MICA/B expression is inhibited by unfolded protein response and associated with poor prognosis in human hepatocellular carcinoma

Journal of Experimental & Clinical Cancer Research

Lihua Chen¹  Boquan Jin¹  Jenny P -Y Ting²  Angang Yang¹  Chaojun Song¹  Chunmei Zhang¹  Yun Zhang¹  Zhe Wang³  Zengshan Li³  Rongrong Liu¹  Ying Wang¹  Jiuyu Gong⁴  Liang Fang¹ 

[1] Department of Immunology, the Fourth Military Medical University, Xi¿an 710032, Shaanxi, China;Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill 27599, NC, USA;Department of Pathology, the Fourth Military Medical University, Xi¿an, Shaanxi, China;Hospital of Hubei Armed Police Corps, Wuhan, Hubei, China

关键词: Innate immunity;    Unfolded protein response;    Natural killer cell;    Hepatocellular carcinoma;    MICA/B;   

Others  :  1145586
DOI  :  10.1186/s13046-014-0076-7

 received in 2014-07-09, accepted in 2014-09-06,  发布年份 2014

【 摘 要 】

Background

MICA/B are major ligands for NK cell activating receptor NKG2D and previous studies showed that the serum level of soluble MICA (sMICA) is an independent prognostic factor for advanced human hepatocellular carcinoma. However, the correlation between cellular MICA/B expression pattern and human hepatocellular carcinoma progression has not been well explored. The unfolded protein response is one of the main causes of resistance to chemotherapy and radiotherapy in tumor cells. However, whether the UPR in HCC could regulate the expression levels of MICA/B and affect the sensitivity of HCC cells to NK cell cytolysis has not been established yet.

Methods

MICA/B expression pattern was evaluated by immunohistochemistry and Kaplan-Meier survival analysis was done to explore the relationship between MICA/B expression level and patient survival. The protein and mRNA expression levels of MICA/B in SMMC7721 and HepG2 cells treated by tunicamycin were evaluated by flow cytometry, Western Blot and RT-PCR. The cytotoxicity analysis was performed with the CytoTox 96 Non-Radioactive LDH Cytotoxicity Assay.

Results

MICA/B was highly expressed in human hepatocellular carcinoma and the expression level was significantly and negatively associated with tumor-node metastasis (TNM) stages. Patients with low level of MICA/B expression showed a trend of shorter survival time. The unfolded protein response (UPR) downregulated the expression of MICA/B. This decreased protein expression occurred via post-transcriptional regulation and was associated with proteasomal degradation. Moreover, decreased expression level of MICA/B led to the attenuated sensitivity of human HCC to NK cell cytotoxicity.

Conclusion

These new findings of the connection of MICA/B, UPR and NK cells may represent a new concrete theoryof NK cell regulation in HCC, and suggest that targeting this novel NK cell-associated immune evasion pathway may be meaningful in treating patients with HCC.

【 授权许可】

   
2014 Fang et al.; licensee BioMed Central Ltd.

【 图 表 】

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