Abstract
Many types of cancer cells are resistant to Fas-mediated apoptosis by several mechanisms, including the mutations of the genes involved in Fas-mediated apoptosis. In this study, to explore the possibility that the mutations of the genes involved in the proximal pathway of Fas-mediated apoptosis (Fas, FADD, caspase 8 and caspase 10) are involved in cancer metastasis, we have analysed somatic mutation and deletion of these genes in 80 non-small cell lung cancers (NSCLCs) with (n=43) and without (n=37) metastasis to the regional lymph nodes. We found 12 mutations (four Fas, four FADD, and four caspase 10 mutations) in 11 of 80 NSCLCs (13.8%). Interestingly, of these mutations, most mutations (10 out of 12) were detected in the NSCLCs with metastasis, and the frequency in the metastasis lesions (23%) was higher than that in the primary lesions of the NSCLCs without metastasis (5.4%). Furthermore, transfection study revealed that the tumor-derived mutants have decreased apoptosis inductions compared to the wild types. These data suggest that the inactivating mutations of the genes in the proximal pathway of Fas-mediated apoptosis may lead to a decreased cancer cell death and play a role in the metastasis of NSCLC.
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References
Boldin MP, Goncharov TM, Goltsev YV, Wallach D . 1996 Cell 2: 803–815
Chan AS, Lam WK, Wong MP, Fu KH, Lee J, Yew WW, Chiu SW, Lung ML . 1996 Lung Cancer 15: 51–65
Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM . 1995 Cell 81: 505–512
Fulda S, Kufer MU, Meyer E, van Valen F, Dockhorn-Dworniczak B, Debatin KM . 2001 Oncogene 20: 5865–5877
Glinsky GV, Glinsky VV . 1996 Cancer Lett. 101: 43–51
Glinsky GV, Glinsky VV, Ivanova AB, Hueser CN . 1996 Cancer Lett. 115: 185–193
Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME . 1995 EMBO J. 14: 5579–5588
Kobzik L . 1999 The lung. Robbins Pathologic Basis of Disease 6th edn Cotran RS, Kumar V and Collins T. (eds) New York, Saunders pp 697–755
Lee JY, Dong SM, Kim SY, Yoo NJ, Lee SH, Park WS . 1998 Virchows. Arch. 433: 305–309
Lee SH, Shin MS, Park WS, Kim SY, Kim HS, Han JY, Park GS, Dong SM, Pi JH, Kim CS, Kim SH, Lee JY, Yoo NJ . 1999a Oncogene 18: 3754–3760
Lee SH, Shin MS, Park WS, Kim SY, Dong SM, Pi JH, Lee HK, Kim HS, Jang JJ, Kim CS, Kim SH, Lee JY, Yoo NJ . 1999b Cancer Res. 59: 3068–3072
Leithäuser F, Dhein J, Mechtersheimer G, Koretz K, Bründerlein S, Henne C, Schmidt A, Debatin K-M, Krammer PH, Möller P . 1993 Lab. Invest. 69: 415–429
Maeda T, Yamada Y, Moriuchi R, Sugahara K, Tsuruda K, Joh T, Atogami S, Tsukasaki K, Tomonaga M, Kamihira S . 1999 J. Exp. Med. 189: 1063–1071
Mandruzzato S, Brasseur F, Andry G, Boon T, van der Bruggen PA . 1997 J. Exp. Med. 186: 785–793
Nagata S . 1997 Cell 88: 355–365
Natoli G, Ianni A, Costanzo A, Petrillo GD, Ilari I, Chirillo P, Balsano C, Levrero M . 1995 Oncogene 11: 1157–1164
Owen-Schaub LB, van Golen KL, Hill LL, Price JE . 1998 J. Exp. Med. 188: 1717–1723
Petersen S, Aninat-Meyer M, Schluns K, Gellert K, Dietel M, Petersen I . 2000 Br. J. Cancer 82: 65–73
Shin MS, Kim HS, Lee SH, Park WS, Kim SY, Park JY, Lee JH, Lee SK, Lee SN, Jung SS, Han JY, Kim H, Lee JY, Yoo NJ . 2001 Cancer Res. 61: 4942–4946
Shin MS, Park WS, Kim SY, Kim HS, Kang SJ, Song K, Park JY, Dong SM, Pi JH, Oh RR, Lee JY, Yoo NJ, Lee SH . 1999 Am. J. Pathol. 154: 1785–1791
Wang J, Zheng L, Lobito A, Chan FK, Dale J, Sneller M, Yao X, Puck JM, Straus SE, Lenardo MJ . 1999 Cell 98: 47–58
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This work was supported by grant No. R03-2001-00053 from the Korea Science and Engineering Foundation.
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Shin, M., Kim, H., Lee, S. et al. Alterations of Fas-pathway genes associated with nodal metastasis innon-small cell lung cancer. Oncogene 21, 4129–4136 (2002). https://doi.org/10.1038/sj.onc.1205527
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DOI: https://doi.org/10.1038/sj.onc.1205527
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