Abstract
TGF-β is a negative regulator of liver growth. Smad family of genes, as mediators of TGF-β pathway, are candidate tumor suppressor genes in hepatocellular carcinoma (HCC). We studied 35 HCC and non-tumour liver tissues for possible mutations in Smad2 and Smad4 genes. Three tumours displayed somatic mutations; two in Smad4 (Asp332Gly and Cys401Arg) and one in Smad2 (Gln407Arg) genes. All three mutations were A:T → G:C transitions suspected to result from oxidative stress as observed in mitochondrial DNA. These observation demonstrate that TGF-β pathway is altered in hepatocellular carcinoma.
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References
Alexandrow MG and Moses HL. . 1995 Cancer Res. 55: 1452–1457.
Baker JC and Harland RM. . 1997 Curr. Opin. Genet. Dev. 7: 467–473.
De la Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A and Perret C. . 1998 Proc. Natl. Acad. Sci. USA 95: 8847–8851.
De Souza AT, Hankins GR, Washington MK, Orton TC and Jirtle RL. . 1995 Nat. Genet. 11: 447–449.
Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, Tsui LC, Bapat B, Gallinger S, Andrulis IL, Thomsen GH, Wrana JL and Attisano L. . 1996 Cell 86: 543–552.
Fausto N, Laird AD and Webber EM. . 1995 FASEB J. 9: 1527–1535.
Fynan TM and Reiss M. . 1993 Crit. Rev. Onco. 4: 493–540.
Grisham JW. . 1996 Carcinogenesis 18: 59–81.
Gressner AM, Lahme B, Mannherz H-G and Polzar B. . 1997 J. Hepatol. 26: 1079–1092.
Hahn SA, Bartsch D, Schroers A, Galehdari H, Becker M, Ramaswamy A, Schwarte-Waldhoff I, Maschek H and Schmiegel W. . 1998 Cancer Res. 58: 1124–1126.
Hahn SA, Schutte M, Shamsul Hoque ATM, Moskaluk CA, da Costa LT, Rosenblum E., Weinstein CL, Fischer A, Yeo CJ, Hruban RH and Kern SE. . 1996 Science 271: 350–353.
Hata A, Lo RS, Wotton D, Lagna G and Massague J. . 1997 Nature 388: 82–87.
Heldin C-H, Miyazono K and Dijke PT. . 1997 Nature 390: 465–471.
Kawate S, Takenoshita S, Ohwada S, Mogi A, Fukusato T, Makita F, Kuwano H and Morishita Y. . 1999 Int. J. Oncol. 14: 127–131.
Kim SK, Fan Y, Papadimitrakopoulou V, Clayman G, Hittelman WN, Ki Hong W, Lotan R and Mao L. . 1996 Cancer Res. 56: 2519–2521.
Miyamura T and Hirohashi S. . 1990 Proc. Natl. Acad. Sci. USA 87: 6791–6794.
Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T and Nakamura Y. . 1988 Cancer Res. 58: 2524–2527.
Moskaluk CA, Hruban RH, Schutte M, Lietman SA, Symrk T, Fusaro L, Fusaro R, Lynch J, Yeo CJ, Jackson CE, Lynch HT and Kern SE. . 1997 Diag. Mol. Pathol. 6: 85–90.
Nagai H, Pineau P, Tiollais P, Buendia MA and Dejean A. . 1997 Oncogene 14: 2927–2933.
Oberhammer FA, Pavelka M, Sharma S, Tiefenbacher R, Purchio AF, Bursch W and Schulte-Hermann R. . 1992 Proc. Natl. Acad. Sci. USA 89: 5408–5412.
Ozturk M. . 1995 Biology of hepatocellular carcinoma. In: Gastrointestinal Cancers—Biology, diagnosis, and therapy, Rustgi AK (ed).. Lippincott-Raven Publishers: Philadelphia pp. 511–525.
Piao Z, Park CH, Park J-H and Kim H. . 1998 Int J. Cancer 75: 29–33.
Polyak K, Li Y, Zhu H, Lengauer C, Willson JKV, Markowitz SD, Trush MA, Kinzler KW and Vogelstein B. . 1998 Nat. Genet. 20: 291–293.
Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, Wilson JKV, Markowitz SD, Kinzler KW and Vogelstein B. . 1996 Nat. Genet. 13: 347–349.
Riggins GJ, Kinzler KW, Vogelstein B and Thiagalingam S. . 1997 Cancer Res. 57: 2578–2580.
Schutte M, Hruban RH, Hedrik L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero RA, Meltzer PS, Hahn SA and Kern SE. . 1996 Cancer Res. 56: 2527–2530.
Shi Y, Hata A, Lo RS, Massague J and Pavletich N. . 1997 Nature 388: 87–93.
Takagi Y, Kohmura H, Futamura M, Kida H, Tanemura H, Shimokowa K and Saji S. . 1996 Gastroenterology 111: 1369–1372.
Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin MF and Taketo MM. . 1998 Cell 92: 645–656.
Tang B, Bottinger EP, Jakowlew SB, Bagnall KM, Mariano J, Anver MR, Letterio JJ and Wakefield LM. . 1998 Nature Med. 4: 802–807.
Tsuda H, Zhang W, Shimosato Y, Yokota J, Terada M, Sugimura T, Miyamura T and Hirohashi S. . 1990 Proc. Natl. Acad. Sci. USA 87: 6791–6794.
Uchida K, Nagatage M, Osada H, Yatabe Y, Kondo M, Mitsudomi T, Masuda A, Takahashi T and Takahashi T. . 1996 Cancer Res. 56: 5583–5585.
Unsal H, Yakicier MC, Marcais C, Kew M, Volkmann M, Zentgraf H, Isselbacher KJ and Ozturk M. . 1994 Proc. Natl. Acad. Sci. USA 91: 822–826.
Acknowledgements
This work was supported by grants from TUBITAK and TWAS. We thank Dr Marie Ricciardone and Ms Birsen Cevher for help in DNA sequence analyses and Mrs Lutfiye Mesci for oligonucleotide synthesis. We also thank Dr SE Kern for providing us with exon-intron boundary sequence information for Smad4 gene.
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Yakicier, M., Irmak, M., Romano, A. et al. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 18, 4879–4883 (1999). https://doi.org/10.1038/sj.onc.1202866
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DOI: https://doi.org/10.1038/sj.onc.1202866
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