title: Expression of G1-S modulators (p53, p16, p27, cyclin D1, Rb) and Smad4/Dpc4 in intrahepatic cholangiocarcinoma.
abstract: Aberrations of G1-S cell cycle arrest and TGF-beta/Smad pathway are critical events in human carcinogenesis. We studied alterations of both pathways by immunohistochemical staining for p53, p16, p27, cyclin D1, Rb and Smad4/Dpc4 in 42 intrahepatic cholangiocarcinomas (ICCs). Abnormal nuclear overexpression of p53 and cyclin D1 was noted in 15 (35.7%) and 26 (61.9%) cases, respectively. Total loss of p16, p27, Rb and Smad4 was detected in 15 (35.7%), 13 (31.0%), 5 (11.9%) and 19 (45.2%) cases, respectively. Forty cases (95.2%) showed aberrations of at least one of the pathways, of which 21 (50%) revealed abnormality in G1-S pathway only, 17 (40.5%) had abnormalities in both pathways and 2 (4.8%) had an abnormality in TGF-beta/Smad pathway only. Among the examined genes, loss of Smad4 was found to have a positive relationship with the pTNM stage (P < 0.05). The overall stage of the high-altered group (alterations in 2 to 5 of the genes, n = 29) was significantly higher than that of the low-altered group (alteration of one or no gene, n = 13) (P < 0.01). We also examined the expression of above genes in the accompanying biliary dysplasia and found out abnormal expression of p53, cyclin D1 or p16 in 7 out of 13 dysplastic lesions. Our data suggest that abnormal G1-S cell cycle and altered TGF-beta/Smad pathway are major events in cholangiocarcinogenesis. Moreover, there might be a possible cumulative effect of the alterations in the examined genes upon the clinical outcome of patients with resectable ICCs.
authors.affiliation: Department of Pathology, Inje University Seoul Paik Hospital and Seoul National University College of Medicine, Korea.
authors.forename: Yun Kyung
authors.initials: YK
authors.lastname: Kang
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Ja June
authors.initials: JJ
authors.lastname: Jang
mesh_terms: D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D009124:Muscle Proteins; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D016160:Retinoblastoma Protein / Q000378:metabolism; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C058992:Tagln protein, mouse; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1