Abstract
Members of the recently identified family of Homo sapiens Aurora/Ipl1‐related kinases (HsAIRKs), homologous to chromosome segregation kinases, fly Aurora and yeast Ipl1, are highly expressed during M phase, and have been suggested to regulate centrosome function, chromosome segregation, and cytokinesis. In the present study, immunohistochemical analyses were performed of HsAIRK1 and HsAIRK3 expression in 78 primary colorectal cancers and 36 colorectal adenomas as well as 15 normal colorectal specimens. In normal colon mucosa, some crypt cells showed weak positive staining in 10 and 12 out of 15 cases for HsAIRK1 and HsAIRK3, respectively, the remaining cases being negative. Elevated expression of HsAIRK1 was observed in 53 (67.9%) of the colorectal cancers, and of HsAIRK3 in 40 (51.3%). Furthermore, colorectal adenomas showed high expression of HsAIRK1 and HsAIRK3 in 11 (30.6%) and 7 (19.4%) cases, respectively, thus being intermediate between colorectal cancers and normal colorectal mucosa. Interestingly, HsAIRK1 overexpression was significantly associated with pT (primary tumor invasion) and p53 accumulation in colorectal cancers. There was no significant correlation between proliferating cell nuclear antigen‐labeling index (PCNA‐LI) and the levels of these proteins. The results suggest that overexpression of HsAIRK1 and HsAIRK3 might be involved in tumorigenesis and/or progression of colorectal cancers.
Keywords: HsAIRK1, HsAIRK3, Colorectal cancer, Colorectal adenoma, PCNA‐LI
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REFERENCES
- 1. ) Perkins , A. S. and Stern , D. F.Molecular biology of cancer: oncogenes . In “ Cancer: Principles & Practices of Oncology ,” 5th Ed. , ed. DeVita V. T., Jr. , Hellman S. and Rosenberg S. A. , pp. 79 – 102 ( 1997. ). Lippincott‐Raven Publ. , Philadelphia . [Google Scholar]
- 2. ) Vogelstein , B. , Fearon , E. R. , Hamilton , S. R. , Kern , S. E. , Preisinger , A. C. , Leppert , M. , Nakamura , Y. , White , R. , Smits , A. M. and Bos , J. L.Genetic alterations during colorectal‐tumor development . N. Engl. J. Med. , 319 , 525 – 532 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Fearon , E. R. and Vogelstein , B.A genetic model for colorectal tumorigenesis . Cell , 61 , 759 – 767 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Lengauer , C. , Kinzler , K. W. and Vogelstein , B.Genetic instabilities in human cancers . Nature , 396 , 643 – 649 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Doxsey , S.The centrosome‐a tiny organelle with big potential . Nat. Genet. , 20 , 104 – 106 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Barlogie , B. , Raber , M. N. , Schumann , J. , Johnson , T. S. , Drewinko , B. , Swartzendruber , D. E. , Gohde , W. , Andreeff , M. and Freireich , E. J.Flow cytometry in clinical cancer research . Cancer Res. , 43 , 3982 – 3997 ( 1983. ). [PubMed] [Google Scholar]
- 7. ) Lengauer , C. , Kinzler , K. W. and Vogelstein , B.Genetic instability in colorectal cancers . Nature , 386 , 623 – 627 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Lingle , W. L. , Lutz , W. H. , Ingle , J. N. , Maihle , N. J. and Salisbury , J. L.Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity . Proc. Natl. Acad. Sci. USA , 95 , 2950 – 2955 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. ) Pihan , G. A. , Purohit , A. , Wallace , J. , Knecht , H. , Woda , B. , Quesenberry , P. and Doxsey , S. J.Centrosome defects and genetic instability in malignant tumors . Cancer Res. , 58 , 3974 – 3985 ( 1998. ). [PubMed] [Google Scholar]
- 10. ) Sato , N. , Mizumoto , K. , Nakamura , M. , Nakamura , K. , Kusumoto , M. , Niiyama , H. , Ogawa , T. and Tanaka , M.Centrosome abnormalities in pancreatic ductal carcinoma . Clin. Cancer Res. , 5 , 963 – 970 ( 1999. ). [PubMed] [Google Scholar]
- 11. ) Ghadimi , B. M. , Sackett , D. L. , Difilippantonio , M. J. , Schrock , E. , Neumann , T. , Jauho , A. , Auer , G. and Ried , T.Centrosome amplification and instability occur exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlate with numerical chromosomal aberrations . Genes Chromosom. Cancer , 27 , 183 – 190 ( 2000. ). [PMC free article] [PubMed] [Google Scholar]
- 12. ) Salisbury , J. L. , Whitehead , C. M. , Lingle , W. L. and Barrett , S. L.Centrosomes and cancer . Biol. Cell , 91 , 451 – 460 ( 1999. ). [PubMed] [Google Scholar]
- 13. ) Francisco , L. , Wang , W. and Chan , C. S.Type 1 protein phosphatase acts in opposition to Ipl1 protein kinase in regulating yeast chromosome segregation . Mol. Cell. Biol. , 14 , 4731 – 4740 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. ) Glover , D. M. , Leibowitz , M. H. , McLean , D. A. and Parry , H.Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles . Cell , 81 , 95 – 105 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Giet , R. and Prigent , C.Aurora/Ipl1p‐related kinases, a new oncogenic family of mitotic serine‐threonine kinases . J. Cell Sci. , 112 , 3591 – 3601 ( 1999. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Kimura , M. , Kotani , S. , Hattori , T. , Sumi , N. , Yoshioka , T. , Todokoro , K. and Okano , Y.Cell cycle‐dependent expression and spindle pole localization of a novel human protein kinase, Aik, related to Aurora of Drosophila and yeast Ipl1 . J. Biol. Chem. , 272 , 13766 – 13771 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Sen , S. , Zhou , H. and White , R. A.A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines . Oncogene , 14 , 2195 – 2200 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Bischoff , J. R. , Anderson , L. , Zhu , Y. , Mossie , K. , Ng , L. , Souza , B. , Schryver , B. , Flanagan , P. , Clairvoyant , F. , Ginther , C. , Chan , C. S. , Novotny , M. , Slamon , D. J. and Plowman , G. D.A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers . EMBO J. , 17 , 3052 – 3065 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. ) Shindo , M. , Nakano , H. , Kuroyanagi , H. , Shirasawa , T. , Mihara , M. , Gilbert , D. J. , Jenkins , N. A. , Copeland , N. G. , Yagita , H. and Okumura , K.cDNA cloning, expression, subcellular localization, and chromosomal assignment of mammalian aurora homologues, aurora‐related kinase (ARK) 1 and 2 . Biochem. Biophys. Res. Commun. , 244 , 285 – 292 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Zhou , H. , Kuang , J. , Zhong , L. , Kuo , W. L. , Gray , J. W. , Sahin , A. , Brinkley , B. R. and Sen , S.Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation . Nat. Genet. , 20 , 189 – 193 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 21. ) Yanai , A. , Arama , E. , Kilfin , G. and Motro , B.ayk1, a novel mammalian gene related to Drosophila aurora centrosome separation kinase, is specifically expressed during meiosis . Oncogene , 14 , 2943 – 2950 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 22. ) Gopalan , G. , Chan , C. S. and Donovan , P. J.A novel mammalian, mitotic spindle‐associated kinase is related to yeast and fly chromosome segregation regulators . J. Cell Biol. , 138 , 643 – 656 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. ) Kimura , M. , Matsuda , Y. , Yoshioka , T. , Sumi , N. and Okano , Y.Identification and characterization of STK12/Aik2: a human gene related to aurora of Drosophila and yeast IPL1 . Cytogenet. Cell Genet. , 82 , 147 – 152 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 24. ) Tatsuka , M. , Katayama , H. , Ota , T. , Tanaka , T. , Odashima , S. , Suzuki , F. and Terada , Y.Multinuclearity and increased ploidy caused by overexpression of the aurora‐ and Ipl1‐like midbody‐associated protein mitotic kinase in human cancer cells . Cancer Res. , 58 , 4811 – 4816 ( 1998. ). [PubMed] [Google Scholar]
- 25. ) Niwa , H. , Abe , K. , Kunisada , T. and Yamamura , K.Cellcycle‐ dependent expression of the STK‐1 gene encoding a novel murine putative protein kinase . Gene , 169 , 197 – 201 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 26. ) Terada , Y. , Tatsuka , M. , Suzuki , F. , Yasuda , Y. , Fujita , S. and Otsu , M.AIM‐1: a mammalian midbody‐associated protein required for cytokinesis . EMBO J. , 17 , 667 – 676 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. ) Kimura , M. , Matsuda , Y. , Yoshioka , T. and Okano , Y.Cell cycle‐dependent expression and centrosome localization of a third human aurora/Ipl1‐related protein kinase, AIK3 . J. Biol. Chem. , 274 , 7334 – 7340 ( 1999. ). [DOI] [PubMed] [Google Scholar]
- 28. ) Bernard , M. , Sanseau , P. , Henry , C. , Couturier , A. and Prigent , C.Cloning of STK13, a third human protein kinase related to Drosophila aurora and budding yeast Ipl1 that maps on chromosome 19q13.3‐ter . Genomics , 53 , 406 – 409 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 29. ) Tseng , T. C. , Chen , S. H. , Hsu , Y. P. and Tang , T. K.Protein kinase profile of sperm and eggs: cloning and characterization of two novel testis‐specific protein kinases (AIE1, AIE2) related to yeast and fly chromosome segregation regulators ,. DNA Cell Biol. , 17 , 823 – 833 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 30. ) Muleris , M. , Salmon , R. J. , Dutrillaux , A. M. , Vielh , P. , Zafrani , B. , Girodet , J. and Dutrillaux , B.Characteristic chromosomal imbalances in 18 near‐diploid colorectal tumors . Cancer Genet. Cytogenet. , 29 , 289 – 301 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 31. ) Schlegel , J. , Stumm , G. , Scherthan , H. , Bocker , T. , Zirngibl , H. , Ruschoff , J. and Hofstadter , F.Comparative genomic in situ hybridization of colon carcinomas with replication error . Cancer Res. , 55 , 6002 – 6005 ( 1995. ). [PubMed] [Google Scholar]
- 32. ) Tanner , M. M. , Tirkkonen , M. , Kallioniemi , A. , Collins , C. , Stokke , T. , Karhu , R. , Kowbel , D. , Shadravan , F. , Hintz , M. , Kuo , W. L. , Waldman , F. M. , Isola , J. J. , Gray , J. W. and Kallioniemi , O. P.Increased copy number at 20q13 in breast cancer: defining the critical region and exclusion of candidate genes . Cancer Res. , 54 , 4257 – 4260 ( 1994. ). [PubMed] [Google Scholar]
- 33. ) Savelieva , E. , Belair , C. D. , Newton , M. A. , DeVries , S. , Gray , J. W. , Waldman , F. and Reznikoff , C. A.20q gain associates with immortalization: 20q13.2 amplification correlates with genome instability in human papillomavirus 16 E7 transformed human uroepithelial cells . Oncogene , 14 , 551 – 560 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 34. ) Kimura , M. , Matsuda , Y. , Eki , T. , Yoshioka , T. , Okumura , K. , Hanaoka , F. and Okano , Y.Assignment of STK6 to human chromosome 20q13.2‐q13.3 and a pseudogene STK6P to 1q41‐q42 . Cytogenet. Cell Genet. , 79 , 201 – 203 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 35. ) Tanaka , T. , Kimura , M. , Matsunaga , K. , Fukada , D. , Mori , H. and Okano , Y.Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast . Cancer Res. , 59 , 2041 – 2044 ( 1999. ). [PubMed] [Google Scholar]
- 36. ) McDonald , J. M. , Douglass , E. C. , Fisher , R. , Geiser , C. F. , Krill , C. E. , Strong , L. C. , Virshup , D. and Huff , V.Linkage of familial Wilms' tumor predisposition to chromosome 19 and a two‐locus model for the etiology of familial tumors . Cancer Res. , 58 , 1387 – 1390 ( 1998. ). [PubMed] [Google Scholar]
- 37. ) Sreekantaiah , C. , Davis , J. R. and Sandberg , A. A.Chromosomal abnormalities in leiomyosarcomas . Am. J. Pathol. , 142 , 293 – 305 ( 1993. ). [PMC free article] [PubMed] [Google Scholar]
- 38. ) Bicher , A. , Ault , K. , Kimmelman , A. , Gershenson , D. , Reed , E. and Liang , B.Loss of heterozygosity in human ovarian cancer on chromosome 19q . Gynecol. Oncol. , 66 , 36 – 40 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 39. ) Jass , J. R. and Sobin , L. H. “ Histological Typing of Intestinal Tumours ,” 2nd Ed. , pp. 29 – 32 ( 1989. ). Springer‐Verlag; , Berlin . [Google Scholar]
- 40. ) Dukes , C. E. and Bussey , H. J. R.The spread of rectal cancer and its effect on prognosis . Br. J. Cancer , 12 , 309 – 320 ( 1958. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. ) Sobin , L. H. and Wittekind , C. “ TNM Classification of Malignant Tumours ,” 5th Ed. , pp. 66 – 69 ( 1997. ). Wiley‐ Liss, Inc. , New York . [Google Scholar]
- 42. ) Bischoff , J. R. and Plowman , G. D.The Aurora/Ipl1p kinase family: regulators of chromosome segregation and cytokinesis . Trends Cell Biol. , 9 , 454 – 459 ( 1999. ). [DOI] [PubMed] [Google Scholar]
- 43. ) Katayama , H. , Ota , T. , Jisaki , F. , Ueda , Y. , Tanaka , T. , Odashima , S. , Suzuki , F. , Terada , Y. and Tatsuka , M.Mitotic kinase expression and colorectal cancer progression . J. Natl. Cancer Inst. , 91 , 1160 – 1162 ( 1999. ). [DOI] [PubMed] [Google Scholar]
- 44. ) Fukasawa , K. , Choi , T. , Kuriyama , R. , Rulong , S. and Van de Woude , G. F.Abnormal centrosome amplification in the absence of p53 . Science , 271 , 1744 – 1747 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 45. ) Carroll , P. E. , Okuda , M. , Horn , H. F. , Biddinger , P. , Stambrook , P. J. , Gleich , L. L. , Li , Y. Q. , Tarapore , P. and Fukasawa , K.Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression . Oncogene , 18 , 1935 – 1944 ( 1999. ). [DOI] [PubMed] [Google Scholar]