title: Induction of apurinic endonuclease 1 overexpression by endoplasmic reticulum stress in hepatoma cells.
abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Previous studies have noted the induction of endoplasmic reticulum stress or apurinic endonuclease 1 (APE1) expression in many tumors. Therefore, the aim of this study was to investigate the relationship between endoplasmic reticulum (ER stress) and APE1 in hepatocellular carcinoma. Here we investigate the expression of APE1 during ER stress in HepG2 and Huh-7 cell lines. Tunicamycin or brefeldin A, two ER stress inducers, increased APE1 and GRP78, an ER stress marker, expression in HepG2 and Huh-7 cells. Induction of APE1 expression was observed through transcription level in response to ER stress. APE1 nuclear localization during ER stress was determined using immunofluorescence assays in HepG2 cells. Furthermore, expression of Hepatitis B virus pre-S2∆ large mutant surface protein (pre-S2∆), an ER stress-induced protein, also increased GRP78 and APE1 expression in the normal hepatocyte NeHepLxHT cell line. Similarly, tumor samples showed higher expression of APE1 in ER stress-correlated liver cancer tissue in vivo. Our results demonstrate that ER stress and HBV pre-S2∆ increased APE1 expression, which may play an important role in resistance to chemotherapeutic agents or tumor development. Therefore, these data provide an important chemotherapeutic strategy in ER stress and HBV pre-S2∆-associated tumors.
authors.affiliation: Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. junglecc@kmu.edu.tw.
authors.forename: Tsung-Lin
authors.initials: TL
authors.lastname: Cheng
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan. pschen@mail.chna.edu.tw.
authors.forename: Pin-Shern
authors.initials: PS
authors.lastname: Chen
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan. spadem39445@gmail.com.
authors.forename: Ren-Hao
authors.initials: RH
authors.lastname: Li
authors.affiliation: Translational Research Center, Cancer Center, Department of Medical Research, and Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. yuanssf@ms33.hinet.net.
authors.forename: Shyng-Shiou
authors.initials: SS
authors.lastname: Yuan
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan. suihjen@nhri.org.tw.
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan. hung86@mail.chna.edu.tw.
authors.forename: Jui-Hsiang
authors.initials: JH
authors.lastname: Hung
mesh_terms: D020126:Brefeldin A / Q000494:pharmacology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; C050807:presurface protein 2, hepatitis B surface antigen; D014415:Tunicamycin; D020126:Brefeldin A; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase