NHERF1 inhibits beta-catenin-mediated proliferation of cervical cancer cells through suppression of alpha-actinin-4 expression.
NHERF1 inhibits beta-catenin-mediated proliferation of cervical cancer cells through suppression of alpha-actinin-4 expression.
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NHERF1 通过抑制 α-actinin-4 表达来抑制 β-catenin 介导的宫颈癌细胞增殖
DOI：
10.1038/s41419-018-0711-x
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发表时间：
2018-06-04
影响因子：
9
通讯作者：
He J
中科院分区：
文献类型：
--
作者：
Wang Q;Qin Q;Song R;Zhao C;Liu H;Yang Y;Gu S;Zhou D;He J
子宫颈癌是女性中最致命的癌症之一。Wnt/β-catenin信号通路的异常激活已被发现参与宫颈癌的发生和发展，但其潜在的分子机制尚不清楚。本研究通过对GEO数据集宫颈癌标本的差异基因表达和基因簇的分析，发现NHERF1是一个与宫颈癌细胞增殖和Wnt信号通路相关的新基因。细胞研究进一步证实，NHERF1通过Wnt/β-catenin信号通路抑制宫颈癌细胞增殖依赖于α-actin -4 （ACTN4）的表达。在小鼠异种移植模型和宫颈癌标本中发现NHERF1表达与ACTN4和β-catenin水平呈负相关。基因集富集分析发现宫颈癌标本中低水平的NHERF1与细胞增殖激活和Wnt/β-catenin信号传导有关，Cox回归分析发现NHERF1是宫颈癌患者预后较差的独立预测因素。这些发现表明，NHERF1通过抑制ACTN4抑制Wnt信号介导的宫颈癌增殖，NHERF1下调可能有助于宫颈癌的进展。这些发现也可能为理解hpv无活性宫颈癌患者顺铂耐药和预后不良的潜在机制提供一些启示。
Cervical cancer is one of the most lethal types of cancer in female. Aberrant activation of Wnt/β-catenin signaling pathway has been found to be involved in cervical cancer development and progression, whereas the underlying molecular mechanisms remain poorly understood. The present study showed that NHERF1 was a novel gene associated with both cell proliferation and Wnt signaling pathway in cervical cancer by analysis of differential gene expression and gene cluster for the cervical cancer specimens from GEO data sets. It was further demonstrated in cellular study that NHERF1 inhibition of cervical cancer cell proliferation through Wnt/β-catenin signaling was dependent on α-actinin-4 (ACTN4) expression. A negative association between NHERF1 expression and levels of ACTN4 and β-catenin was found in mouse xenograft model and cervical cancer specimens. Low levels of NHERF1 in cervical cancer specimens were found to associate with activation of cell proliferation and Wnt/β-catenin signaling by gene set enrichment analysis, and also were an independent predictive factor for worse prognosis of cervical cancer patients by Cox regression analysis. These findings demonstrate that NHERF1 inhibits Wnt signaling-mediated proliferation of cervical cancer via suppression of ACTN4, and NHERF1 downregulation may contribute to the progression of cervical cancer. These findings may also shed some lights for understanding the underlying mechanisms of cisplatin resistance and worse prognosis of HPV-inactive cervical cancer patients.
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