title: Identification and characterization of BH3 domain protein Bim and its isoforms in human hepatocellular carcinomas.
abstract: BH3-only protein Bim is a critical regulator of apoptosis and plays an essential role in mammalian development, but the characterization of Bim and its isoforms in hepatocellular carcinoma (HCC) has not been studied before. Here we investigated the expression, distribution, regulation and role of Bim isoforms in HCC cells. Fifteen Bim isoforms were identified in HCC, with six newly identified isoforms and two newly identified exons. Among of them, Bim EL, L, S, a1, a2, a3, b2, b4 and b6 are abundant isoforms according to their mRNA levels. However only Bim EL, L and S proteins could be clearly detected. Bim mRNA and protein were strongly expressed in HCC tissues compared to relevant non-tumorous regions, but the ratio of variant isoforms showed no difference between tumorous and non-tumorous tissues. Bim isoforms were differentially regulated after chemotherapeutic drug 5-Fluorouracil (5-FU) treatment. Interestingly, Bim EL, L and S, the isoforms known to induce apoptosis strongly, are the least inducible isoforms at their mRNA levels when exposed to the stress, suggesting that post-transcriptional rather than transcriptional, modulations may play a role to enhance their functions. Finally, overexpression of Bim EL, L, S and all alpha isoforms induced apoptosis in HCC cells, while overexpression of Bim beta isoforms showed no effects on cell survival after 5-FU treatment. In conclusion, Bim alpha isoforms appears to have a role in the regulation of apoptosis in HCC cells, which may contribute to not only the growth of tumor cells but also the sensitivity of HCC cells to chemotherapy.
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
authors.forename: Ji
authors.initials: J
authors.lastname: Miao
authors.forename: George G
authors.initials: GG
authors.lastname: Chen
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Yun
authors.forename: Suk-Ying
authors.initials: SY
authors.lastname: Chun
authors.forename: Zi-Zheng
authors.initials: ZZ
authors.lastname: Zheng
authors.forename: Rocky L K
authors.initials: RL
authors.lastname: Ho
authors.forename: Ernest C W
authors.initials: EC
authors.lastname: Chak
authors.forename: Ning-Shao
authors.initials: NS
authors.lastname: Xia
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000302:isolation & purification / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000302:isolation & purification / Q000502:physiology*; D020033:Protein Isoforms / Q000302:isolation & purification / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000302:isolation & purification / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D005472:Fluorouracil