Prognostic significance of cyclin A in gastric cancer†
Johanna Mrena
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorJan-Patrik Wiksten
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorArto Kokkola
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorStig Nordling
Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
Haartman Institute, University of Helsinki, Helsinki, Finland
Search for more papers by this authorCorresponding Author
Caj Haglund
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
Fax: 1358-9-471-71403
Department of Surgery, Helsinki University Central Hospital, P.O. Box 340, 00029 HUS, Helsinki, FinlandSearch for more papers by this authorAri Ristimäki
Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
Molecular and Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
Search for more papers by this authorJohanna Mrena
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorJan-Patrik Wiksten
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorArto Kokkola
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorStig Nordling
Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
Haartman Institute, University of Helsinki, Helsinki, Finland
Search for more papers by this authorCorresponding Author
Caj Haglund
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
Fax: 1358-9-471-71403
Department of Surgery, Helsinki University Central Hospital, P.O. Box 340, 00029 HUS, Helsinki, FinlandSearch for more papers by this authorAri Ristimäki
Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
Molecular and Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
Search for more papers by this authorThere are no relationships resulting in an actual, potential or apparent conflict of interest with regard to this manuscript.
Abstract
High level of cyclin A promotes carcinogenesis, and overexpression of cyclin A has been associated with poor prognosis of cancer patients. We validated the prognostic role of cyclin A in gastric cancer and evaluated its correlation with expression of an mRNA stability factor HuR. From 342 consecutive histologically confirmed gastric cancer patients were obtained 325 representative tissue specimens for cyclin A and 316 for HuR immunohistochemistry. Specimens were stained by cyclin A and HuR specific monoclonal antibodies. Nuclear immunostaining detected in ≥≥≥≥5% of the tumor cells was considered the cut-off for cyclin A positivity. Positive HuR immunoreactivity was scored as nuclear or cytoplasmic. Associations between scores, clinicopathological factors and survival were calculated by the χ2-test, Fisher's exact test, Kaplan-Meier test and Cox model. Cyclin A detected in the nuclei of cancer cells was positive in 55% (179 of 325) of the specimens; 40% (127 of 316) of the specimens had cytoplasmic and 88% (279of 316) nuclear immunoreactivity of HuR. Cyclin A expression was an independent prognostic factor for poor survival. Cyclin A immunoreactivity was associated with old age, high stage, proximal location of the tumor, intestinal type, noncurative resection, advanced penetration depth and with nodal metastases but not distant metastases. Furthermore, cyclin A expression was associated with cytoplasmic HuR expression, whereas no association with nuclear HuR was evident. Cyclin A is an independent prognostic factor in gastric cancer, and one mechanism for its overexpression may depend on cytoplasmic localization of HuR. © 2006 Wiley-Liss, Inc.
References
- 1 Sherr CJ. Cancer cell cycles. Science 1996; 274: 1672–7.
- 2 Yam CH, Fung TK, Poon RY. Cyclin A in cell cycle control and cancer. Cell Mol Life Sci 2002; 59: 1317–26.
- 3 Yasui W, Oue N, Aung PP, Matsumura S, Shutoh M, Nakayama H. Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer 2005; 8: 86–94.
- 4 Xiangming C, Natsugoe S, Takao S, Hokita S, Tanabe G, Baba M, Kuroshima K, Aikou T. The cooperative role of p27 with cyclin E in the prognosis of advanced gastric carcinoma. Cancer 2000; 89: 1214–19.
- 5 Bani-Hani KE, Almasri NM, Khader YS, Sheyab FM, Karam HN. Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer. Clin Cancer Res 2005; 11: 1447–53.
- 6 Chetty R, Sitti CW. Cyclin E immunoexpression in gastric cancer does not correlate with clinicopathological parameters. Histopathology 2003; 42: 66–9.
- 7 Takano Y, Kato Y, van Diest PJ, Masuda M, Mitomi H, Okayasu I. Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. Am JPathol 2000; 156: 585–94.
- 8 Brien TP, Depowski PL, Sheehan CE, Ross JS, McKenna BJ. Prognostic factors in gastric cancer. Mod Pathol 1998; 11: 870–7.
- 9 Zwicker J, Lucibello FC, Wolfraim LA, Gross C, Truss M, Engeland K, Muller R. Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression. EMBO J 1995; 14: 4514–22.
- 10 Koepp DM, Harper JW, Elledge SJ. How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell 1999; 97: 431–4.
- 11 Brennan CM, Steitz JA. HuR and mRNA stability. Cell Mol Life Sci 2001; 58: 266–77.
- 12 Gallouzi IE, Steitz JA. Delineation of mRNA export pathways by the use of cell-permeable peptides. Science 2001; 294: 1895–901.
- 13 Wang W, Caldwell MC, Lin S, Furneaux H, Gorospe M. HuR regulates cyclin A and cyclin B1 mRNA stability during cell proliferation. EMBO J 2000; 19: 2340–50.
- 14 Heinonen M, Bono P, Narko K, Chang SH, Lundin J, Joensuu H, Furneaux H, Hla T, Haglund C, Ristimaki A. Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res 2005; 65: 2157–61.
- 15 Erkinheimo TL, Lassus H, Sivula A, Sengupta S, Furneaux H, Hla T, Haglund C, Butzow R, Ristimaki A. Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase 2 expression in serous ovarian carcinoma. Cancer Res 2003; 63: 7591–4.
- 16 Mrena J, Wiksten JP, Thiel A, Kokkola A, Pohjola L, Lundin J, Nordling S, Ristimaki A, Haglund C. Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res 2005; 11: 7362–8.
- 17 Florenes VA, Maelandsmo GM, Faye R, Nesland JM, Holm R. Cyclin A expression in superficial spreading malignant melanomas correlates with clinical outcome. J Pathol 2001; 195: 530–6.
- 18 Bondi J, Husdal A, Bukholm G, Nesland JM, Bakka A, Bukholm IR. Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome. J Clin Pathol 2005; 58: 509–14.
- 19 Furihata M, Ishikawa T, Inoue A, Yoshikawa C, Sonobe H, Ohtsuki Y, Araki K, Ogoshi S. Determination of the prognostic significance of unscheduled cyclin A overexpression in patients with esophageal squamous cell carcinoma. Clin Cancer Res 1996; 2: 1781–5.
- 20
Handa K,
Yamakawa M,
Takeda H,
Kimura S,
Takahashi T.
Expression of cell cycle markers in colorectal carcinoma: superiority of cyclin A as an indicator of poor prognosis.
Int J Cancer
1999;
84:
225–33.
10.1002/(SICI)1097-0215(19990621)84:3<225::AID-IJC5>3.0.CO;2-A CAS PubMed Web of Science® Google Scholar
- 21 Bahnassy AA, Zekri AR, El-Houssini S, El-Shehaby AM, Mahmoud MR, Abdallah S, El-Serafi M. Cyclin A and cyclin D1 as significant prognostic markers in colorectal cancer patients. BMC Gastroenterol 2004; 4: 22.
- 22 Nozoe T, Inutsuka S, Honda M, Ezaki T, Korenaga D. Clinicopathologic significance of cyclin A expression in colorectal carcinoma. JExp Clin Cancer Res 2004; 23: 127–33.
- 23 Li JQ, Miki H, Wu F, Saoo K, Nishioka M, Ohmori M, Imaida K. Cyclin A correlates with carcinogenesis and metastasis, and p27(kip1) correlates with lymphatic invasion, in colorectal neoplasms. Hum Pathol 2002; 33: 1006–15.
- 24 Furihata M, Ohtsuki Y, Sonobe H, Shuin T, Yamamoto A, Terao N, Kuwahara M. Cyclin A overexpression in carcinoma of the renal pelvis and ureter including dysplasia: immunohistochemical findings in relation to prognosis. Clin Cancer Res 1997; 3: 1399–404.
- 25 Dobashi Y, Shoji M, Jiang SX, Kobayashi M, Kawakubo Y, Kameya T. Active cyclin A-CDK2 complex, a possible critical factor for cell proliferation in human primary lung carcinomas. Am J Pathol 1998; 153: 963–72.
- 26 Volm M, Rittgen W, Drings P. Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas. Br J Cancer 1998; 77: 663–9.
- 27 Chao Y, Shih YL, Chiu JH, Chau GY, Lui WY, Yang WK, Lee SD, Huang TS. Overexpression of cyclin A but not Skp 2 correlates with the tumor relapse of human hepatocellular carcinoma. Cancer Res 1998; 58: 985–90.
- 28 Molendini L, Benassi MS, Magagnoli G, Merli M, Sollazzo MR, Ragazzini P, Gamberi G, Ferrari C, Balladelli A, Bacchini P, Picci P. Prognostic significance of cyclin expression in human osteosarcoma. Int J Oncol 1998; 12: 1007–11.
- 29
Zhai YL,
Nikaido T,
Shiozawa T,
Orii A,
Fujii S.
Expression of cyclins and cyclin-dependent kinases in smooth muscle tumors of the uterus.
Int J Cancer
1999;
84:
244–50.
10.1002/(SICI)1097-0215(19990621)84:3<244::AID-IJC8>3.0.CO;2-2 CAS PubMed Web of Science® Google Scholar
- 30 Huuhtanen RL, Blomqvist CP, Bohling TO, Wiklund TA, Tukiainen EJ, Virolainen M, Tribukait B, Andersson LC. Expression of cyclin A in soft tissue sarcomas correlates with tumor aggressiveness. Cancer Res 1999; 59: 2885–90.
- 31 Wolowiec D, Berger F, Ffrench P, Bryon PA, Ffrench M. CDK1 and cyclin A expression is linked to cell proliferation and associated with prognosis in non-Hodgkin's lymphomas. Leuk Lymphoma 1999; 35: 147–57.
- 32 Noguchi T, Dobashi Y, Minehara H, Itoman M, Kameya T. Involvement of cyclins in cell proliferation and their clinical implications in soft tissue smooth muscle tumors. Am J Pathol 2000; 156: 2135–47.
- 33 Bukholm IR, Bukholm G, Nesland JM. Over-expression of cyclin A is highly associated with early relapse and reduced survival in patients with primary breast carcinomas. Int J Cancer 2001; 93: 283–7.
- 34 Aaltomaa S, Lipponen P, Ala-Opas M, Eskelinen M, Syrjanen K, Kosma VM. Expression of cyclins A and D and p21(waf1/cip1) proteins in renal cell cancer and their relation to clinicopathological variables and patient survival. Br J Cancer 1999; 80: 2001–7.
- 35 Wolgemuth DJ, Lele KM, Jobanputra V, Salazar G. The A-type cyclins and the meiotic cell cycle in mammalian male germ cells. Int J Androl 2004; 27: 192–9.
- 36 Yang R, Morosetti R, Koeffler HP. Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines. Cancer Res 1997; 57: 913–20.
- 37 Murphy M, Stinnakre MG, Senamaud-Beaufort C, Winston NJ, Sweeney C, Kubelka M, Carrington M, Brechot C, Sobczak-Thepot J. Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nat Genet 1997; 15: 83–6.
- 38 Yasmeen A, Berdel WE, Serve H, Muller-Tidow C. E- and A-type cyclins as markers for cancer diagnosis and prognosis. Expert Rev Mol Diagn 2003; 3: 617–33.
- 39 Kawashima R, Haisa M, Kimura M, Takaoka M, Shirakawa Y, Takeda H, Uetsuka H, Gunduz M, Nagai N, Tanaka N, Naomoto Y. Cyclin A correlates with the sensitivity of human cancer cells to cytotoxic effects of 5-FU. Int J Oncol 2004; 24: 273–8.
- 40 Volm M, Koomagi R, Mattern J, Stammler G. Cyclin A is associated with an unfavourable outcome in patients with non-small-cell lung carcinomas. Br J Cancer 1997; 75: 1774–8.
- 41 Huuhtanen RL, Wiklund TA, Blomqvist CP, Bohling TO, Virolainen MJ, Tribukait B, Andersson LC. A high proliferation rate measured by cyclin A predicts a favourable chemotherapy response in soft tissue sarcoma patients. Br J Cancer 1999; 81: 1017–21.
- 42 Rodriguez-Pinilla M, Rodriguez-Peralto JL, Hitt R, Sanchez JJ, Ballestin C, Diez A, Sanchez-Verde L, Alameda F, Sanchez-Cespedes M. Cyclin A as a predictive factor for chemotherapy response in advanced head and neck cancer. Clin Cancer Res 2004; 10: 8486–92.
Citing Literature
