells. 2011; 29(3):430-9. PMC: 3339631. DOI: 10.1002/stem.599. View

10.

Tang X, Kadara H, Behrens C, Liu D, Xiao Y, Rice D . Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC: implications in lung cancer pathogenesis and prognosis. Clin Cancer Res. 2011; 17(8):2434-43. PMC: 3078948. DOI: 10.1158/1078-0432.CCR-10-1412. View

11.

Al-Azawi D, Ilroy M, Kelly G, Redmond A, Bane F, Cocchiglia S . Ets-2 and p160 proteins collaborate to regulate c-Myc in endocrine resistant breast cancer. Oncogene. 2007; 27(21):3021-31. DOI: 10.1038/sj.onc.1210964. View

12.

Dulak A, Gubish C, Stabile L, Henry C, Siegfried J . HGF-independent potentiation of EGFR action by c-Met. Oncogene. 2011; 30(33):3625-35. PMC: 3126872. DOI: 10.1038/onc.2011.84. View

13.

Neznanov N, Man A, Yamamoto H, Hauser C, Cardiff R, Oshima R . A single targeted Ets2 allele restricts development of mammary tumors in transgenic mice. Cancer Res. 1999; 59(17):4242-6. View

14.

Nunes-Xavier C, Tarrega C, Cejudo-Marin R, Frijhoff J, Sandin A, Ostman A . Differential up-regulation of MAP kinase phosphatases MKP3/DUSP6 and DUSP5 by Ets2 and c-Jun converge in the control of the growth arrest versus proliferation response of MCF-7 breast cancer cells to phorbol ester. J Biol Chem. 2010; 285(34):26417-30. PMC: 2924073. DOI: 10.1074/jbc.M110.121830. View

15.

Radtke S, Milanovic M, Rosse C, De Rycker M, Lachmann S, Hibbert A . ERK2 but not ERK1 mediates HGF-induced motility in non-small cell lung carcinoma cell lines. J Cell Sci. 2013; 126(Pt 11):2381-91. DOI: 10.1242/jcs.115832. View

16.

Liao Y, Hu L, Tsai K, Wu C, Chan W, Li S . Transcriptional regulation of miR-196b by ETS2 in gastric cancer cells. Carcinogenesis. 2012; 33(4):760-9. PMC: 3324441. DOI: 10.1093/carcin/bgs023. View

17.

Sharrocks A . The ETS-domain transcription factor family. Nat Rev Mol Cell Biol. 2001; 2(11):827-37. DOI: 10.1038/35099076. View

18.

Hever A, Oshima R, Hauser C . Ets2 is not required for Ras or Neu/ErbB-2 mediated cellular transformation in vitro. Exp Cell Res. 2003; 290(1):132-43. DOI: 10.1016/s0014-4827(03)00315-x. View

19.

Hsu T, Trojanowska M, Watson D . Ets proteins in biological control and cancer. J Cell Biochem. 2004; 91(5):896-903. PMC: 2265084. DOI: 10.1002/jcb.20012. View

20.

Siegel R, Naishadham D, Jemal A . Cancer statistics, 2012. CA Cancer J Clin. 2012; 62(1):10-29. DOI: 10.3322/caac.20138. View