Emerging evidences have shown that long noncoding RNA (lncRNA) plays an important role in the immune escape of cancer cells. Our previous study has demonstrated that lncRNA MIAT is associated with the immune infiltration of hepatocellular carcinoma (HCC). However, the underlying mechanism of MIAT regulating the PD-L1-mediated immune escape of HCC is poorly understood. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of MIAT and PD-L1 mRNA in HCC. The relationship between MIAT, miR-411-5p, STAT3 and PD-L1 was explored by dual-luciferase reporter assay, cytotoxicity assay, Western blot and RNA immunoprecipitation (RIP). In addition, the xenograft model was established to determine the effect of MIAT on PD-L1 expression in vivo. We found that MIAT and PD-L1 were significantly upregulated in HCC tissues and the expression of PD-L1 was regulated by MIAT. The knockdown of MIAT enhanced the cytotoxicity of T cells on HCC cells. MIAT negatively regulated miR-411-5p expression, upregulated STAT3 and ultimately increased PD-L1 expression from the transcription level. The inhibition of miR-411-5p reversed STAT3 and PD-L1 expression inhibited by MIAT knockdown in HCC cells. This study suggests a novel lncRNA-mediated mechanism for HCC cells to evade the immune response; MIAT/miR-411-5p/STAT3/PD-L1 may be a novel therapeutic target for HCC.

中文翻译：

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lncRNA MIAT靶向miR-411-5p/STAT3/PD-L1轴介导肝细胞癌免疫反应

新出现的证据表明，长链非编码 RNA (lncRNA) 在癌细胞的免疫逃逸中起着重要作用。我们之前的研究表明，lncRNA MIAT 与肝细胞癌 (HCC) 的免疫浸润有关。然而，人们对 MIAT 调节 PD-L1 介导的 HCC 免疫逃逸的潜在机制知之甚少。采用实时定量PCR（qRT-PCR）检测HCC中MIAT和PD-L1 mRNA的表达。MIAT、miR-411-5p、STAT3 和 PD-L1 之间的关系通过双荧光素酶报告基因测定、细胞毒性测定、蛋白质印迹和 RNA 免疫沉淀 (RIP) 进行了探索。此外，建立异种移植模型以确定MIAT对体内PD-L1表达的影响。我们发现 MIAT 和 PD-L1 在 HCC 组织中显着上调，并且 PD-L1 的表达受 MIAT 调节。MIAT 的敲低增强了 T 细胞对 HCC 细胞的细胞毒性。MIAT负向调节miR-411-5p表达，上调STAT3并最终从转录水平增加PD-L1表达。miR-411-5p 的抑制逆转了 HCC 细胞中 MIAT 敲低所抑制的 STAT3 和 PD-L1 表达。这项研究提出了一种新的 lncRNA 介导的 HCC 细胞逃避免疫反应的机制；MIAT/miR-411-5p/STAT3/PD-L1 可能是 HCC 的新治疗靶点。miR-411-5p 的抑制逆转了 HCC 细胞中 MIAT 敲低所抑制的 STAT3 和 PD-L1 表达。这项研究提出了一种新的 lncRNA 介导的 HCC 细胞逃避免疫反应的机制；MIAT/miR-411-5p/STAT3/PD-L1 可能是 HCC 的新治疗靶点。miR-411-5p 的抑制逆转了 HCC 细胞中 MIAT 敲低所抑制的 STAT3 和 PD-L1 表达。这项研究提出了一种新的 lncRNA 介导的 HCC 细胞逃避免疫反应的机制；MIAT/miR-411-5p/STAT3/PD-L1 可能是 HCC 的新治疗靶点。