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Differential Expression of p16 INK4a in Azoxymethane‐Induced Mouse Colon Tumorigenesis
Author(s) -
Wang QianShu,
Papanikolaou Alexandros,
Nambiar Prashant R.,
Rosenberg Daniel W.
Publication year - 2000
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/1098-2744(200007)28:3<139::aid-mc2>3.0.co;2-v
Subject(s) - azoxymethane , biology , carcinogenesis , immunohistochemistry , immunostaining , cancer research , tumor suppressor gene , pathology , gene expression , microbiology and biotechnology , gene , immunology , medicine , genetics
Alterations in the p16 INK4a gene have been implicated in the pathogenesis of different human cancers and animal tumors. We postulated that alterations in the p16 INK4a gene may also be involved in mouse colon tumorigenesis induced by the chemical carcinogen azoxymethane (AOM). In the present study, p16 INK4a deletion status and its expression were examined in an AOM‐induced mouse colon tumor model. Polymerase chain reaction–based deletion analysis of p16 INK4a exon 2 showed no deletions in the colon tumors. The expression and localization of p16 INK4a and its gene product were examined by reverse transcription–polymerase chain reaction and immunohistochemical analyses, respectively. The p16 INK4a mRNA levels were low, and in some cases undetectable, in control colon tissue. However, colon tumors exhibited an eightfold increase in p16 INK4a mRNA level when compared with control colon tissue ( P < 0.01). Whereas control colon epithelium was uniformly negative for p16 INK4a immunoreactivity, p16 INK4a ‐immunoreactive cells were markedly increased in preneoplastic lesions and adenomas isolated from AOM‐treated mice. To further examine the p16 INK4a regulatory pathway, the retinoblastoma tumor‐suppressor protein (Rb) was also examined immunohistochemically in these tissues. A heterogeneous Rb immunostaining was observed in preneoplastic lesions and adenomas. Immunohistochemical analysis also showed a reciprocal relationship between p16 INK4a and Rb protein expression. These findings suggest that alterations in the p16 INK4a /Rb pathway may play an important role in AOM‐induced mouse colon tumorigenesis. Mol. Carcinog. 28:139–147, 2000. © 2000 Wiley‐Liss, Inc.