MicroRNA-375 通过抑制 JAK2/STAT3 信号通路逆转胃癌中 PD-L1 的表达。
MicroRNA-375 reverses the expression of PD-L1 by inactivating the JAK2/STAT3 signaling pathways in gastric cancer.
机构信息
Department of Experimental Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, P.R. China.
Department of Experimental Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, P.R. China; Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, P.R. China.
出版信息
Clin Res Hepatol Gastroenterol. 2021 Sep;45(5):101574. doi: 10.1016/j.clinre.2020.10.015. Epub 2020 Dec 4.
BACKGROUND
The mechanism of PD-L1 expression in gastric cancer patients remains unclear. microRNAs (miRs) have been reported to be crucial components of the crosstalk between tumor-immune cells and emerging evidence suggests that microRNA-375 (miR-375) is significantly downregulated in digestive system tumors, but its association with PD-L1 expression in gastric cancer remains to be determined.
METHODS
The expression level of miR-375 was first investigated in human gastric cancer tissues and cell lines. Its effect on gastric cancer cell proliferation, migration, invasion, and apoptosis were evaluated in vitro via CCK8, colony formation assays, wound healing assays, transwell assays, and flow cytometry. In vivo experiments using immunodeficient BALB/c nude female mice were also performed. Luciferase reporter assays were employed to identify interactions between miR-375 and its target genes.
RESULTS
Quantitative real-time PCR showed that the expression of miR-375 was negatively correlated with PD-L1 in gastric cancer tissues. The overexpression of miR-375 inhibited gastric cancer cell proliferation, migration, invasion, and the knockdown of miR-375 demonstrated opposite effects, both in vitro and in vivo. Luciferase reporter assays showed that miR-375 could bind to the 3'-UTR regions of JAK2 and an inverse association between miR-375 and JAK2/STAT3/PD-L1 expression in gastric cancer cell lines was also observed. In vivo experiments showed that miR-375-overexpression decreased the growth of xenograft tumors in immunodeficient BALB/c mice.
CONCLUSIONS
miR-375 negatively regulates PD-L1 expression in gastric cancer via the JAK2/STAT3 signaling pathway and could be a promising novel therapeutic target in gastric cancer.
背景
胃癌患者 PD-L1 表达的机制尚不清楚。microRNAs（miRs）已被报道是肿瘤免疫细胞相互作用的关键组成部分，并且有新的证据表明，miR-375 在消化系统肿瘤中显著下调，但它与胃癌中 PD-L1 的表达的关系尚待确定。
方法
首先检测人胃癌组织和细胞系中 miR-375 的表达水平。通过 CCK8、集落形成实验、划痕愈合实验、Transwell 实验和流式细胞术评估其对胃癌细胞增殖、迁移、侵袭和凋亡的影响。还在免疫缺陷 BALB/c 裸鼠体内进行了实验。荧光素酶报告实验用于鉴定 miR-375 与其靶基因之间的相互作用。
结果
实时定量 PCR 显示 miR-375 的表达与胃癌组织中的 PD-L1 呈负相关。miR-375 的过表达抑制了胃癌细胞的增殖、迁移、侵袭，而 miR-375 的敲低则表现出相反的效果，无论是在体外还是体内。荧光素酶报告实验表明，miR-375 可以结合 JAK2 的 3'-UTR 区域，并且在胃癌细胞系中观察到 miR-375 与 JAK2/STAT3/PD-L1 表达之间的负相关。体内实验表明，miR-375 过表达可降低免疫缺陷 BALB/c 小鼠异种移植瘤的生长。
结论
miR-375 通过 JAK2/STAT3 信号通路负调控胃癌中的 PD-L1 表达，可能成为胃癌有前途的新型治疗靶点。
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