Lower protein expression levels of MHC class I chain-related gene A in hepatocellular carcinoma are at high risk of recurrence after surgical resection

Chung-Feng Huang,Yao-Li Chen,Ching-I Huang,Wen-Tsan Chang,Ming-Lung Yu,Ming-Lun Yeh,Wan-Long Chuang,Zu-Yau Lin,Shinn-Cherng Chen,Jee-Fu Huang,Shu-Chi Wang,Chia-Yen Dai

doi:10.1038/s41598-018-34155-7

Abstract

MHC class I chain-related gene A (MICA) variants have been associated with hepatocellular carcinoma (HCC). Their association with MICA expression in cancer cells and cancer recurrence is unknown. SNP rs2596542 of MICA was tested in 193 HCC patients with surgical resection. The corresponding MICA expression in the cancer tissue was measured by immunochemistry microarray. Patients with the SNP rs2596542 A allele had significantly lower MICA expression in tumor tissue than did those with the GG genotype (24.7 ± 15.1% vs. 41.5 ± 23.4%, P < 0.001). Patients who had HCC recurrence had significantly lower MICA expression in tumor tissue (34.2 ± 21.8% vs. 24.0 ± 19.8%, P = 0.03). Cox regression analysis revealed that the factors independently predictive of HCC recurrence included low MICA expression (hazard ratio [HR]/95%confidence intervals [CI]: 2.77/1.07–7.14, P = 0.035) and tumor size (HR/CI: 5.22/2.11–12.96, P < 0.001). Compared to patients with tumors <5 cm and MICA expression >30%, patients with either one and both two risk factors had HCC HRs of 9.76 (C.I. 1.27–75.03, P = 0.03) and 27.30 (C.I. 3.46–215.6, P = 0.002), respectively. We concluded that low cellular MICA expressions were at a greater risk of HCC recurrence after curative treatment.

Highlights

MHC class I chain-related gene A (MICA) has been linked to hepatocellular carcinoma (HCC) susceptibility in patients with hepatitis B virus (HBV) and HCV infection
A total of 193 HCC patients who underwent surgical resection were enrolled for analysis
The risk of HCC recurrence did not differ between patients with “tumor 5 cm but MICA > 30%” (P = 0.13). This is the largest clinical study that has addressed the issue of the expression of membrane-bound MICA in HCC patients with different MICA genetic variants and the corresponding cancer recurrence outcomes

Summary

Introduction

MHC class I chain-related gene A (MICA) has been linked to HCC susceptibility in patients with hepatitis B virus (HBV) and HCV infection. Genetic predisposition may contribute to HCC occurrence with variable impacts depending on different etiologies and ethnicities[7,8,9]. MICA is the ligand for the natural killer cell group 2D receptor (NKG2D). Overproduction of soluble MICA in the circulation may down-regulate NKG2D expression in immune cells, further diminishing NKG2D-mediated anti-tumor immunity. MICA is a transmembrane protein, and the expression of cellular MICA in HCC patients in the clinical setting has rarely been explored. No studies have investigated whether the expression of cellular MICA differs among Asian HCC patients with different MICA genetic predispositions. We aimed to study the effects of the host genetics of MICA and MICA expression on the cancer tissues. We further sought to elucidate the association of MICA expression in the cancer tissues with patient prognosis in terms of HCC recurrence

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