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ZNF191 转录调控的 Wnt8B 通过 Wnt 信号通路促进肝癌细胞增殖。

Wnt8B, transcriptionally regulated by ZNF191, promotes cell proliferation of hepatocellular carcinoma via Wnt signaling.

机构信息

Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

The State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.

出版信息

Cancer Sci. 2021 Feb;112(2):629-640. doi: 10.1111/cas.14738. Epub 2020 Dec 4.

DOI:10.1111/cas.14738
PMID:33197287
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7894019/
Abstract

Dysregulation of wingless-type (Wnt) signaling is implicated in hepatocellular carcinoma (HCC). Wnt family member 8B (Wnt8B), one of the canonical Wnt ligands, is implicated in oncogenesis. However, the role of Wnt8B in human HCCs and its transcriptional regulation mechanism are presently unknown . Here, we report that Wnt8B expression was frequently increased in HCCs and was significantly associated with poorer patient prognosis. Wnt8B knockdown suppresses HCC cell growth both in vitro and in vivo via inhibiting the canonical Wnt signaling. Zinc finger transcription factor 191 (ZNF191) can positively regulate Wnt8B mRNA and protein expression, and promoter luciferase assay indicated that ZNF191 can increase the transcription activity of the 2-Kbps WNT8B promoter. Chromatin immunoprecipitation-qPCR and electrophoretic mobility shift assay showed that ZNF191 protein directly binds to the WNT8B promoter, and the binding sites are at nt-1491(ATTAATT) and nt-1178(ATTCATT). Moreover, Wnt8B contributes to the effect of ZNF191 on cell proliferation, and Wnt8B expression correlates positively with ZNF191 in human HCCs. Our findings suggested that Wnt8B, directly transcriptionally regulated by ZNF191, plays a pivotal role in HCC proliferation via the canonical Wnt pathway and may serve as a new prognostic biomarker and a potential therapeutic target for HCC patients.

摘要

Wnt 信号通路失调与肝细胞癌（HCC）有关。Wnt 家族成员 8B（Wnt8B）是经典 Wnt 配体之一，与肿瘤发生有关。然而，Wnt8B 在人 HCC 中的作用及其转录调控机制目前尚不清楚。在这里，我们报告 Wnt8B 表达在 HCC 中经常增加，并与患者预后不良显著相关。Wnt8B 敲低通过抑制经典 Wnt 信号通路在体外和体内均抑制 HCC 细胞生长。锌指转录因子 191（ZNF191）可以正向调节 Wnt8B mRNA 和蛋白表达，启动子荧光素酶报告基因实验表明 ZNF191 可以增加 2-Kbps WNT8B 启动子的转录活性。染色质免疫沉淀-qPCR 和电泳迁移率变动分析显示 ZNF191 蛋白直接结合在 WNT8B 启动子上，结合位点位于 nt-1491（ATTAATT）和 nt-1178（ATTCATT）。此外，Wnt8B 有助于 ZNF191 对细胞增殖的影响，并且 Wnt8B 在人 HCC 中的表达与 ZNF191 呈正相关。我们的研究结果表明，Wnt8B 由 ZNF191 直接转录调控，通过经典 Wnt 途径在 HCC 增殖中发挥关键作用，可能作为 HCC 患者新的预后生物标志物和潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/caa63bfa9750/CAS-112-629-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/ee272383a73d/CAS-112-629-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/7cb9b4bc7722/CAS-112-629-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/fdd8733d616b/CAS-112-629-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/62322e1e699a/CAS-112-629-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/d6eb0a249cd3/CAS-112-629-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/caa63bfa9750/CAS-112-629-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/ee272383a73d/CAS-112-629-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/7cb9b4bc7722/CAS-112-629-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/fdd8733d616b/CAS-112-629-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/62322e1e699a/CAS-112-629-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/d6eb0a249cd3/CAS-112-629-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c82b/7894019/caa63bfa9750/CAS-112-629-g006.jpg

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