Ubc9 promotes invasion and metastasis of lung cancer cells

Li,Hui; Niu,Huiyan; Peng,Yang; Wang,Jiahe; He,Ping

doi:10.3892/or.2013.2268

Ubc9 promotes invasion and metastasis of lung cancer cells

Authors:
- Hui Li
- Huiyan Niu
- Yang Peng
- Jiahe Wang
- Ping He
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Affiliations: Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: February 1, 2013 https://doi.org/10.3892/or.2013.2268
Pages: 1588-1594

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Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide. The mortality is high mainly due to the lack of known effective screening procedures; there is a high tendency for early spread and systemic therapies do not cure metastatic disease. Thus, it is important to investigate the molecular mechanism(s) of lung cancer development and, specifically, to identify an effective method by which to inhibit the invasion and metastasis of lung cancer. Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays a key role in tumorigenesis. Whether Ubc9 is involved in the invasion and metastasis of lung cancer remains unknown. Herein, we report that Ubc9 exhibits an important role in lung cancer invasion and metastasis. We first investigated the biological effect of Ubc9 on lung cancer by cloning the Ubc9 gene into a eukaryotic expression plasmid and stably expressing it in the human small cell lung cancer cell line NCI-H446 in order to observe any biological changes. We further analyzed the effect of Ubc9 in an in vivo experiment, injecting NCI-H446 cells stably overexpressing Ubc9 into nude mice and analyzing their metastatic ability. Our results demonstrated that Ubc9 is expressed at higher levels in primary lung cancer tissue and metastatic nodules as compared to premalignant and/or normal tissue. Furthermore, we demonstrated that upregulation of Ubc9 expression promotes migration and invasion. Ubc9 likely plays an important role in cancer progression by promoting invasion and metastasis in lung cancer.

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1	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
2	Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun M: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar
3	Hirsch FR, Franklin WA, Gazdar AF and Bunn PA Jr: Early detection of lung cancer: clinical perspectives of recent advances in biology and radiology. Clin Cancer Res. 7:5–22. 2001.PubMed/NCBI
4	Erridge S, Moller H, Price A and Brewster D: International comparisons of survival from lung cancer: pitfalls and warnings. Nat Clin Pract Oncol. 4:570–577. 2007. View Article : Google Scholar : PubMed/NCBI
5	Kligerman S and White C: Epidemiology of lung cancer in women: risk factors, survival, and screening. AJR Am J Roentgenol. 196:287–295. 2011. View Article : Google Scholar : PubMed/NCBI
6	Cagle PT, Allen TC, Dacic S, Beasley MB, Borczuk AC, Chirieac LR, Laucirica R, Ro JY and Kerr KM: Revolution in lung cancer: new challenges for the surgical pathologist. Arch Pathol Lab Med. 135:110–116. 2011.PubMed/NCBI
7	Steeg PS: Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer. 3:55–63. 2003. View Article : Google Scholar : PubMed/NCBI
8	Muller S, Hoege C, Pyrowolakis G and Jentsch S: SUMO, ubiquitin’s mysterious cousin. Nat Rev Mol Cell Biol. 2:202–210. 2001.
9	Gill G: SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev. 18:2046–2059. 2004. View Article : Google Scholar : PubMed/NCBI
10	Hay RT: SUMO: a history of modification. Mol Cell. 18:1–12. 2005. View Article : Google Scholar : PubMed/NCBI
11	Lin D, Tatham MH, Yu B, Kim S, Hay RT and Chen Y: Identification of a substrate recognition site on Ubc9. J Biol Chem. 277:21740–21748. 2002. View Article : Google Scholar : PubMed/NCBI
12	Duan X, Trent JO and Ye H: Targeting the SUMO E2 conjugating enzyme Ubc9 interaction for anti-cancer drug design. Anticancer Agents Med Chem. 9:51–54. 2009. View Article : Google Scholar : PubMed/NCBI
13	Niedenthal R: Ubc9 fusion-directed SUMOylation (UFDS). Biochem Soc Trans. 35:1430–1432. 2007. View Article : Google Scholar
14	Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM and Jackson SP: Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature. 462:935–939. 2009. View Article : Google Scholar : PubMed/NCBI
15	Vertegaal AC: SUMO chains: polymeric signals. Biochem Soc Trans. 38:46–49. 2010. View Article : Google Scholar : PubMed/NCBI
16	Ahn JH, Xu Y, Jang WJ, Matunis MJ and Hayward GS: Evaluation of interactions of human cytomegalovirus immediate-early IE2 regulatory protein with small ubiquitin-like modifiers and their conjugation enzyme Ubc9. J Virol. 75:3859–3872. 2001. View Article : Google Scholar : PubMed/NCBI
17	Moschos SJ, Smith AP, Mandic M, et al: SAGE and antibody array analysis of melanoma-infiltrated lymph nodes: identification of Ubc9 as an important molecule in advanced-stage melanomas. Oncogene. 26:4216–4225. 2007. View Article : Google Scholar
18	Wu F, Zhu S, Ding Y, Beck WT and Mo YY: MicroRNA-mediated regulation of Ubc9 expression in cancer cells. Clin Cancer Res. 15:1550–1557. 2009. View Article : Google Scholar : PubMed/NCBI
19	Johnson ES: Protein modification by SUMO. Annu Rev Biochem. 73:355–382. 2004. View Article : Google Scholar
20	Geiss-Friedlander R and Melchior F: Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol. 8:947–956. 2007. View Article : Google Scholar : PubMed/NCBI
21	Driscoll JJ, Pelluru D, Lefkimmiatis K, et al: The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome. Blood. 115:2827–2834. 2010. View Article : Google Scholar : PubMed/NCBI
22	Moschos SJ, Jukic DM, Athanassiou C, et al: Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues. Hum Pathol. 41:1286–1298. 2010. View Article : Google Scholar : PubMed/NCBI
23	Vertegaal AC: Small ubiquitin-related modifiers in chains. Biochem Soc Trans. 35:1422–1423. 2007. View Article : Google Scholar : PubMed/NCBI
24	Wu SY and Chiang CM: p53 sumoylation: mechanistic insights from reconstitution studies. Epigenetics. 4:445–451. 2009. View Article : Google Scholar : PubMed/NCBI
25	Nowak M and Hammerschmidt M: Ubc9 regulates mitosis and cell survival during zebrafish development. Mol Biol Cell. 17:5324–5336. 2006. View Article : Google Scholar : PubMed/NCBI
26	Fu M, Wang C, Wang J, Zhang X, et al: Androgen receptor acetylation governs transactivation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Mol Cell Biol. 22:3373–3388. 2002. View Article : Google Scholar
27	Vatsyayan J, Qing G, Xiao G and Hu J: SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing. EMBO Rep. 9:885–890. 2008. View Article : Google Scholar : PubMed/NCBI
28	Moschos SJ and Mo YY: Role of SUMO/Ubc9 in DNA damage repair and tumorigenesis. J Mol Histol. 37:309–319. 2006. View Article : Google Scholar : PubMed/NCBI
29	Mo YY and Moschos SJ: Targeting Ubc9 for cancer therapy. Expert Opin Ther Targets. 9:1203–1216. 2005. View Article : Google Scholar : PubMed/NCBI
30	Lu Z, Wu H and Mo YY: Regulation of bcl-2 expression by Ubc9. Exp Cell Res. 312:1865–1875. 2006. View Article : Google Scholar : PubMed/NCBI
31	Mo YY, Yu Y, Theodosiou E, Ee PL and Beck WT: A role for Ubc9 in tumorigenesis. Oncogene. 24:2677–2683. 2005. View Article : Google Scholar : PubMed/NCBI