Gleizes Antoine, Triki Mouna, Bonnet Sandrine, Baccari Naomi, Jimenez-Dominguez Gabriel, Covinhes Aurélie, Pirot Nelly, Blache Philippe, Yuan Rong, Győrffy Balázs, Cavaillès Vincent, Lapierre Marion
IRCM-Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier, CNRS, 208 rue des Apothicaires, F-34298 Montpellier, France.
BioCampus, RHEM, Université de Montpellier, CNRS, INSERM, F-34093 Montpellier, France.
Cancers (Basel). 2021 Jun 26;13(13):3192. doi: 10.3390/cancers13133192.
RIP140 is a major transcriptional coregulator of gut homeostasis and tumorigenesis through the regulation of Wnt/APC signaling. Here, we investigated the effect of RIP140 on Paneth cell differentiation and its interplay with the transcription factor SOX9. Using loss of function mouse models, human colon cancer cells, and tumor microarray data sets we evaluated the role of RIP140 in SOX9 expression and activity using RT-qPCR, immunohistochemistry, luciferase reporter assays, and GST-pull down. We first evidence that RIP140 strongly represses the Paneth cell lineage in the intestinal epithelium cells by inhibiting Sox9 expression. We then demonstrate that RIP140 interacts with SOX9 and inhibits its transcriptional activity. Our results reveal that the Wnt signaling pathway exerts an opposite regulation on SOX9 and RIP140. Finally, the levels of expression of RIP140 and SOX9 exhibit a reverse response and prognosis value in human colorectal cancer biopsies. This work highlights an intimate transcriptional cross-talk between RIP140 and SOX9 in intestinal physiopathology.
RIP140是肠道稳态和肿瘤发生的主要转录共调节因子，通过调节Wnt/APC信号通路发挥作用。在此，我们研究了RIP140对潘氏细胞分化的影响及其与转录因子SOX9的相互作用。我们使用功能缺失小鼠模型、人结肠癌细胞和肿瘤微阵列数据集，通过RT-qPCR、免疫组织化学、荧光素酶报告基因检测和GST下拉实验评估了RIP140在SOX9表达和活性中的作用。我们首先证明，RIP140通过抑制Sox9表达强烈抑制肠上皮细胞中的潘氏细胞谱系。然后我们证明，RIP140与SOX9相互作用并抑制其转录活性。我们的结果表明，Wnt信号通路对SOX9和RIP140发挥相反的调节作用。最后，RIP140和SOX9的表达水平在人大肠癌活检中呈现反向反应和预后价值。这项工作突出了RIP140和SOX9在肠道生理病理学中密切的转录相互作用。
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