Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Biomedical Center, Box 815, 75108 Uppsala, Sweden.
Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Biomedical Center, Box 815, 75108 Uppsala, Sweden.
Carcinogenesis. 2014 Dec;35(12):2633-42. doi: 10.1093/carcin/bgu215. Epub 2014 Oct 20.
The major histocompatibility complex class I polypeptide-related sequence A gene (MICA) encodes a membrane-bound protein acting as a ligand to stimulate an activating receptor, NKG2D, expressed on the surface of essentially all human natural killer (NK), γδ T and CD8(+) αβ T cells. MICA protein is absent from most cells but can be induced by infections and oncogenic transformation and is frequently expressed in epithelial tumors. Upon binding to MICA, NKG2D activates cytolytic responses of NK and γδ T cells against infected and tumor cells expressing MICA. Therefore, membrane-bound MICA acts as a signal during the early immune response against infection or spontaneously arising tumors. On the other hand, human tumor cells spontaneously release a soluble form of MICA, causing the downregulation of NKG2D and in turn severe impairment of the antitumor immune response of NK and CD8(+) T cells. This is considered to promote tumor immune evasion and also to compromise host resistance to infections. MICA is the most polymorphic non-classical class I gene. A possible association of MICA polymorphism with genetic predisposition to different cancer types has been investigated in candidate gene-based studies. Two genome-wide association studies have identified loci in MICA that influence susceptibility to cervical neoplasia and hepatitis C virus-induced hepatocellular carcinoma, respectively. Given the current level of interest in the field of MICA gene, we discuss the genetics and biology of the MICA gene and the role of its polymorphism in cancer. Gaps in our understanding and future research needs are also discussed.
主要组织相容性复合体Ⅰ类相关序列 A 基因（MICA）编码一种膜结合蛋白，作为配体刺激表面表达的激活受体 NKG2D，该受体存在于几乎所有人类自然杀伤（NK）、γδ T 和 CD8(+)αβ T 细胞表面。MICA 蛋白不存在于大多数细胞中，但可被感染和致癌转化诱导，并在上皮肿瘤中频繁表达。MICA 与 NKG2D 结合后，NKG2D 激活 NK 和 γδ T 细胞对表达 MICA 的感染和肿瘤细胞的细胞溶解反应。因此，膜结合的 MICA 作为针对感染或自发发生的肿瘤的早期免疫反应的信号。另一方面，人类肿瘤细胞会自发释放 MICA 的可溶性形式，导致 NKG2D 的下调，从而严重损害 NK 和 CD8(+) T 细胞的抗肿瘤免疫反应。这被认为促进了肿瘤的免疫逃逸，并损害了宿主对感染的抵抗力。MICA 是最具多态性的非经典 I 类基因。基于候选基因的研究已经调查了 MICA 多态性与不同癌症类型遗传易感性的可能关联。两项全基因组关联研究分别确定了 MICA 中影响宫颈癌易感性和丙型肝炎病毒诱导的肝细胞癌易感性的位点。鉴于目前人们对 MICA 基因领域的兴趣，我们讨论了 MICA 基因的遗传学和生物学及其多态性在癌症中的作用。我们还讨论了我们理解中的差距和未来的研究需求。
