Njei Lea-Pearl, Sampaio Moura Natalia, Schledwitz Alyssa, Griffiths Kelly, Cheng Kunrong, Raufman Jean-Pierre
Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD, United States.
Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States.
Front Cell Dev Biol. 2024 Oct 18;12:1489321. doi: 10.3389/fcell.2024.1489321. eCollection 2024.
Despite many diagnostic and therapeutic advances, colorectal cancer (CRC) remains the second leading cause of cancer death for men and women in the United States. Alarmingly, for reasons currently unknown, the demographics of this disease have shifted towards a younger population. Hence, understanding the molecular mechanisms underlying CRC initiation and progression and leveraging these findings for therapeutic purposes remains a priority. Here, we review critically the evidence that canonical and noncanonical actions of guanine nucleotide exchange factors (GEFs) play important roles in CRC evolution. Rho GEF GTPases, which switch between inactive GDP-bound and active GTP-bound states, are commonly overexpressed and activated in a variety of cancers, including CRC, and may be tractable therapeutic targets. In addition to comprehensively reviewing this field, we focus on Rho/Rac GEFs that are involved in regulating key functions of normal and neoplastic cells like cell polarity, vesicle trafficking, cell cycle regulation, and transcriptional dynamics. Prime examples of such Rho/Rac GEFs include βPak-interacting exchange factor (βPix), a Rho family GEF for Cdc42/Rac1, Tiam1, GEF-H1, RGNEF, and other GEFs implicated in CRC development and progression. Throughout this analysis, we explore how these findings fill key gaps in knowledge regarding the molecular basis of colon carcinogenesis and how they may be leveraged to treat advanced CRC. Lastly, we address potential future directions for research into the role of GEFs as CRC biomarkers and therapeutic targets. In this regard, leveraging the noncanonical actions of GEFs appears to provide a relatively unexplored opportunity requiring further investigation.
尽管在诊断和治疗方面取得了许多进展，但结直肠癌（CRC）仍是美国男性和女性癌症死亡的第二大主要原因。令人担忧的是，由于目前尚不清楚的原因，这种疾病的人口统计学特征已转向更年轻的人群。因此，了解CRC发生和发展的分子机制并将这些发现用于治疗目的仍然是当务之急。在这里，我们批判性地回顾了鸟嘌呤核苷酸交换因子（GEFs）的经典和非经典作用在CRC演变中起重要作用的证据。Rho GEF GTP酶在无活性的GDP结合状态和活性的GTP结合状态之间转换，在包括CRC在内的多种癌症中通常过表达并被激活，可能是易于处理的治疗靶点。除了全面回顾这一领域外，我们还关注参与调节正常细胞和肿瘤细胞关键功能（如细胞极性、囊泡运输、细胞周期调节和转录动力学）的Rho/Rac GEFs。此类Rho/Rac GEFs的主要例子包括βPak相互作用交换因子（βPix），一种Cdc42/Rac1的Rho家族GEF、Tiam1、GEF-H1、RGNEF以及其他与CRC发展和进展有关的GEFs。在整个分析过程中，我们探讨了这些发现如何填补关于结肠癌发生分子基础的关键知识空白，以及如何利用它们来治疗晚期CRC。最后，我们讨论了GEFs作为CRC生物标志物和治疗靶点作用的潜在未来研究方向。在这方面，利用GEFs的非经典作用似乎提供了一个相对未被探索的机会，需要进一步研究。
