title: Overexpressed nuclear BAG-1 in human hepatocellular carcinoma is associated with poor prognosis and resistance to doxorubicin.
abstract: Bcl-2-associated athanogene-1 (BAG-1) is a multifunctional anti-apoptotic protein which regulates an array of cellular processes, including apoptosis, signaling, proliferation, transcription, and cell motility and has been reported to be over-expressed in a number of human malignancies. To investigate the possible involvement of BAG-1 in tumorigenesis of hepatocellular carcinoma (HCC), we performed Western blot analysis in eight paired samples of HCC and adjacent peritumoral tissues and immunohistochemistry in 65 paraffin sections of HCC, which both showed an enhanced expression of nuclear BAG-1 isoform in HCC tissues. Statistical analysis confirmed that overexpression of nuclear BAG-1 in HCC tissues was significantly associated with histological grading (P < 0.001), poor prognosis (P = 0.004), and was found to be an independent prognostic indicator for HCC (P = 0.023). We also noted that BAG-1 was overexpressed in four HCC cell lines compared with a normal hepatocyte cell line, and BAG-1 overexpression increased resistance of HCC cells to doxorubicin, a common chemotherapeutic agent for HCC. Furthermore, we observed that knock down of BAG-1 with siRNA in HepG2 cells increased the chemosensitivity of cells, a process mediated through inhibition of doxorubicin-triggered NF-κB activation; and knock down of BAG-1 suppressed proliferation and cell cycle transition of HepG2 cells. In consequence, our results for the first time indicated that BAG-1 was dysregulated in HCC and suppression of BAG-1 expression which resulted in inhibiting of NF-κB signaling might be developed into a new strategy in HCC therapy.
authors.affiliation: Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, P.R., China.
authors.forename: Wenkai
authors.initials: W
authors.lastname: Ni
authors.forename: Buyou
authors.initials: B
authors.lastname: Chen
authors.forename: Guoxiong
authors.initials: G
authors.lastname: Zhou
authors.forename: Cuihua
authors.initials: C
authors.lastname: Lu
authors.forename: Mingbing
authors.initials: M
authors.lastname: Xiao
authors.forename: Chengqi
authors.initials: C
authors.lastname: Guan
authors.forename: Yixing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Song
authors.initials: S
authors.lastname: He
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
authors.forename: Runzhou
authors.initials: R
authors.lastname: Ni
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D004317:Doxorubicin
keywords: BCL-2-ASSOCIATED ATHANOGENE-1 (BAG-1); CHEMORESISTANCE; HEPATOCELLULAR CARCINOMA (HCC); NUCLEAR FACTOR-κB (NF-κB); PROGNOSIS