Wnt8B, transcriptionally regulated by ZNF191, promotes cell proliferation of hepatocellular carcinoma via Wnt signaling.
Wnt8B, transcriptionally regulated by ZNF191, promotes cell proliferation of hepatocellular carcinoma via Wnt signaling.
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Wnt8B受ZNF191转录调控，通过Wnt信号传导促进肝细胞癌细胞增殖
DOI：
10.1111/cas.14738
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发表时间：
2021-03
期刊：
影响因子：
5.7
通讯作者：
Liu G
中科院分区：
文献类型：
--
作者：
Liu Y;Wu D;Cheng H;Chen L;Zhang W;Zou L;Gao Q;Zhao Z;Chen Q;Zeng W;Zhang Z;Jiang W;Huang C;Liu G
无翅型（Wnt）信号转导失调与肝细胞癌（HCC）有关。Wnt家族成员8B（Wnt 8B）是典型的Wnt配体之一，与肿瘤发生有关。然而，Wnt 8B在人类HCC中的作用及其转录调控机制目前尚不清楚。在这里，我们报告说，Wnt 8B表达经常增加，在肝癌和显着相关的不良预后患者。Wnt 8B敲低通过抑制经典Wnt信号转导在体外和体内均抑制HCC细胞生长。锌指转录因子191（ZNF 191）可正向调节Wnt 8B mRNA和蛋白的表达，启动子荧光素酶检测表明ZNF 191可提高Wnt 8B启动子2-Kbps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ZNF 191蛋白与WNT 8B启动子直接结合，结合位点位于nt-1491（ATTAATT）和nt-1178（ATTCATT）。此外，Wnt 8B参与了ZNF 191对细胞增殖的影响，并且在人HCC中Wnt 8B表达与ZNF 191正相关。我们的研究结果表明，Wnt 8B，直接转录调控ZNF 191，通过经典的Wnt通路在肝癌细胞增殖中起着关键作用，并可能作为一个新的预后生物标志物和肝癌患者的潜在治疗靶点。典型无翅型（Wnt）信号传导的异常激活与肝细胞癌（HCC）有关。在这里，我们报告了经典Wnt配体之一Wnt 8B在人类HCC中上调，并且与预后不良显著相关。锌指转录因子191（ZNF 191）可以直接结合WNT 8B启动子并反式激活WNT 8B基因，随后激活Wnt途径以促进细胞增殖。在HCC标本中，Wnt 8B表达与ZNF 191呈正相关。因此，Wnt 8B可能作为一种新的预后生物标志物和HCC患者的潜在治疗靶点。
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. Aberrant activation of the canonical wingless‐type (Wnt) signaling is involved in hepatocellular carcinoma (HCC). Here, we report Wnt8B, one of the canonical Wnt ligands, is upregulated in human HCCs and is significantly associated with poorer prognosis. Zinc finger transcription factor 191 (ZNF191) can directly bind to the WNT8B promoter and transactivate the WNT8B gene and subsequently activate the Wnt pathway to promote cell proliferation. Wnt8B expression correlates positively with ZNF191 in HCC specimens. Thus, Wnt8B may serve as a new prognostic biomarker and a potential therapeutic target for HCC patients.
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