Abstract
Background: Survivin is a recently described anti-apoptotic protein that is suppressed by wild-type p53 and is overexpressed in 41–70% of hepatocellular carcinomas from Asia. Two alternatively spliced transcripts have also been described: anti-apoptotic survivin-ΔEx3 and non—anti-apoptotic survivin-2B. Survivin splice variant expression has not been studied in HCC, and little is known about survivin expression in hepatocellular carcinomas arising in other parts of the world, where risk factors are often different than they are in Asia.
Aim of the Study: We studied survivin mRNA and protein expression in a United States cohort of hepatocellular carcinomas and correlated the findings with p53 immunopositivity.
Methods: RT-PCR was performed for survivin, survivin-2B, and survivin-ΔEx3 in 20 HCCs and one intrahepatic cholangiocarcinoma. Expression levels of total survivin were evaluated with real-time PCR. Protein expression was examined by immunohistochemistry.
Results: Survivin was the major transcript, and all transcripts were present in all normal and neoplastic tissues; 11/20 (55%) HCCs and the one cholangiocarcinoma showed twofold or greater overexpression of survivin. Next, we examined survivin and p53 protein expression by immunohistochemistry on a separate series of 79 HCC, 13 fibrolamellar carcinomas, and 15 hepatic adenomas; 14/79 (17%) HCC, but none of the fibrolamellar carcinomas or hepatic adenomas, showed survivin protein overexpression, and 25/79 HCC (32%) showed abnormal nuclear accumulation of p53, which correlated with increased survivin expression.
Conclusions: All three survivin transcripts are present in normal liver and HCC. Survivin is the dominant transcript in HCC and is overexpressed in 55% of cases. Survivin protein overexpression is associated with aberrant p53 nuclear positivity.
Similar content being viewed by others
References
Adida C, Crotty PL, McGrath J, Berrebi D, Diebold J, Altieri DC. Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am J Pathol 1998;152:43–49.
Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997;3:917–921.
Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998;396:580–584.
Deguchi M, Shiraki K, Inoue H, et al. Expression of survivin during liver regeneration. Biochem Biophys Res Commun 2002;297:59–64.
Shiraki K, Nakano T, Hisatomi H. Survivin in liver. Gastroenterology 2003;124:1565–1566; author reply 1566–1567.
Ikeguchi M, Ueta T, Yamane Y, Hirooka Y, Kaibara N. Inducible nitric oxide synthase and survivin messenger RNA expression in hepatocellular carcinoma. Clin Cancer Res 2002;8:3131–3136.
Ito T, Shiraki K, Sugimoto K, et al. Survivin promotes cell proliferation in human hepatocellular carcinoma. Hepatology 2000;31:1080–1085.
Ikeguchi M, Hirooka Y, Kaibara N. Quantitative analysis of apoptosis-related gene expression in hepatocellular carcinoma. Cancer 2002;95:1938–1945.
Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003;3:46–54.
Grossman D, Kim PJ, Blanc-Brude OP, et al. Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. J Clin Invest 2001;108:991–999.
Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem 2002;277:3247–3257.
Mirza A, McGuirk M, Hockenberry TN, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53 dependent apoptotic pathway. Oncogene 2002;21:2613–2622.
Mahotka C, Wenzel M, Springer E, Gabbert HE, Gerharz CD. Survivin-deltaEx3 and survivin-2B: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. Cancer Res 1999;59:6097–6102.
Mahotka C, Liebmann J, Wenzel M, et al. Differential subcellular localization of functionally divergent survivin splice variants. Cell Death Differ 2002;9:1334–1342.
Hung CJ, Ginzinger DG, Zarnegar R, et al. Expression of vascular endothelial growth factor-C in benign and malignant thyroid tumors. J Clin Endocrinol Metab 2003;88:3694–3699.
Nzeako UC, Goodman ZD, Ishak KG. Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinicohistopathologic study of 804 North American patients. Am J Clin Pathol 1996;105:65–75.
Torbenson M, Lee JH, Choti M, et al. Hepatic adenomas: analysis of sex steroid receptor status and the Wnt signaling pathway. Mod Pathol 2002;15:189–196.
Ikeguchi M, Ueda T, Sakatani T, Hirooka Y, Kaibara N. Expression of survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma. Diagn Mol Pathol 2002;11:33–40.
Krieg A, Mahotka C, Krieg T, et al. Expression of different survivin variants in gastric carcinomas: first clues to a role of survivin-2B in tumour progression. Br J Cancer 2002;86:737–743.
Li F. Survivin study: what is the next wave? J Cell Physiol 2003;197:8–29.
Marwoto W, Miskad UA, Siregar NC, et al. Immunohistochemical study of P53, PCNA and AFP in hepatocellular carcinoma, a comparison between Indonesian and Japanese cases. Kobe J Med Sci 2000;46:217–229.
Moon WS, Tarnawski AS. Nuclear translocation of survivin in hepatocellular carcinoma: a key to cancer cell growth? Hum Pathol 2003;34:1119–1126.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kannangai, R., Wang, J., Liu, Q.Z. et al. Survivin overexpression in hepatocellular carcinoma is associated with p53 dysregulation. Int J Gastrointest Canc 35, 53–60 (2005). https://doi.org/10.1385/IJGC:35:1:053
Issue Date:
DOI: https://doi.org/10.1385/IJGC:35:1:053