title: Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer.
abstract: Hepatocyte nuclear factor-4alpha (HNF4alpha) exists in multiple isoforms that are generated by alternative promoter (P1 and P2) usage and splicing. Here we establish monoclonal antibodies (mAbs) for detecting P1 and P2 promoter-driven HNF4alpha, and evaluate their expression in normal adult human tissues and surgically resected carcinomas of different origins. Using immunohistochemical analysis, we demonstrate that, while P1 promoter-driven HNF4alpha is expressed in hepatocytes, small intestine, colon, kidney and epididymis, P2 promoter-driven HNF4alpha is expressed in bile duct, pancreas, stomach, small intestine, colon and epididymis. Altered expression patterns of P1 and P2 promoter-driven HNF4alpha were observed in gastric, hepatocellular and colorectal carcinomas. HNF4alpha was expressed in lung metastases from renal cell, hepatocellular and colorectal carcinoma but was not observed in lung tumours. The P1 and P2 promoter-driven HNF4alpha expression pattern of tumour metastases correlated with the primary site of origin. P1 promoter-driven HNF4alpha was also found in intestinal metaplasia of the stomach. These data provide evidence for the tissue distribution of P1 and P2 promoter-driven HNF4alpha at the protein level and suggest that HNF4alpha may be a novel diagnostic marker for metastases of unknown primary. We propose that the dysregulation of alternative promoter usage of HNF4alpha is associated with the pathogenesis of certain cancers.
authors.affiliation: Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Jiang
authors.forename: H
authors.initials: H
authors.lastname: Hotta
authors.forename: K
authors.initials: K
authors.lastname: Takano
authors.forename: H
authors.initials: H
authors.lastname: Iwanari
authors.forename: K
authors.initials: K
authors.lastname: Sumi
authors.forename: K
authors.initials: K
authors.lastname: Daigo
authors.forename: R
authors.initials: R
authors.lastname: Ohashi
authors.forename: M
authors.initials: M
authors.lastname: Sugai
authors.forename: C
authors.initials: C
authors.lastname: Ikegame
authors.forename: H
authors.initials: H
authors.lastname: Umezu
authors.forename: Y
authors.initials: Y
authors.lastname: Hirayama
authors.forename: Y
authors.initials: Y
authors.lastname: Midorikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Hippo
authors.forename: A
authors.initials: A
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: G
authors.initials: G
authors.lastname: Hasegawa
authors.forename: Pc
authors.initials: P
authors.lastname: Reid
authors.forename: H
authors.initials: H
authors.lastname: Aburatani
authors.forename: T
authors.initials: T
authors.lastname: Hamakubo
authors.forename: J
authors.initials: J
authors.lastname: Sakai
authors.forename: M
authors.initials: M
authors.lastname: Naito
authors.forename: T
authors.initials: T
authors.lastname: Kodama
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011230:Precancerous Conditions / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013274:Stomach Neoplasms / Q000378:metabolism; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D051557:Hepatocyte Nuclear Factor 4; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm