Abstract
Purpose
The aim of this study was to determine the expression of cellular FLICE-like inhibitory protein (cFLIP) in head and neck squamous cell carcinoma (HNSCC) and revealed its possible correlation to Fas protein and tumour clinical parameters.
Methods
The expression of cFLIP was analysed in 58 HNSCC samples and 30 morphologically normal tissues adjacent to the carcinomas using immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. Furthermore, its possible correlation to the expression of Fas protein and tumour clinicopathologic parameters were discussed.
Results
Cellular FLICE-like inhibitory protein was demonstrated to be up regulated in most HNSCC than in normal tissues by immunohistochemistry (p < 0.01). Although the mRNA levels of both isoforms of cFLIP, long form (cFLIPL) and short form (cFLIPS), in HNSCC were higher than those in normal tissues (p < 0.01), only cFLIPL protein could be detected by western blot. Furthermore, the expression of cFLIPL protein was significantly associated with tumour clinical stage (p < 0.01) and lymph node metastasis (p = 0.01). Since all of the tumours with Fas immunostaining also express cFLIP protein, there was no significant correlation between them (p > 0.05).
Conclusions
Overexpression of cFLIPL is a frequent event in HNSCC and HNSCC cells in vivo may need it to evade apoptosis mediated by Fas or other receptors, which might contribute to tumour development and progression.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bayazit Y, Mumbuc S, Ucak R, Kanlikama M, Bakir K (2000) Significance of Fas protein in squamous cell carcinoma of the larynx. Acta Otolaryngol 120:557–561
Dikshit RP, Boffetta P, Bouchardy C, Merletti F, Crosignani P, Cuchi T, Ardanaz E, Brennan P (2005) Risk factors for the development of second primary tumors among men after laryngeal and hypopharyngeal carcinoma. Cancer 103:2326–2333
Forastiere A, Koch W, Trotti A, Sidransky D (2001) Head and neck cancer. N Engl J Med 345:1890–1900
Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ (1998) Intracellular regulation of TRAIL induced apoptosis in human melanoma cells. J Immunol 161:2833–2840
Irisarri M, Plumas J, Bonnefoix T, Jacob MC, Roucard C, Pasquier MA, Sotto JJ, Lajmanovich A (2000) Resistance to CD95-mediated apoptosis through constitutive c-FLIP expression in a non-Hodgkin’s lymphoma B cell line. Leukemia 14:2149–2158
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195
Jackel MC, Mitteldorf C, Schweyer S, Fuzesi L (2001) Clinical relevance of Fas (APO-1/CD95) expression in laryngeal squamous cell carcinoma. Head Neck 23:646–652
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ (2004) American Cancer Society. Cancer statistics. CA Cancer J Clin 54:8–29
Kamsteeg M, Rutherford T, Sapi E, Hanczaruk B, Shahabi S, Flick M Brown D, Mor G (2003) Phenoxodiol–an isoflavone analog—induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 22:2611–2620
Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J (2000) The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways. Curr Biol 10:640–648
Lee SW, Park Y, Yoo JK, Choi SY, Sung YC (2003) Inhibition of TCR-induced CD8 T cell death by IL-12: regulation of Fas ligand and cellular FLIP expression and caspase activation by IL-12. J Immunol 170:2456–2460
Medema JP, de Jong J, van Hall T, Melief CJ, Offringa R (1999) Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein. J Exp Med 190:1033–8
Mork J (1998) Forty years of monitoring head and neck cancer in Norway: no good news. Anticancer Res 18:3705–3708
Nagaraju K, Casciola-Rosen L, Rosen A, Thompson C, Loeffler L, Parker T, Danning C, Rochon PJ, Gillespie J, Plotz P (2000) The inhibition of apoptosis in myositis and in normal muscle cells. J Immunol 164:5459–5465
Nagata S (1997) Apoptosis by death factor. Cell 88:355–365
Okano H, Shiraki K, Inoue H, Kawakita T, Yamanaka T, Deguchi M, Sugimoto K, Sakai T, Ohmori S, Fujikawa K, Murata K, Nakano T (2003) Cellular FLICE/caspase-8-inhibitory protein as a principal regulator of cell death and survival in human hepatocellular carcinoma. Lab Invest 83:1033–1043
Park SJ, Kim YY, Ju JW, Han BG, Park SI, Park BJ (2001) Alternative splicing variants of c-FLIP transduce the differential signal through the Raf or TRAF2 in TNF-induced cell proliferation. Biochem Biophys Res Commun 289:1205–1210
Parkin DM, Bray F, Ferlay J, Pisani P (1999) Global cancer statistics. CA Cancer J Clin 49:33–64
Poukkula M, Kaunisto A, Hietakangas V, Denessiouk K, Katajamäki T, Johnson MS, Sistonen L, Eriksson JE (2005) Rapid turnover of c-FLIPshort is determined by its unique C-terminal tail. J Biol Chem 280:27345–27355
Rippo MR, Moretti S, Vescovi S, Tomasetti M, Orecchia S, Amici G, Catalano A, Procopio A (2004) FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells. Oncogene 23:7753–7760
Ryu BK, Lee MG, Chi SG, Kim YW, Park JH (2001) Increased expression of cFLIP(L) in colonic adenocarcinoma. J Pathol 194:15–19
Seiwert TY, Cohen EE (2005) State-of-the-art management of locally advanced head and neck cancer. Br J Cancer 92:1341–1348
Silva SD, Agostini M, Nishimoto IN, Coletta RD, Alves FA, Lopes MA, Kowalski LP, Graner E (2004) Expression of fatty acid synthase, ErbB2 and Ki-67 in head and neck squamous cell carcinoma. A clinicopathological study. Oral Oncol 40:688–696
Thomas RK, Kallenborn A, Wickenhauser C, Schultze JL, Draube A, Vockerodt M, Re D, Diehl V, Wolf J (2002) Constitutive expression of c-FLIP in Hodgkin and Reed-Sternberg cells. Am J Pathol 160:1521–1528
Toyozumi Y, Arima N, Izumaru S, Kato S, Morimatsu M, Nakashima T (2004) Loss of caspase-8 activation pathway is a possible mechanism for CDDP resistance in human laryngeal squamous cell carcinoma, HEp-2 cells. Int J Oncol 25:721–728
Vokes EE, Weichselbaum RR, Lippman SM, Hong WK (1993) Head and neck cancer. N Engl J Med 328:184–194
Zhou XD, Yu JP, Liu J, Luo HS, Chen HX, Yu HG (2004) Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma. Clin Sci (Lond) 106:397–405
Acknowledgments
We thank the Institute of Basic Medical Sciences of Qilu Hospital of Shandong University for assistance in technology and apparatus.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Li, X., Pan, X., Zhang, H. et al. Overexpression of cFLIP in head and neck squamous cell carcinoma and its clinicopathologic correlations. J Cancer Res Clin Oncol 134, 609–615 (2008). https://doi.org/10.1007/s00432-007-0325-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-007-0325-7