title: MICA/B expression is inhibited by unfolded protein response and associated with poor prognosis in human hepatocellular carcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Jiuyu
authors.initials: J
authors.lastname: Gong
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Rongrong
authors.initials: R
authors.lastname: Liu
authors.forename: Zengshan
authors.initials: Z
authors.lastname: Li
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhang
authors.forename: Chaojun
authors.initials: C
authors.lastname: Song
authors.forename: Angang
authors.initials: A
authors.lastname: Yang
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
authors.forename: Boquan
authors.initials: B
authors.lastname: Jin
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D011379:Prognosis; D059748:Proteolysis; D012323:RNA Processing, Post-Transcriptional; D056811:Unfolded Protein Response; D015854:Up-Regulation
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; C098080:MICB antigen