title: Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy.
abstract: A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention.
authors.affiliation: Shogo Ohkoshi, Department of Internal Medicine, School of Life Dentistry at Niigata, The Nippon Dental University, Chuo-ku, Niigata 951-8580, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ohkoshi
authors.affiliation: Shogo Ohkoshi, Department of Internal Medicine, School of Life Dentistry at Niigata, The Nippon Dental University, Chuo-ku, Niigata 951-8580, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yano
authors.affiliation: Shogo Ohkoshi, Department of Internal Medicine, School of Life Dentistry at Niigata, The Nippon Dental University, Chuo-ku, Niigata 951-8580, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Matsuda
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D015513:Oncogene Proteins / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D028884:Karyopherins; D015513:Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D025521:Tumor Suppressor Proteins; D000097606:Exportin 1 Protein; C493956:CDKN1A protein, human
keywords: Chromosome region maintenance 1; HBx; Hepatocellular carcinoma; Interferon; Nucleo-cytoplasmic export; Oncogene; Selective inhibitors of nuclear export; Subcellular localization; Tumor suppressors; p21