RhoA function in Intestinal Epithelial Cells as a key element in Colorectal Cancer

RhoA 在肠上皮细胞中发挥作用，是结直肠癌的关键因素

• 批准号: 461063481
• 负责人: Privatdozentin Dr. Rocío López Posadas, Ph.D.
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/461063481?language=en
• 关键词: RhoA; function; Intestinal; Epithelial; Cells

Based on our previous study, we believe that RhoA within intestinalepithelial cells (IECs) is a key driver of cytoskeleton rearrangementand maintenance of intestinal homeostasis. On the other hand, RhoAhas been postulated as a cancer biomarker, since its activationcontributes to cancer initiation, as well as tumor growth and malignantbehavior. However, our own preliminary data demonstrate thatinhibition of RhoA function in mice lacking epithelial RhoA(RhoAΔIEC) causes spontaneous colonic tumorigenesis. Together,the key hypothesis of the project is that RhoA-dependent cytoskeletonrearrangement within IECs together with the subjacent intestinalinflammation in RhoAΔIEC mice act as drivers and modulators oftumor growth in the context of Colorectal Cancer (CRC). Altogether,we think that the analysis of the in vivo function of RhoA in intestinalepithelium might provide relevant information about homeostasis andtumor formation in the gut. In the present project, we would then aimat the identification of the molecular mechanism behind spontaneoustumorigenesis in the absence of epithelial RhoA in the context ofCRC. We will focus on two main scientific questions: thecolonrestricted epithelial alterations in RhoA-deficient IECs leading tothe spontaneous tumorigenesis; and the role of inflammation as driverand modulator of tumor growth in RhoAΔIEC mice. Finally, we intendto translate our findings to patients with CRC in the presence orabsence of colitis by studying patient samples. Our findings willcontribute to the mechanistic knowledge required for theunderstanding of CRC pathogenesis. We believe that basic researchon the role of the RhoA pathway will allow insights into the molecularpathogenesis of CRC and hopefully pave the way for new therapeuticapproaches for patients with CRC.

根据我们之前的研究，我们认为肠上皮细胞（IEC）内的 RhoA 是细胞骨架重排和维持肠道稳态的关键驱动因素。另一方面，RhoA 被认为是一种癌症生物标志物，因为它的激活有助于癌症的发生、肿瘤的生长和恶性行为。然而，我们自己的初步数据表明，在缺乏上皮 RhoA (RhoAΔIEC) 的小鼠中抑制 RhoA 功能会导致自发性结肠肿瘤发生。总之，该项目的关键假设是，IEC 内依赖于 RhoA 的细胞骨架重排与 RhoAΔIEC 小鼠的邻近肠道炎症一起，在结直肠癌 (CRC) 中充当肿瘤生长的驱动器和调节器。总之，我们认为对肠上皮中RhoA的体内功能的分析可能提供有关肠道内稳态和肿瘤形成的相关信息。在本项目中，我们的目标是鉴定 CRC 背景下上皮 RhoA 缺失情况下自发性肿瘤发生背后的分子机制。我们将重点关注两个主要科学问题：RhoA 缺陷 IEC 中结肠限制性上皮改变导致自发性肿瘤发生；以及炎症作为 RhoAΔIEC 小鼠肿瘤生长驱动器和调节器的作用。最后，我们打算通过研究患者样本，将我们的发现转化为存在或不存在结肠炎的结直肠癌患者。我们的研究结果将有助于了解结直肠癌发病机制所需的机制知识。我们相信，关于 RhoA 通路作用的基础研究将有助于深入了解 CRC 的分子发病机制，并有望为 CRC 患者的新治疗方法铺平道路。