Summary
To investigate involvement of an aberrant expression of the FHIT (fragile histidine triad) gene in the process of carcinogenesis and progression in cervical carcinoma, we examined its expression by the reverse transcriptase polymerase chain reaction (RT-PCR) and cDNA sequence method in 32 cervical invasive carcinomas (25 squamous cell carcinomas and seven adeno- or adenosquamous carcinomas) and 18 of its precursor lesions [four low-grade and 14 high-grade cervical intraepithelial neoplasias (CINs)]. We also examined a link between the occurrence of the aberrant expression and human papillomavirus (HPV). We detected the aberrant FHIT transcripts in 11 of 25 (44%) cervical invasive squamous cell carcinomas and in 5 of 14 (36%) high-grade CINs (CIN 2 or 3), whereas they were not found in seven non-squamous type and four low-grade CINs (CIN 1). The alteration patterns of the FHIT gene expression in high-grade CINs were virtually similar to those found in invasive carcinomas, such that the exons 5–7 were consistently deleted associated or unassociated with loss of the exon 4 and/or 8. The incidence of the aberrant expression was not related to the presence of HPV and its type. These data indicate that the aberrant expression of the FHIT gene is observed in precursor lesions of cervical carcinoma as well as invasive carcinomas, with its incidence not increasing with advance of clinical stage. Given the squamous cell type dominant expression, the aberrant expression may play a critical role in the generation of squamous cell carcinoma of the uterine cervix, but not the consequence of the progression of the cancer.
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References
Choo, K-B & Chong, K. Y. (1993). Absence of mutation in the p53 and the retinoblastoma susceptibility genes in primary cervical carcinomas. Virology 193: 1042–1046.
Crook, T. & Vousden, K. H. (1992). Properties of p53 mutations detected in primary and secondary cervical cancers suggest mechanisms of metastasis and involvement of environmental carcinogens. EMBO J 11: 3935–3940.
Crook, T., Wrede, D. & Vousden, K. H. (1991). p53 point mutation in HPV negative human cervical carcinoma cell lines. Oncogene 6: 873–875.
Fong, K. M., Biesterveld, E. J., Virmani, A., Wistuba, I., Sekido, Y., Bader, S. A., Ahmadian, M., Ong, S. T., Rassool, F. V., Zimmerman, P. V., Giaccone, G., Gazdar, A. F. & Minna, J. D. (1997). FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res 57: 2256–2267.
Fujita, M., Inoue, M., Tanizawa, O., Iwamoto, S. & Enomoto, T. (1992). Alterations of the p53 gene in human primary cervical carcinoma with and without human papillomavirus infection. Cancer Res 52: 5323–5328.
Gemma, A., Hagiwara, K., Ke, Y., Burke, L. M., Khan, M. A., Nagashima, M., Bennett, W. P. & Harris, C. C. (1997). FHIT mutations in human primary gastric cancer. Cancer Res 57: 1435–1437.
Greenspan, D. L., Connolly, D. C., Wu, R., Lei, R. Y., Vogelstein, J. T. C., Kim, Y-T, Mok, J. E., Munoz, N., Bosch, F. X., Shah, K. & Cho, K. R. (1997). Loss of FHIT expression in cervical carcinoma cell lines and primary tumors. Cancer Res 57: 4692–4698.
Helland, A., Holm, R., Kristensen, G., Laern, J., Kaern, J., Karlsen, F., Trope, C., Nesland, J. M. & Borresen, A. L. (1993). Genetic alterations of the TP53 gene, p53 protein expression and HPV infection in primary cervical carcinomas. J Pathol 171: 105–114.
Hendricks, D. T., Taylor, R., Reed, M. & Birrer, M. J. (1997). FHIT gene expression in human ovarian, endometrial, and cervical cancer cell lines. Cancer Res 57: 2112–2115.
Huibregtse, J. M., Scheffner, M. & Howley, P. M. (1991). A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J 10: 4129–4135.
Larson, A. A., Kern, S., Curtiss, S., Gordon, R., Cavenee, W. K. & Hampton, G. M. (1997). High resolution analysis of chromosome 3p alterations in cervical carcinoma. Cancer Res 57: 4082–4090.
Mao, L., Fan, Y. H., Lotan, R. & Hong, W. K. (1996). Frequent abnormalities of FHIT, a candidate tumor suppressor gene, in head and neck cancer cell lines. Cancer Res 57: 5128–5131.
Miwa, K., Miyamoto, S., Imamura, T., Nishida, M., Yoshikawa, Y., Nagata, Y. & Wake, N. (1995). The role of p53 inactivation in human cervical cell carcinoma development. Br J Cancer 71: 219–226.
Munger, K., Werness, B. A., Dyson, N., Phelps, W. C., Harlow, E. & Howley, P. M. (1989). Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J 8: 4099–4105.
Ohta, M., Inoue, H., Cotticelli, M. G., Kastury, K., Baffa, R., Palazzo, J., Siprashvili, Z., Mori, M., McCue, P., Druck, T., Croce, C. M. & Hebner, K. (1996). The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84: 587–597.
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. (1990). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63: 1129–1136.
Sozzi, G., Veronese, M. L., Negrini, M., Baffa, R., Cotticelli, M. G., Inoue, H., Tornielli, S., Pilotti, S., De Gregorio, L., Pastorino, U., Pierotti, M. A., Ohta, M., Huebner, K. & Croce, C. M. (1996). The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 85: 17–26.
Werness, B. A., Levine, A. J. & Howley, P. M. (1990). Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248: 76–79.
Wilke, C. M., Hall, B. K., Hoge, A., Paradee, W., Smith, D. I. & Glover, T. W. (1996). FRA3B extends over a broad region and contains a spontaneous HPV16 integration site: direct evidence for the coincidence of viral integration sites and fragile sites. Hum Mol Genet 5: 187–195.
Wistuba, I., Montellano, F. D., Milchgrub, S., Virmani, A. K., Behrens, C., Chen, H., Ahmadian, M., Nowak, J. A., Muller, C., Minna, J. D. & Gazdar, A. F. (1997). Deletions of chromosome 3p are frequent and early events in the pathogenesis of uterine cervical carcinoma. Cancer Res 57: 3154–3158.
Yoshikawa, H., Kawana, T., Kitagawa, K., Mizuno, M., Yoshikura, H. & Iwamoto, A. (1991). Detection and typing of multiple genital human papillomaviruses by DNA amplification with consensus primers. Jpn J Cancer Res 82: 524–531.
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Nakagawa, S., Yoshikawa, H., Kimura, M. et al. A possible involvement of aberrant expression of the FHIT gene in the carcinogenesis of squamous cell carcinoma of the uterine cervix. Br J Cancer 79, 589–594 (1999). https://doi.org/10.1038/sj.bjc.6690093
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DOI: https://doi.org/10.1038/sj.bjc.6690093
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