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The Role of MAPK-ERK Pathway in 67-kDa Laminin Receptor-Induced FasL Expression in Human Cholangiocarcinoma Cells

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Abstract

Background and Aims

Cancer cells are thought to possess immune evasion properties due to FasL overexpression in many types of human tumors. In the present study, we set out to investigate the role of MAPK-ERK pathway in 67-kDa laminin receptor induced FasL expression and FasL-mediated apoptosis in human cholangiocarcinoma cells.

Methods

The expression of FasL and its promoter activity in cultured cholangiocarcinoma cells were examined after treatment with laminin or transfection with plasmids containing siRNA targeted to 67-kDa laminin receptor. The effects of MAPK-ERK cascade inhibitor and c-Myc inhibition by siRNA on 67-kDa laminin receptor-induced FasL expression were determined. Apoptosis assay was performed to analyze the apoptosis of lymphocytes cocultured with cholangiocarcinoma cells treated with or without MAPK-ERK cascade inhibitor.

Results

Our results revealed that the specific MAPK-ERK cascade inhibitor, PD98059, significantly attenuated phosphorylation of c-Myc on Ser-62 and FasL upregulation in QBC-939 cells and these cells showed decreased cytotoxicity against Fas-sensitive Jurkat T cells. A luciferase reporter assay revealed that FasL promoter activity was significantly reduced in cells treated with PD98059 or transfected with c-Myc siRNA.

Conclusions

Based on these results, we conclude that 67LR induces FasL expression and cytotoxicity against Fas-sensitive Jurkat T cells in human cholangiocarcinoma cells through the phosphorylation of c-Myc on Ser-62 and the subsequent activation of the FasL promoter through the ERK pathway.

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Acknowledgments

This work was supported by the National Natural Science Foundation (No. 30772109). The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Hepatobiliary Surgery Hospital and Institute, Southwest Hospital, Third Military Medical University, 400038, Chongqing, China

    Shi-Gang Duan, Long Cheng, Da-Jiang Li, Jin Zhu, Yan Xiong, Xiao-Wu Li & Shu-Guang Wang

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  1. Shi-Gang Duan
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  2. Long Cheng
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  3. Da-Jiang Li
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  4. Jin Zhu
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  5. Yan Xiong
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Correspondence to Shu-Guang Wang.

Additional information

Shi-Gang Duan, Long Cheng, and Da-Jiang Li contributed equally to this work.

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Duan, SG., Cheng, L., Li, DJ. et al. The Role of MAPK-ERK Pathway in 67-kDa Laminin Receptor-Induced FasL Expression in Human Cholangiocarcinoma Cells. Dig Dis Sci 55, 2844–2852 (2010). https://doi.org/10.1007/s10620-009-1121-9

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  • DOI: https://doi.org/10.1007/s10620-009-1121-9

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