CD44 3′-Untranslated Region Functions as a Competing Endogenous RNA to Enhance NK Sensitivity of Liver Cancer Stem Cell by Regulating ULBP2 Expression
CD44 3′-Untranslated Region Functions as a Competing Endogenous RNA to Enhance NK Sensitivity of Liver Cancer Stem Cell by Regulating ULBP2 Expression
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DOI：
10.7150/ijbs.35216
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Gao, Yi
中科院分区：
文献类型：
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作者：
Weng, Jun;Han, Xu;Gao, Yi
肝肿瘤干细胞是一种罕见的异质性肝癌细胞亚群，具有自我更新和分化特性，已成为一种有前途的治疗靶点。令人信服的数据表明，NK细胞选择性地消除人类癌症衍生的CSC，如结直肠癌、黑色素瘤和胶质母细胞瘤。但NK细胞对肝CSCs的影响尚不清楚。为了研究NK细胞对肝CSC的细胞毒性作用及其机制，我们使用两种类型的从HCC重编程的CSC进行细胞毒性测定、ELISA测定、CRISPRi、qRT-PCR、免疫印迹、RNA免疫沉淀和荧光素酶报告基因。来源于肝癌的CSC对NK细胞介导的细胞毒性敏感。通过CRISPRi介导的基因敲低沉默CD 44后，肝脏CSC对NK细胞介导的细胞毒性的易感性显著下降。CD 44 3 β UTR主要通过竞争miR-34 a作为ceRNA调控ULBP 2的表达。CD 44 3 β UTR作为一种ceRNA通过调控ULBP 2的表达而增强肝癌干细胞的NK敏感性。
Liver CSCs are a rare subpopulation of heterogenous liver cancer cells with self-renewal and differentiation properties, which has emerged as a promising therapeutic target. Compelling data shows that NK cells selectively eliminate human cancer derived CSCs like colorectal carcinoma, melanoma, and glioblastoma. But the effect of NK cells on liver CSCs still remains unknown. To study the cytotoxic effect of NK cells on liver CSCs and the mechanism, we performed cytotoxicity assay, ELISA assays, CRISPRi, qRT-PCR, immunoblotting, RNA immunoprecipitation, and luciferase reporter using two types of CSCs reprogrammed from HCC. CSCs derived from liver cancer were susceptible to NK cell mediated cytotoxicity. The susceptibility of liver CSCs to NK cell-mediated cytotoxicity declined significantly after silencing CD44 by CRISPRi-mediated gene knockdown. CD44 3ʹ UTR functioned as a ceRNA to regulate the expression of ULBP2 mainly by competing miR-34a. CD44 3ʹ UTR functioned as a ceRNA to enhance NK sensitivity of liver cancer stem cell by regulating ULBP2 expression.