Identification of the Genes Chemosensitizing Hepatocellular Carcinoma Cells to Interferon-α/5-Fluorouracil and Their Clinical Significance

Autor: Kohei Shomori, Yusuke Mizuta, Tomohiko Sakabe, Kazue Gonda, Hiroshi Wada, Hiroyuki Tsuchiya, Junya Azumi, Goshi Shiota, Hiroaki Nagano, Keita Kanki, Daisaku Yamada
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Male
Mouse
Cancer Treatment
lcsh:Medicine
Apoptosis
Mice
SCID
AMP-Activated Protein Kinases
Mice
Gene expression
Pathology
lcsh:Science
Multidisciplinary
Liver Neoplasms
Transfection
Animal Models
Gene Therapy
Hep G2 Cells
Middle Aged
Endoplasmic Reticulum Stress
Prognosis
Gene Expression Regulation
Neoplastic
Treatment Outcome
Oncology
Liver
Hepatocellular carcinoma
Medicine
Female
Fluorouracil
Research Article
Adult
Programmed cell death
Antimetabolites
Antineoplastic
Carcinoma
Hepatocellular
Cell Survival
Biology
Protein Serine-Threonine Kinases
N-Acetylglucosaminyltransferases
Model Organisms
Diagnostic Medicine
Gastrointestinal Tumors
Carcinoma
medicine
Animals
Humans
Immunologic Factors
Protein kinase A
Aged
lcsh:R
Receptor
Transforming Growth Factor-beta Type II
Cancers and Neoplasms
Interferon-alpha
Hepatocellular Carcinoma
Chemotherapy and Drug Treatment
medicine.disease
Molecular biology
Cancer research
lcsh:Q
Receptors
Transforming Growth Factor beta
Biomarkers
Transforming growth factor
General Pathology
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 2, p e56197 (2013)
ISSN: 1932-6203
Popis: The incidence of advanced hepatocellular carcinoma (HCC) is increasing worldwide, and its prognosis is extremely poor. Interferon-alpha (IFN-α)/5-fluorouracil (5-FU) therapy is reportedly effective in some HCC patients. In the present study, to improve HCC prognosis, we identified the genes that are sensitizing to these agents. The screening strategy was dependent on the concentration of ribozymes that rendered HepG2 cells resistant to 5-FU by the repeated transfection of ribozymes into the cells. After 10 cycles of transfection, which was initiated by 5,902,875 sequences of a ribozyme library, three genes including protein kinase, adenosine monophosphate (AMP)-activated, gamma 2 non-catalytic subunit (PRKAG2); transforming growth factor-beta receptor II (TGFBR2); and exostosin 1 (EXT1) were identified as 5-FU-sensitizing genes. Adenovirus-mediated transfer of TGFBR2 and EXT1 enhanced IFN-α/5-FU-induced cytotoxicity as well as 5-FU, although the overexpression of these genes in the absence of IFN-α/5-FU did not induce cell death. This effect was also observed in a tumor xenograft model. The mechanisms of TGFBR2 and EXT1 include activation of the TGF-β signal and induction of endoplasmic reticulum stress, resulting in apoptosis. In HCC patients treated with IFN-α/5-FU therapy, the PRKAG2 mRNA level in HCC tissues was positively correlated with survival period, suggesting that PRKAG2 enhances the effect of IFN-α/5-FU and serves as a prognostic marker for IFN-α/5-FU therapy. In conclusion, we identified three genes that chemosensitize the effects of 5-FU and IFN-α/5-FU on HCC cells and demonstrated that PRKAG2 mRNA can serve as a prognostic marker for IFN-α/5-FU therapy.
Databáze: OpenAIRE
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