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Identification and characterization of BH3 domain protein Bim and its isoforms in human hepatocellular carcinomas

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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.

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Acknowledgements

We thank Genome Research Centre of the University of Hong Kong and, Department of Biochemistry, The Chinese University of Hong Kong for providing DAN facilities for this study.

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Authors and Affiliations

  1. Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong

    Ji Miao, George G. Chen, Suk-Ying Chun, Rocky L. K. Ho, Ernest C. W. Chak & Paul B. S. Lai

  2. The Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, Xiamen University, Xiamen, China

    Ji Miao, Zi-Zheng Zheng & Ning-Shao Xia

  3. Department of Pathology, Cancer Center of Sun Yat-Sen University, Guangzhou, China

    Jing-Ping Yun

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  1. Ji Miao
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  2. George G. Chen
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  9. Paul B. S. Lai
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Correspondence to George G. Chen.

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Miao, J., Chen, G.G., Yun, JP. et al. Identification and characterization of BH3 domain protein Bim and its isoforms in human hepatocellular carcinomas. Apoptosis 12, 1691–1701 (2007). https://doi.org/10.1007/s10495-007-0093-5

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