Abstract
KAI1, a metastasis suppressor gene of prostate cancer, is located on human chromosome 11p11.2. Down‐regulation of KAI1 mRNA during tumor progression and metastasis has been reported for several kinds of cancer, but the mechanism of this down‐regulation is not known. In the present study, our aim was to ascertain the relationship between down‐regulation of KAI1 mRNA expression and KAI1 gene alterations in lung cancer. Forty‐nine cases of adenocarcinoma of the lung were studied by reverse‐transcriptase polymerase chain reaction (RT‐PCR) assay of KAI1 mRNA and by immunohistochemical detection of KAI1 protein. In addition, markers of the microsatellite loci D11S1344 and D11S1326 were used to investigate loss of heterozygosity (LOH) and replication errors (RERs) of the KAI1 gene region. The RT‐PCR assay showed that there was no correlation between KAI1 mRNA expression and either the age of the patients or tumor size. By contrast, KAI1 mRNA expression was significantly correlated with gender (P=0.047), metastasis to the lymph nodes or other organs (P=0.004), the histological grade of the tumor (P=0.036) and the pathological stage (P=0.049). Immunohistochemical staining showed that in one case without metastasis, loss of KAI1 mRNA was associated with invasion of the stroma by KAI1 protein‐negative cancer cells. The numbers of informative cases by microsatellite analysis were 14 (28.6%) of 49 at D11S1344 and 27 (55.1%) of 49 at D11S1326; none of 49 adenocarcinomas showed LOH or RERs at these loci. These results suggest that down‐regulation of KAI1 mRNA expression rarely if ever involves LOH or RERs of the KAI1 gene region in primary lung adenocarcinoma.
Keywords: KAI1, Lung adenocarcinoma, RT‐PCR, Immunohistochemistry, Microsatellite analysis
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REFERENCES
- 1).Health and Welfare Statistics Association . Annu. Stat. Rep. Natl. Health , 44 , 433 – 434 ( 1997. ). [Google Scholar]
- 2).Mountain , C. F.Revisions in the international system for staging lung cancer . Chest , 111 , 1710 – 1717 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 3).Dong , J.‐T. , Lamb , P. W. , Rinker‐Schaeffer , C. W. , Yukanovic , J. , Ichikawa , T. , Isaacs , J. T. and Barrett , J. C.KAI‐1, a metastatic suppressor gene for prostatic cancer on human chromosome 1 1p1 1.2 . Science , 268 , 884 – 886 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 4).Miyake , M. , Koyama , M. , Seno , M. and Ikeyama , S.Identification of the motility‐related protein (MRP‐1), recognized by monoclonal antibody M31–15, which inhibits cell motility . J. Exp. Med. , 174 , 1347 – 1354 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5).Classon , B. J. , Williams , A. F. , Willis , A. C. , Seed , B. and Stamenkovic , I.The primary structure of the human leukocyte antigen CD37, a species homologue of the rat MRC OX‐44 antigen . J. Exp. Med. , 169 , 1497 – 1502 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6).Amiot , M.Identification and analysis of cDNA clones encoding CD53: a panleukocyte antigen related to membrane transport proteins . J. Immunol. , 145 , 4322 – 4325 ( 1990. ). [PubMed] [Google Scholar]
- 7).Hotta , H. , Ross , A. H. , Huebner , K. , Isobe , M. , Wendeborn , S. , Chao , M. V. , Ricciardi , R. P. , Tsujimoto , Y. , Croce , C. M. and Koprowski , H.Molecular cloning and characterization of an antigen associated with early stages of melanoma tumor progression . Cancer Res. , 48 , 2955 – 2962 ( 1988. ). [PubMed] [Google Scholar]
- 8).Oren , R. , Takahashi , S. , Doss , C. , Levy , R. and Levy , S.TAPA‐1, the target of an antiproliferative antibody, defines a new family of transmembrane proteins . Mol. Cell. Biol. 10 , 4007 – 4015 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9).Wright , M. D. and Tomlinson , M. G.The ins and outs of the transmembrane‐4 superfamily . Immunol. Today , 15 , 588 – 594 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 10).Hakomori , S.Aberrant glycosylation in tumors and tumor‐associated carbohydrate antigens . Adv. Cancer Res. , 52 , 257 – 331 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 11).Adachi , M. , Taki , T. , Ieki , Y. , Huang , C. L. , Higashiyama , M. and Miyake , M.Correlation of KAI1/CD82 gene expression with good prognosis in patients with non‐small cell lung cancer . Cancer Res. , 56 , 1751 – 1755 ( 1996. ). [PubMed] [Google Scholar]
- 12).Higashiyama , M. , Kodama , K. , Yokouchi , H. , Takami , K. , Adachi , M. , Taki , T. , Ishiguro , S. , Nakamori , S. , Yoshie , O. and Miyake , M.KAI1/CD82 expression in nonsmall cell lung carcinoma is a novel, favorable prognostic factor . Cancer , 83 , 466 – 474 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 13).Guo , X. , Friess , H. , Graber , H. U. , Kashiwagi , M. , Zimmermann , A. , Korc , M. and Buchler , M. W.KAI1 expression is up‐regulated in early pancreatic cancer and decreased in the presence of metastasis . Cancer Res. , 56 , 4876 – 4880 ( 1996. ). [PubMed] [Google Scholar]
- 14).Yang , X. , Welch , D. R. , Phillips , K. K. , Weissman , B. E. and Wei , L. L.KAI1, a putative marker for metastatic potential in human breast cancer . Cancer Lett. , 119 , 149 – 155 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 15).Yu , Y. , Yang , J.‐L. , Markovic , B. , Jackson , P. , Yardley , G. , Barrett , J. C. and Russell , P. J.Loss of KAI1 messenger RNA expression in both high‐grade and invasive human bladder cancers . Clin. Cancer Res. , 3 , 1056 – 1059 ( 1997. ). [PubMed] [Google Scholar]
- 16).Takaoka , A. , Hinoda , Y. , Satoh , S. , Adachi , Y. , Itoh , F. , Adachi , M. and Imai , K.Suppression of invasive properties of colon cancer cells by a metastasis suppressor KAI1 gene . Oncogene , 16 , 1443 – 1453 ( 1998. ). [DOI] [PubMed] [Google Scholar]
- 17).International Union Against Cancer (UICC) . “ TNM Classification of Malignant Tumors ” 5th Ed. , ed. Sobin L. H. and Wittekind C. H. ( 1997. ). John Wiley & Sons, Inc. , New York . [Google Scholar]
- 18).Kawana , Y. , Komiya , A. , Ueda , T. , Nihei , N. , Kuramochi , H. , Suzuki , H. , Yatani , R. , Imai , T. , Dong , J.‐T. , Imai , T. , Yoshie , O. , Barrett , J. C. , Isaacs , J. T. , Shimazaki , J. , Ito , H. and Ichikawa , T.Location of KAI1 on the short arm of human chromosome 11 and frequency of allelic loss in advanced human prostate cancer . Prostate , 32 , 205 – 213 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 19).Dong , J.‐T. , Suzuki , H. , Pin , S. S. , Bova , G. S. , Schaalken , J. A. , Isaacs , W. B. , Barrett , J. C. and Isaacs , J. T.Down‐regulation of the KAI1 metastasis suppressor gene during the progression of human prostatic cancer infrequently involves gene mutation or allelic loss . Cancer Res. , 56 , 4387 – 4390 ( 1996. ). [PubMed] [Google Scholar]
- 20).Ueda , T. , Ichikawa , T. , Tamaru , J. , Mikata , A. , Akakura , K. , Akimoto , S. , Imai , T. , Yoshie , O. , Shiraishi , T. , Yatani , R. , Ito , H. and Shimazaki , J.Expression of the KAI1 protein in benign prostatic hyperplasia and prostatic cancer . Am. J. Pathol. , 149 , 1435 – 1440 ( 1996. ). [PMC free article] [PubMed] [Google Scholar]
- 21).Takaoka , A. , Hinoda , Y. , Sato , S. , Itoh , F. , Adachi , M. , Hareyama , M. and Imai , K.Reduced invasive and metastatic potentials of KAI1‐transfected melanoma cells . Jpn. J. Cancer Res. , 89 , 397 – 404 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22).Dong , J.‐T. , Isaacs , W. B. , Barret , J. C. and Isaacs , J. T.Genomic organization of the human KAI1 metastasis‐suppressor gene . Genomics , 41 , 25 – 32 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 23).Mashimo , T. , Watabe , M. , Hirota , S. , Hosobe , S. , Miura , K. , Tegtmeyer , P. J. , Rinker‐Shaeffer , C. W. and Watabe , K.The expression of the KAI1 gene, a tumor metastasis suppressor, is directly activated by p53 . Proc. Natl. Acad. Sci. USA , 95 , 11307 – 11311 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]