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

Liang Fang,Chunmei Zhang,Rongrong Liu,Jenny P.y Ting ,Jiuyu Gong,Ying Wang,Zhe Wang,Zengshan Li,Chaojun Song,Angang Yang,Boquan Jin,Yun Zhang,Lihua Chen

doi:10.1186/preaccept-5392694761352251

Abstract

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. 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. 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. These new findings of the connection of MICA/B, UPR and NK cells may represent a new concrete theory of 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.

Highlights

Hepatocellular carcinoma (HCC) is the third most common of cancer-related deaths worldwide and accounts for approximately 70%-80% of all primary liver cancer cases [1]
We studied the value of MICA/B for prognosis in HCC patients and showed that the expression levels of MICA/B on hepatoma cells were significantly down-regulated during unfolded protein response (UPR), which led to more resistance of hepatoma cells to NK cell cytotoxicity
Clinical significance of MICA/B expression profile in HCC tissue MICA/B expression pattern was evaluated by immunohistochemistry in a retrospective cohort of HCC patients after tumor resection

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third most common of cancer-related deaths worldwide and accounts for approximately 70%-80% of all primary liver cancer cases [1]. The interaction between NK cell activating receptors and their ligands are known to modulate immune surveillance and affect the tumor progression. The cell surface expression of MICA/B is regulated by heat shock, viral or bacterial infections or pharmacological agents which are known to affect the antitumor immunity [5,8,9]. This raises the possibility that MICA/B may be specific targets on tumor cells for NK-mediated cytolytic activity. 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. 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

Results

Conclusion