MicroRNA-34a promotes MICB expression in hepatocytes.
MicroRNA-34a promotes MICB expression in hepatocytes.
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MicroRNA-34a促进肝细胞中MICB的表达
DOI：
10.1093/carcin/bgy128
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发表时间：
2018
期刊：
影响因子：
4.7
通讯作者：
Tang KF
中科院分区：
文献类型：
--
作者：
Zhou MT;Zhao C;Chen X;Zhang HC;Li G;Lou H;Huang WJ;Wei LJ;Li DW;Wu X;Zhang ZC;Liu H;Ou R;Yang WJ;Hu S;Xu Y;Tang KF
MicroRNA-34a (miR-34a) 通过降低参与多种致癌途径的癌基因的表达来发挥肿瘤抑制因子的作用。临床试验中已经研究了静脉注射 miR-34a 模拟物作为晚期癌症的潜在治疗方法；然而，miR-34a 对癌症免疫监视的影响存在争议。在目前的研究中，我们发现miR-34a在调节主要组织相容性复合物I类相关序列B（MICB）蛋白（NKG2D受体的配体）中发挥双重作用。 MiR-34a 可以分别通过上调共济失调毛细血管扩张和 Rad3 相关 (ATR) 蛋白激酶以及下调转录因子 E2F1 来诱导和减少 MICB 表达。 miR-34a 对 MICB 表达的净效应取决于内源 E2F1 水平。 miR-34a 的过表达促进了 E2F1 水平较低的肝细胞和肝细胞癌 (HCC) 细胞中 MICB 的表达，但在 E2F1 水平较高的 HCC 细胞中则不然。在HCC患者中，miR-34a和MICB的表达在E2F1水平较低的癌旁肝组织中呈正相关，但在E2F1水平较高的HCC组织中则不然。我们发现，未转化肝细胞中 miR-34a 的过表达增强了 NK-92MI 细胞的细胞溶解和干扰素-γ 的产生。此外，HCC 患者的肿瘤和癌旁组织中较高的 miR-34a 表达分别与阳性结果和阴性结果相关。我们的研究结果表明，miR-34a 诱导癌旁肝组织中 MICB 表达，这可能导致肝损伤和严重的细胞因子释放综合征，从而揭示了 miR-34a 在抗癌治疗中全身给药的潜在副作用。
MicroRNA-34a (miR-34a) behaves as a tumor suppressor by decreasing the expression of oncogenes involved in multiple carcinogenic pathways. Intravenous delivery of miR-34a mimics has been investigated in clinical trials as a potential treatment for advanced cancers; however, the effect of miR-34a on cancer immune surveillance is controversial. In the current study, we found that miR-34a plays a dual role in the regulation of major histocompatibility complex class I-related sequence B (MICB) protein, a ligand of the NKG2D receptor. MiR-34a could both induce and reduce MICB expression by upregulating ataxia telangiectasia and Rad3-related (ATR) protein kinase and downregulating the transcription factor E2F1, respectively. The net effect of miR-34a on MICB expression depended on endogenous E2F1 levels. Overexpression of miR-34a promoted MICB expression in hepatocytes and hepatocellular carcinoma (HCC) cells that have low E2F1 levels but not in HCC cells that have high E2F1 levels. In HCC patients, the expression of miR-34a and MICB showed positive correlation in paratumor liver tissues, which have low E2F1 levels, but not in HCC tissues, which have high E2F1 levels. We showed that miR-34a overexpression in non-transformed liver cells enhanced cytolysis and interferon-γ production by NK-92MI cells. Furthermore, higher miR-34a expression in tumor and paratumor tissues was associated with positive and negative outcomes, respectively, in HCC patients. Our findings suggest that miR-34a induces MICB expression in paratumor liver tissues, which may cause liver damage and serious cytokine release syndrome, thus disclosing potential side effects of systemic administration of miR-34a in anticancer therapy.