前列腺癌中与种族相关的 MHC Ⅰ类多肽相关序列 A（MICA）的表达。
Race-associated expression of MHC class I polypeptide-related sequence A (MICA) in prostate cancer.
机构信息
Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA; CAPES Foundation, Ministry of Education of Brazil, Brasília, DF 70040-020, Brazil.
Department of Preventive Medicine, University of Mississippi Medical Center, Jackson, MS, USA; Center for Clinical and Translational Science (CCTS), University of Mississippi School of Pharmacy & University of Mississippi Medical Center, Jackson, MS, USA.
出版信息
Exp Mol Pathol. 2019 Jun;108:173-182. doi: 10.1016/j.yexmp.2019.04.010. Epub 2019 Apr 17.
Despite the lack of a complete understanding of the disparities involved, prostate cancer (PCa) has both higher incidence and death rates in African American Men (AAM) relative to those of Caucasian American Men (CAM). MHC class I polypeptide related sequence A (MICA) is an innate immunity protein involved in tumor immunoevasion. Due to a lack of reports of race-specific expression of MICA in PCa, we evaluated MICA expression in patients' tumors and in cell lines from a racially diverse origin. Immunohistochemistry was done on a tissue microarray (TMA) with antibodies against MICA. Tumor MICA mRNA was assessed by data mining using Oncomine and PROGeneV2. Surface MICA and release rate of soluble (s) MICA was evaluated in PCa cell lines originally derived from African American (MDA-PCa-2b) or Caucasian (LNCaP and DU-145) PCa patients. Prostate tumor tissue had a 1.7-fold higher MICA expression relative to normal tissue (p < .0001). MICA immunoreactivity in PCa tissue from AAM was 24% lower (p = .002) compared to CAM. Survival analysis revealed a marginal association of low MICA with poor overall survival (OS) (p = .058). By data mining analysis, a 2.9-fold higher level of MICA mRNA was evidenced in tumor compared to normal tissue (p < .0001). Tumors from AAM had 24% lower levels of MICA mRNA compared to tumors from CAM (p = .038), and poor prognosis was found for patients with lower MICA mRNA (p = .028). By flow cytometry analysis, cell fraction positive for surface MICA was of 3% in MDA-PCa-2b cells, 54% in DU-145 cells, and 67% in LNCaP cells (p < .0001). sMICA was detected in DU-145 and LNCaP cells, but was not detected in MDA-PCa-2b cells. Both LNCaP and DU-145 cells were sensitive to cytolysis mediated by Natural killer (NK) cells. MDA-PCa-2b cells, however were between 1.3-fold at 10:1 Effector:Target (E:T) ratio (p < .0001) and 2-fold at 50:1 E:T ratio (p < .0001) more resistant to NK-mediated cytolysis relative to cells from Caucasian origin. These results suggest that MICA expression may be related to the aggressive nature of PCa. Our findings also demonstrate for the first time that there are variations in MICA expression in the context of racial differences. This study establishes a rationale for further investigation of MICA as a potential race-specific prognostic marker in PCa.
尽管人们对所涉及的差异还没有完全了解，但与白种美国男性（CAM）相比，前列腺癌（PCa）在非裔美国男性（AAM）中的发病率和死亡率都更高。主要组织相容性复合体Ⅰ类多肽相关序列 A（MICA）是一种参与肿瘤免疫逃逸的先天免疫蛋白。由于缺乏关于 MICA 在 PCa 中种族特异性表达的报告，我们评估了来自不同种族来源的患者肿瘤和细胞系中的 MICA 表达。使用针对 MICA 的抗体在组织微阵列（TMA）上进行了免疫组织化学染色。使用 Oncomine 和 PROGeneV2 通过数据挖掘评估肿瘤 MICA mRNA。最初源自非裔美国人（MDA-PCa-2b）或白种人（LNCaP 和 DU-145）PCa 患者的 PCa 细胞系中评估了表面 MICA 和可溶性（s）MICA 的释放率。与正常组织相比，前列腺肿瘤组织的 MICA 表达高 1.7 倍（p < 0.0001）。与 CAM 相比，AAM 中 PCa 组织的 MICA 免疫反应性低 24%（p = 0.002）。生存分析显示，低 MICA 与总体生存（OS）不良之间存在边缘关联（p = 0.058）。通过数据挖掘分析，与正常组织相比，肿瘤中 MICA mRNA 的水平高 2.9 倍（p < 0.0001）。与 CAM 相比，AAM 中的肿瘤中 MICA mRNA 的水平低 24%（p = 0.038），并且发现 MICA mRNA 水平较低的患者预后较差（p = 0.028）。通过流式细胞术分析，在 MDA-PCa-2b 细胞、DU-145 细胞和 LNCaP 细胞中，表面 MICA 阳性的细胞分数分别为 3%、54%和 67%（p < 0.0001）。在 DU-145 和 LNCaP 细胞中检测到 sMICA，但在 MDA-PCa-2b 细胞中未检测到。LNCaP 和 DU-145 细胞对自然杀伤（NK）细胞介导的细胞溶解均敏感。然而，与源自白种人的细胞相比，MDA-PCa-2b 细胞在 10:1 效应物：靶标（E:T）比（p < 0.0001）和 50:1 E:T 比（p < 0.0001）时对 NK 介导的细胞溶解的抗性高 1.3 倍。这些结果表明 MICA 表达可能与 PCa 的侵袭性有关。我们的发现还首次表明，在种族差异的背景下，MICA 表达存在差异。这项研究为进一步研究 MICA 作为 PCa 的潜在种族特异性预后标志物提供了依据。
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