Abstract
Major histocompatibility complex (HLA) class I chain-related protein A (MICA) regulates immune surveillance through activation of NKG2D (natural killer group 2D) receptor. However, the genetic association, potential function, and predictive ability of MICA alleles with colorectal cancer (CRC) prognosis remain undefined. In this study, we characterized MICA alleles in tissue samples from 104 patients with CRC and 536 healthy controls and carried out genetic association studies by molecular and clinical CRC phenotypes. Preliminary sequence analysis revealed that MICA ∗009:01 or ∗049 alleles were significantly decreased in patients with CRC (p = 0.0049), and further stratification analysis indicated that MICA ∗012:01 allele was associated with patients with CRC and carrying KRAS codon 12 mutation (p = 0.027). The functional consequences of MICA alleles were examined via transfected CRC cell lines which showed that overexpression of MICA ∗012:01 enhanced the proliferation, invasion, and metastatic phenotype of CRC. Preliminary analysis of disease-free survival time in patients with and without MICA ∗012:01 suggest this allele may be predictive for poor prognosis of patients with KRAS codon 12 mutated CRC, as no somatic mutation of MICA gene was detected in CRC tumors compared to paracancerous tissues. Our study indicates that MICA ∗012:01 allele is associated with KRAS-mutated CRC, facilitates CRC invasion and metastasis, and possibly reduces the survival of patients with KRAS-mutated CRC.
Highlights
RESULTSColorectal cancer is the third most common cancer diagnosed and the second leading cause of cancer deaths in the United States (Siegel et al, 2019) and China (Chen W. et al, 2016)
MICA is commonly expressed in tumor cells as a tumorassociated antigen that works in tandem with natural killer group 2D (NKG2D) receptor to regulate immunosurveillance (Groh et al, 2002; Choy and Phipps, 2010)
Our genetic association studies indicate that MICA ∗009:01 or ∗049 were associated with decreased frequency of certain colorectal cancer (CRC) subtypes, and MICA ∗012:01 was increased in patient samples carrying Kirsten rat sarcoma oncogene homolog (KRAS) codon 12 mutation
Summary
Colorectal cancer is the third most common cancer diagnosed and the second leading cause of cancer deaths in the United States (Siegel et al, 2019) and China (Chen W. et al, 2016). Further analysis of MICA alleles in the context of MICA codon 295 polymorphism and CRC molecular subtype determined that A4 was significantly increased in MSI or MSI-H compared with CIN (p = 0.011 and p = 0.026, respectively; Supplementary Table S2). We conducted further association studies of MICA codon 295 polymorphisms and MICA alleles with tumor characteristics such as differential status, UICC stage, tumor size, invasion depth, lymph nodes metastasis, and gross classification, and discovered that A5.1 was significantly increased in highly differentiated CRC compared to that in medium state (p = 0.019; Supplementary Table S4). Western blot analysis of extracellular matrix degrading enzyme matrix metalloproteinase-9 (MMP-9) and cell-cell adhesion protein E-cadherin revealed notably increased MMP-9 expression in the MICA ∗012:01 overexpressed group compared to MICA ∗008, and transfection control groups in SW480, DLD1, and HCT116 cells (Figures 3E,G,I,K). MICA ∗012:01 allele expression may be a predictive marker for poor prognosis in patients with KRAS codon 12 mutated CRC
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