Dlc-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas

ABSTRACT The deleted in liver cancer (DLC-1) gene at chromosome 8p21–22 is altered mainly by genomic deletion or aberrant promoter methylation in a large number of human cancers such as

breast, liver, colon and prostate and is known to have an inhibitory effect on breast and liver tumor cell growth. Given the high frequency of deletion involving region 8p21–22 in human

non-small cell lung carcinoma (NSCLC), we examined alterations of DLC-1 in a series of primary tumors and tumor cell lines and tested effects of DLC-1 on tumor cell growth. A significant

decrease or absence of the DLC-1 mRNA expression was found in 95% of primary NSCLC (20/21) and 58% of NSCLC cell lines (11/19). Transcriptional silencing of DLC-1 was primarily associated

with aberrant DNA methylation, rather than genomic deletion as 5-aza-2′-deoxycytidine induced reactivation of DLC-1 expression in 82% (9/11) NSCLC cell lines showing downregulated DLC-1. It

was further evidenced by an aberrant DLC-1 promoter methylation pattern, which was detected by Southern blotting in 73% (8/11) of NSCLC cell lines with downregulation of the gene. The

transfer of DLC-1 into three DLC-1 negative cell lines caused a significant inhibition in cell proliferation and/or a decrease in colony formation. Furthermore, stable transfer of DLC-1

abolished tumorigenicity in nude mice of two cell lines, suggesting that DLC-1 plays a role in NSCLC by acting as a bona fide new tumor suppressor gene. Access through your institution Buy

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access 10 September 2020 REFERENCES * Arbieva ZH, Banerjee K, Kim SY, Edassery SL, Maniatis VS, Horrigan SK and Westbrook CA . (2000). _Genome Res._, 10, 244–257. * Belinsky SA, Palmisano

WA, Gilliland FD, Crooks LA, Divine KK, Winters SA, Grimes MJ, Harms HJ, Tellez CS, Smith TM, Moots PP, Lechner JF, Stidley CA and Crowell RE . (2002). _Cancer Res._, 62, 2370–2377. *

Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, Loncarevic IF, Bohle RM, Harbott J, Repp R, Jaeger U, Viehmann S, Henn T, Korth P, Scharr D and Lampert F . (2000). _Proc. Natl.

Acad. Sci. USA_, 97, 9168–9173. * Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY and Ng IO . (2003). _J. Biol. Chem._, 278, 10824–10830. Article  CAS  Google Scholar  * Doll R and Peto

R . (1981). _J. Natl. Cancer Inst._, 66, 1191–1308. * Fritz G, Just I and Kaina B . (1999). _Int. J. Cancer_, 81, 682–687. Article  CAS  Google Scholar  * Girard L, Zochbauer-Muller S,

Virmani AK, Gazdar AF and Minna JD . (2000). _Cancer Res._, 60, 4894–4906. * Homma Y and Emori Y . (1995). _EMBO J._, 14, 286–291. * Jemal A, Chu KC and Tarone RE . (2001). _J. Natl. Cancer

Inst._, 93, 277–283. * Khosravi-Far R, Solski PA, Clark GJ, Kinch MS and Der CJ . (1995). _Mol. Cell. Biol._, 15, 6443–6453. Article  CAS  Google Scholar  * Kim TY, Jong HS, Song SH,

Dimtchev A, Jeong SJ, Lee JW, Kim NK, Jung M and Bang YJ . (2003). _Oncogene_, 22, 3943–3951. Article  CAS  Google Scholar  * Knudson AG . (1993). _Proc. Natl. Acad. Sci. USA_, 90,

10914–10921. * Kurimoto F, Gemma A, Hosoya Y, Seike M, Takenaka K, Uematsu K, Yoshimura A, Shibuya M and Kudoh S . (2001). _Int. J. Mol. Med._, 8, 89–93. * Minna JD, Fong K, Zochbauer-Muller

S and Gazdar AF . (2002). _Cancer J._, 8, S41–6. * Ng IO, Liang ZD, Cao L and Lee TK . (2000). _Cancer Res._, 60, 6581–6584. * Niklinski J, Niklinska W, Chyczewski L, Becker HD and Pluygers

E . (2001). _Eur. J. Cancer Prev._, 10, 213–226. * Park SW, Durkin ME, Thorgeirsson SS and Popescu NC . (2003). _Int. J. Oncol._, 23, 133–137. * Pei J, Balsara BR, Li W, Litwin S,

Gabrielson E, Feder M, Jen J and Testa JR . (2001). _Genes Chromosomes Cancer_, 31, 282–287. * Plaumann M, Seitz S, Frege R, Estevez-Schwarz L and Scherneck S . (2003). _J. Cancer Res. Clin.

Oncol._, 129, 349–354. * Qiu RG, Chen J, McCormick F and Symons M . (1995). _Proc. Natl. Acad. Sci. USA_, 92, 11781–11785. * Shopland DR . (1995). _Environ. Health Perspect._, 103, 131–142.

* Soria JC, Rodriguez M, Liu DD, Lee JJ, Hong WK and Mao L . (2002). _Cancer Res._, 62, 351–355. * Steenland K, Loomis D, Shy C and Simonsen N . (1996). _Am. J. Ind. Med._, 29, 474–490.

Article  CAS  Google Scholar  * Tikoo A, Czekay S, Viars C, White S, Heath JK, Arden K and Maruta H . (2000). _Gene_, 257, 23–31. Article  CAS  Google Scholar  * Vecchione A, Ishii H, Shiao

YH, Trapasso F, Rugge M, Tamburrino JF, Murakumo Y, Alder H, Croce CM and Baffa R . (2001). _Clin. Cancer Res._, 7, 1546–1552. * Wilson PJ, McGlinn E, Marsh A, Evans T, Arnold J, Wright K,

Biden K, Young J, Wainwright B, Wicking C and Chenevix-Trench G . (2000). _Hum. Mutat._, 15, 156–165. Article  CAS  Google Scholar  * Wistuba II, Behrens C, Virmani AK, Milchgrub S, Syed S,

Lam S, Mackay B, Minna JD and Gazdar AF . (1999). _Cancer Res._, 59, 1973–1979. * Yin XL, Hui AB, Pang JC, Poon WS and Ng HK . (2002). _Cancer Genet. Cytogenet._, 134, 71–76. * Yuan BZ,

Durkin ME and Popescu NC . (2003a). _Cancer Genet. Cytogenet._, 140, 113–117. * Yuan BZ, Miller MJ, Keck CL, Zimonjic DB, Thorgeirsson SS and Popescu NC . (1998). _Cancer Res._, 58,

2196–2199. * Yuan BZ, Zhou X, Durkin ME, Zimonjic DB, Gumundsdottir K, Eyfjord JE, Thorgeirsson SS and Popescu NC . (2003b). _Oncogene_, 22, 445–450. Article  CAS  Google Scholar  * Zheng

SL, Mychaleckyj JC, Hawkins GA, Isaacs SD, Wiley KE, Turner A, Chang BL, von Kap-Herr C, Carpten JD, Pettenati M, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB and Xu J . (2003).

_Mutat. Res._, 528, 45–53. * Zochbauer-Muller S, Fong KM, Maitra A, Lam S, Geradts J, Ashfaq R, Virmani AK, Milchgrub S, Gazdar AF and Minna JD . (2001). _Cancer Res._, 61, 3581–3585. *

Zochbauer-Muller S, Minna JD and Gazdar AF . (2002). _Oncologist_, 7, 451–457. Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Health Effects Laboratory Division,

Laboratory of Genetic Susceptibility, Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, Morgantown, 26505, WV, USA Bao-Zhu Yuan, Amy M

Jefferson, Kimberly T Baldwin & Steven H Reynolds * Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, 20892, MD, USA Snorri S Thorgeirsson & Nicholas C

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THIS ARTICLE CITE THIS ARTICLE Yuan, BZ., Jefferson, A., Baldwin, K. _et al._ DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas. _Oncogene_ 23, 1405–1411

(2004). https://doi.org/10.1038/sj.onc.1207291 Download citation * Received: 08 September 2003 * Revised: 14 October 2003 * Accepted: 16 October 2003 * Published: 08 December 2003 * Issue

Date: 19 February 2004 * DOI: https://doi.org/10.1038/sj.onc.1207291 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry,

a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * DLC-1 * tumor suppressor gene *

non-small cell lung carcinoma * aberrant DNA methylation * tumorigenicity