近日，比利时布鲁塞尔自由大学Cédric Blanpain及其研究组发现，RHOJ控制EMT相关的化疗耐药。这一研究成果于2023年3月22日在线发表在国际学术期刊《自然》上。
通过使用一个皮肤鳞状细胞癌的小鼠模型，其在肿瘤发生过程中经历了自发的上皮-间质转化（EMT），研究人员发现EMT肿瘤细胞对体内和体外的各种抗癌疗法都有很强的抗性。利用体外和体内的功能获得和丧失研究，研究人员发现RHOJ（一种在EMT癌细胞中优先表达的小GTP酶）控制着对治疗的抵抗。
利用全基因组的转录组和蛋白质组分析，研究人员发现RHOJ通过增强对复制压力的反应和激活DNA损伤反应，使肿瘤细胞能够迅速修复化疗引起的DNA损伤，从而调控EMT相关的化疗抗性。RHOJ与调节核肌动蛋白的蛋白质相互作用，抑制肌动蛋白聚合使EMT肿瘤细胞以RHOJ依赖的方式对化疗引起的细胞死亡敏感。总之，这项研究揭示了RHOJ作为EMT相关化疗抗性的关键调节器的作用和机制。
据了解，癌细胞对治疗的抵抗是导致大多数癌症患者死亡的原因。EMT与不同癌症细胞的治疗抗性有关。然而，EMT介导耐药性的机制仍然知之甚少。
附：英文原文
Title: RHOJ controls EMT-associated resistance to chemotherapy
Author: Debaugnies, Maud, Rodrguez-Acebes, Sara, Blondeau, Jeremy, Parent, Marie-Astrid, Zocco, Manuel, Song, Yura, de Maertelaer, Viviane, Moers, Virginie, Latil, Mathilde, Dubois, Christine, Coulonval, Katia, Impens, Francis, Van Haver, Delphi, Dufour, Sara, Uemura, Akiyoshi, Sotiropoulou, Panagiota A., Mndez, Juan, Blanpain, Cdric
Issue&Volume: 2023-03-22
Abstract: The resistance of cancer cells to therapy is responsible for the death of most patients with cancer1. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells2,3. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ—a small GTPase that is preferentially expressed in EMT cancer cells—controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy.
DOI: 10.1038/s41586-023-05838-7
Source: https://www.nature.com/articles/s41586-023-05838-7
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
