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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2001 Mar;92(3):285–292. doi: 10.1111/j.1349-7006.2001.tb01093.x

Aberrant Expression of pRb, p16, p14ARF, MDM2, p21 and p53 in Squamous Cell Carcinomas of Lung

Qi Xue 1, Takaaki Sano 1, Kenji Kashiwabara 1, Tetsunari Oyama 1, Takashi Nakajima 1,
PMCID: PMC5926708  PMID: 11267938

Abstract

Expression of cell cycle regulatory proteins in both the RB and p53 pathways was investigated in 50 cases of squamaous cell carcinoma (SCC) of the lung using immunohistochemical techniques.Abnormality of pRb and p16 expression was seen at the frequencies of 16% and 78%, respectively, and appeared to be in a reciprocal relationship. On the other hand, strong and diffuse p53 immunoreactivity was seen in 60% of SCCs. MDM2 and p14ARF expression. Moreover, strong p53 expression Moreover, strong p53 expression was not correlated with the expression of p21. In comparing clinicopathological status with immunohistochemical results, lack of p16 immunoreactivity was observed in the elderly group (over 65 years) as compared with the younger group (less than 65 years) Strong p53 expression was frequently observed in higher stages of SCC, with the developing tumor located in the central field of the lung. Similarly, the frequency of p14ARF expression was high in centrally developed SCC, but low in SCC developed in the periphery. These results suggest that disruption of the RB and p53 pathways is a frequent event in SCC, and that abnormal expression of p16 and p53 plays a more critical role than that of pRB, p14ARF and MDM2 in the development of SCC of the lung.

Keywords: tochemistry pRB pathway, p53 pathway, Squamous cell carcinoma, Lung, Immunohistochemistry

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References

  • 1.Serrano , M. , Hannon , G. J. . and Beach , D.A new regulatory motif in cell‐cycle control causing specific inhibition of cyclin D/CDK4 . Nature , 366 , 704 – 707 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 2.Burns , K. L. , Ueki , K. , Jhung , S. L. , Koh , J. . and Louis , D. N.Molecular genetic correlates of p16, cdk4 and pRb immunohistochemistry in glioblastomas . J. Neuropathol. Exp. Neural. , 57 , 122 – 130 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 3.Sherr , C. J.Cancer cell cycles . Science , 274 , 1672 – 1677 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 4.Hollstein , M. , Sidransky , D. , Vogelstein , B. . and Harris , C. C.p53 mutations in human cancers . Science , 253 , 49 – 53 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 5.Prives , C. . and Hall , P. A.The p53 pathway . J. Pathol , 187 , 112 – 126 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 6.Hirano , A. , Kong , Y.‐Y. , Matsuoka , S. , Wakeham , A. , Ruland , J. , Yoshida , H. , Liu , D. , Elledge , S. J. . and Mak , T. W.DNA damage‐induced activation of p53 by the checkpoint kinase Chk2 . Science , 287 , 1824 – 1827 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 7.Kamb , A. , Gruis , N. A. , Weaver‐Feldhaus , J. , Liu , Q. , Harshman , K. , Tavtigian , S. V. , Stockert , E. , Day , R. S. , III , Johnson , B. E. . and Skolnik , M. H.A cell cycle regulator potentially involved in genesis of many tumor types . Science , 264 , 436 – 440 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 8.Geradts , J. , Kratzke , R. A. , Niehans , G. A. . and Lincoln , C. E.Immunohistochemical detection of the cyclin‐dependent kinase inhibitor 2/multiple tumor suppressor gene 1 (CDKN2/MTS1) product p16 in archival human solid tumors: correlation with retinoblastoma protein expression . Cancer Res. , 55 , 6006 – 6011 ( 1995. ). [PubMed] [Google Scholar]
  • 9.Cairns , P. , Polascik , T. J. , Eby , Y. , Tokino , K. , Califano , J. , Merlo , A. , Mao , L. , Herath , J. , Jenkins , R. . and Westra , W.Frequency of homozygous deletion at p16/CDKN2 in primary human tumors . Nat. Genet. , 11 , 210 – 212 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 10.Hebert , J. , Cayuela , J. M. , Berkeley , J. . and Sigaux , F.Candidate tumor‐suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T‐ but not from B‐cell lineage acute lymphoblastic leukemias . Blood , 84 , 4038 – 4044 ( 1994. ). [PubMed] [Google Scholar]
  • 11.Merlo , A. , Herman , J. G. , Mao , L. , Lee , D. J. , Gabrielson , E. , Baylin , S. B. . and Sidransky , D.5′ CpG island methyla‐tion is associated with transcriptional silencing of the tumor suppressor p16/CDKN2/MTSl in human cancers . Nat Med. , 1 , 686 – 692 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 12.Herman , J. G. , Merlo , A. , Mao , L. , Lapidus , R. G. , Issa , J. P. , Davidson , N. E. , Sidransky , D. . and Baylin , S. B.Inactivation of the CDKN2A/pl6/MTSl gene is frequently associated with aberrant DNA methylation in all common human cancers . Cancer Res. , 55 , 4525 – 4530 ( 1995. ). [PubMed] [Google Scholar]
  • 13.Gonzales‐Zulueta , M. , Bender , C. M. , Yang , A. S. , Nguyen , T. , Beart , R. W. , van Tornout , J. M. . and Jones , P. A.Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing . Cancer Res. , 55 , 4531 – 4535 ( 1995. ). [PubMed] [Google Scholar]
  • 14.Quelle , D. E. , Zindy , F. , Ashmun , R. A. . and Sherr , C. J.Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest . Cell , 83 , 993 – 1000 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 15.Pomerantz , J. , Schreber‐Agus , N. , Liegeois , N. J. , Silverman , A. , Alland , L. , Poles , J. , Chen , K. , Orlow , L , Lee , H. W. , Cordon‐Cardo , C. . and Depinho , R. A.The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2′s inhibition of p53 . Cell , 92 , 713 – 723 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 16.Zhang , Y. , Xiong , Y. . and Yarbrough , W. G.ARF promotes MDM2 degradation and stabilizes p53: ARF‐INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways . Cell , 92 , 725 – 734 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 17.Bates , S. , Phillips , A. C. , Clark , P. A. , Stott , F. , Peters , G. , Ludwig , R. L. . and Vousden , K. H.P14ARF links the tumour suppressors RB and p53 . Nature , 395 , 124 – 125 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 18.Stott , F. J. , Bates , S. , James , M. C. , McConnell , B. B. , Starborg , M. , Brookes , S. , Palmero , I. , Ryan , K. , Kara , E. , Vousden , K. H. . and Peters , G.The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2 . EMBO J. , 17 , 5001 – 5014 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Levin , N. A. , Brzoska , P. , Gupta , N. , Minna , J. D. , Gray , J. W. . and Christman , M. F.Identification of frequent novel genetic alteration in small cell lung carcinoma . Cancer Res. , 54 , 5086 – 5091 ( 1994. ). [PubMed] [Google Scholar]
  • 20.Kratzke , R. A. , Greatens , T. M. , Rubins , J. B. , Maddaus , M. A. , Niewoehner , D. E. , Niehans , G. A. . and Geradts , J.Rb and p16INK4a expression in resected non‐small cell lung tumors . Cancer Res. , 56 , 3415 – 3420 ( 1996. ). [PubMed] [Google Scholar]
  • 21.Gorgoulis , V. G. , Zacharators , P. , Kotsinas , A. , Liloglou , T. , Veslemes , M. , Kittas , C. , Rassidakis , A. , Halazonetis , T. D. . and Field , J. K.Alteration of the p16‐pRb pathway and the chromosome locus 9p21‐22 in non‐small cell lung carcinomas: relationship with p53 and MDM2 protein expression . Am. J. Pathol. , 153 , 1749 – 1765 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Kashiwabara , K. , Oyama , T. , Sano , T. , Fukuda , T. . and Nakajima , T.Correlation between methylation status of the p16/CDKN2 gene and the expression of p16 and Rb proteins in primary non‐small cell lung cancers . Int. J. Cancer , 79 , 215 – 220 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 23.Saito , T. , Nakajima , T. . and Mogi , K.Immunohistochemical analysis of cell cycle‐associated proteins p16, pRb, p53, p27 and Ki‐67 in oral cancer and precancer with special reference to verrucous carcinomas . J. Oral Pathol. Med. , 28 , 226 – 232 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 24.Kato , H. , Yoshikawa , M. , Fukai , Y. , Tajima , K. , Mazuda , N. , Tsukada , K. , Kuwano , H. . and Nakajima , T.An immunohistochemical study of p16, pRb, p21 and p53 proteins in human esophageal cancers . Anticancer Res. , 20 , 345 – 349 ( 2000. ). [PubMed] [Google Scholar]
  • 25.Sano , T. , Hikino , T. , Xue , Q. , Saito , T. , Kashiwabara , K. , Oyama , T. . and Nakajima , T.Immunohistochemical inactivation of p14ARF concomitant with MDM2 overexpression inversely correlated with p53 overexpression in oral squamous cell carcinoma . Pathol. Int. , 50 , 709 – 716 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 26.Yuan , J. , Knorr , J. , Altmannsberger , M. , Goeckenjan , G. , Ahr , A. , Scharl , A. . and Strebhardt , K.Expression of p16 and lack of pRB in primary small cell lung cancer . J. Pathol. , 189 , 358 – 362 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 27.Marchetti , A. , Dolgioni , C. , Barbareschi , M. , Buttitta , F. , Pellegrin , S. , Gaeta , P. , La‐Rocca , R. , Merlo , G. , Chella , A. , Angeletti , C. A. , Dalla‐Palma , P. . and Bevilacqua , G.Cyclin Dl and retinoblastoma susceptibility gene alteration in non‐small cell lung cancer . Int. J. Cancer , 75 , 187 – 192 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 28.Higashiyama , M. , Doi , O. , Kodama , K. , Yokouchi , H. . and Tateishi , R.Retinoblastoma protein expression in lung cancer: and immunohistochemical analysis . Oncology , 51 , 544 – 551 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 29.Reissmann , P. T. , Koga , H. , Takahashi , R. , Figlin , R. A. , Holmes , E. C. , Piantadosi , S. , Cordon‐Cardo , C. . and Slamon , D. J.Inactivation of the retinoblastoma susceptibility gene in non‐small cell lung cancer. The Lung Cancer Study Group . Oncogene , 8 , 1913 – 1919 ( 1993. ). [PubMed] [Google Scholar]
  • 30.Gazzeri , S. , Gouyer , V. , Vour'ch , C. , Brambilla , C. . and Brambilla , E.Mechanisms of p16INK4A inactivation in non small‐cell lung cancers . Oncogene , 16 , 497 – 504 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 31.Huang , C. I. , Taki , T. , Higashiyama , M. , Kohno , N. . and Miyake , M.p16 protein expression is associated with a poor prognosis in squamous cell carcinoma of the lung . Br. J. Cancer , 82 , 374 – 380 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Sanchez‐Cespedes , M. , Reed , A. L. , Buta , M. , Wu , L. , Westra , W. H. , Herman , J. G. , Yang , S. C. , Jen , J. . and Sidransky , D.Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutation in non‐small cell lung cancer . Oncogene , 18 , 5843 – 5849 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 33.Lee , Y. C. , Chang , Y. L. , Luh , S. P. , Lee , J. M. . and Chen , J. S.Significance of p53 and Rb protein expression in surgically treated non‐small cell lung cancers . Ann. Thorac. Surg. , 68 , 343 – 347 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 34.Shapiro , G. L , Edwards , C. D. , Kobzik , L. , Godleski , J. , Richards , W. , Sugarbaker , D. J. . and Rollins , B. J.Reciprocal Rb inactivation and p16INK4 expresssion in primary lung cancers and cell lines . Cancer Res. , 55 , 505 – 509 ( 1995. ). [PubMed] [Google Scholar]
  • 35.Sano , T. , Oyama , T. , Kashiwabara , K. , Fukuda , T. . and Nakajima , T.Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions . Am. J. Pathol. , 153 , 1741 – 1748 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Gage , J. R. , Meyers , C. . and Wettstein , F. O.The E7 proteins of the non‐nic human oncogenic papillomavirus type 6b (HPV‐6b) and of the oncogenic HPV‐16 differ in retinoblastoma protein binding and other properties . J. Virol. , 64 , 723 – 730 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Vonlanthen , S. , Heighway , J. , Tschan , M. P. , Borner , M. M. , Altermatt , H. J. , Kappeler , A. , Tobler , A. , Fey , M. F. , Thatcher , N. , Yarbrough , W. G. . and Betticher , D. C.Expression of pl6INK4a/p16α and p19ARF/pl6β is frequently altered in non‐small cell lung cancer and correlates with p53 overexpression . Oncogene , 17 , 2779 – 2785 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 38.Gazzeri , S. , Valle , V. D. , Chaussade , L. , Brambilla , C. , Larsen , C. J. . and Brambilla , E.The human p19ARF protein encoded by the β transcript of the p16INK4a gene is frequently lost in small cell lung cancer . Cancer Res. , 58 , 3926 – 3931 ( 1998. ). [PubMed] [Google Scholar]
  • 39.Sanchez‐Cespedes , M. , Reed , A. L. , Buta , M. , Wu , L. , Westra , W. H. , Herman , J. G. , Yang , S. C. , Jen , J. . and Sidransky , D.Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non‐small cell lung cancer . Oncogene , 18 , 5843 – 5849 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 40.Oliner , J. D. , Kinzler , K. W. , Meltzer , P. S. , George , D. L. . and Vogelstein , B.Amplification of a gene encoding a p53‐associated protein in human sarcomas . Nature , 358 , 80 – 83 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 41.Reifenberger , G. , Liu , L. , Ichimura , K. , Schmidt , E. E. . and Collins , V. P.Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations . Cancer Res. , 53 , 2736 – 2739 ( 1993. ). [PubMed] [Google Scholar]
  • 42.Capoulade , C. , Bressac‐de Paillerets , B. , Lefrere , L , Ronsin , M. , Feunteun , J. . and Tursz , T.Overexpression of MDM2, due to enhanced translation, results in inactivation of wild‐type p53 in Burkitt's lymphoma cells . Oncogene , 16 , 1603 – 1610 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 43.Soslow , R. A. , Altorki , N. K. , Yang , G. , Xie , D. . and Yang , C. S.mdm‐2 expression correlates with wild‐type p53 status in esophageal adenocarcinoma . Mod. Pathol. , 12 , 580 – 586 ( 1999. ). [PubMed] [Google Scholar]
  • 44.Agarwal , S. , Mathur , M. , Srivastava , A. . and Ralhan , R.MDM2/p53 co‐expression in oral premalignant and malignant lesions: potential prognostic implications . Oral. Oncol. , 35 , 209 – 216 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 45.Moller , M. B. , Ino , Y. , Gerdes , A.‐M. , Skjodt , K. , Louis , D. N. . and Pedersen , N. T.Aberrations of the p53 pathway components p53, MDM2, and CDKN2A appear independent in diffuse large B‐cell lymphoma . Leukemia , 13 , 453 – 459 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 46.Ichimura , K. , Bolin , M. B. , Goike , H. M. , Schmidt , E. E. , Moshref , A. . and Collins , V. P.Deregulation of the p14ARF/ MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with GrS transition control gene abnormalities . Cancer Res. , 60 , 417 – 424 ( 2000. ). [PubMed] [Google Scholar]
  • 47.Kamijo , T. , Zindy , F. , Roussel , M. F. , Quelle , D. E. , Downing , J. R. , Ashmun , R. A. , Grosveld , G. . and Sherr , C. J.Tumor suppression at the mouse INK4A locus mediated by the alternative reading frame product p19ARF . Cell , 91 , 649 – 659 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 48.Michieli , P. , Chedid , M. , Lin , D. , Pierce , J. H. , Mercer , W. E. . and Givol , D.Induction of WAF1/CIP1 by a p53‐inde‐pendent pathway . Cancer Res. , 54 , 3391 – 3395 ( 1994. ). [PubMed] [Google Scholar]
  • 49.Steinman , R. A. , Hoffman , B. , Iro , A. , Guillouf , C. , Liebermann , D. A. . and el‐Houseini , M. E.Induction of p21 (WAF‐1/CIP1) during differentiation . Oncogene , 9 , 3389 – 3396 ( 1994. ). [PubMed] [Google Scholar]
  • 50.Hou , M. , Morishita , Y. , Lijima , T. , Inadome , Y. , Mase , K. , Dai , Y. . and Noguchi , M.DNA methylation and expression of p16 (INK4A) gene in pulmonary adenocarcinoma and anthracosis in background lung . Int. J. Cancer , 84 , 608 – 613 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 51.Quinlain , D. C. , Davidson , A. G. , Summers , C. L. , Warden , H. E. . and Doshi , H. M.Accumulation of p53 protein correlates with a poor prognosis in human lung cancer . Cancer Res. , 52 , 4828 – 4831 ( 1992. ). [PubMed] [Google Scholar]
  • 52.Malara , N. M. , Sgambato , A. , Granone , P. , Flamini , G. , Margaritora , S. , Boninsegna , A. , Cesario , A. , Galetta , D. , Yang , Q. . and Cittadini , A.Biological characterization of central and peripheral primary non‐small cell lung cancers (NSCLC) . Anticancer Res. , 19 , 2249 – 2252 ( 1999. ). [PubMed] [Google Scholar]
  • 53.Nuorva , K. , Soini , Y. , Kamel , D. , Autio‐Harmainen , H. , Risteli , L. , Risteli , J. , Vahakangas , K. . and Paakko , P.Concurrent p53 expression in bronchial dysplasias and squamous cell lung carcinomas . Am. J. Pathol. , 142 , 725 – 732 ( 1993. ). [PMC free article] [PubMed] [Google Scholar]

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