| Autor: |
Runhui Lu, Yafan Zhang, Ran Chen, Lian Li, Caihu Huang, Zihan Zhou, Yingting Cao, Hongyan Li, Junya Li, Yixin Zhang, Yanli Wang, Jian Huang, Xian Zhao, Jing Feng, Jianxiu Yu, Chunling Du |
| Jazyk: |
angličtina |
| Rok vydání: |
2025 |
| Předmět: |
|
| Zdroj: |
Neoplasia: An International Journal for Oncology Research, Vol 59, Iss , Pp 101082- (2025) |
| Druh dokumentu: |
article |
| ISSN: |
1476-5586 |
| DOI: |
10.1016/j.neo.2024.101082 |
| Popis: |
The KRAS/ERK pathway is crucial in cancer progression and chemotherapy resistance, yet its upstream regulatory mechanism remains elusive. We identified MSI2 as a new promoter of chemotherapy resistance in cancers. MSI2 directly binds to a specific class of mature miRNAs by recognizing the 'UAG' motif and interacts with the essential effector AGO2, highlighting MSI2 as a novel regulatory factor within the miRNA pathway. Specifically, MSI2 recruits UAG-miRNA miR-30a-3p to facilitate its loading onto AGO2, efficiently inhibiting the expression of CGRRF1. Further analysis reveals that CGRRF1 functions as a new ubiquitin E3 ligase for KRAS, mediating the ubiquitination and proteasome degradation of KRAS. Consequently, a novel regulatory axis involving MSI2-AGO2/miR-30a-3p-CGRRF1 positively regulates the KRAS/ERK pathway. Remarkably, platinum-based chemotherapy drugs significantly enhance the levels of phosphorylated ERK1/2 (p-ERK1/2) in cancer cells, and the EGFR inhibitor Gefitinib also increases p-ERK1/2 levels in Gefitinib-resistant cancer cells. Combining small-molecule inhibitors targeting MSI2, such as Ro 08-2750, efficiently alleviated chemoresistance in tumor cells exposed to Platinum and Gefitinib. These findings suggest that MSI2 could be a novel therapeutic target for developing strategies to counteract cancer resistance to treatment. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
