KHSRP, the KH-type splicing regulatory protein, is a multifunctional RNA-binding protein. It is involved in mRNA decay, alternative splicing, and miRNA biogenesis, regulating crucial cellular functions such as proliferation, differentiation, and response to stimuli. It is associated with pathways like FAK signaling and is important in processes such as monocytic differentiation, neuronal development, and various disease-related pathways [1-10]. Genetic models, like gene knockout (KO) mouse models, are valuable for studying KHSRP's functions.

In KO mouse models, KHSRP deficiency suppressed pancreatic ductal adenocarcinoma (PDAC) growth and metastasis in vivo, as KHSRP stabilizes FAK pathway mRNAs in an m6A-dependent manner to promote PDAC progression [1]. In adult Khsrp-/-mice, upregulation of 1460 mRNAs was found in neocortex, leading to increased axon growth, dendritic spine density, and changes in memory consolidation [2]. In Wilms tumor cell lines, down-regulation of KHSRP inhibited cell proliferation and arrested the cell cycle [3]. Also, KHSRP knockdown in papillary renal cell carcinoma cells alleviated migration, invasion, and proliferation [4]. In breast cancer MDA-MB-231 cells, silencing KHSRP repressed proliferation, invasion, and migration, and increased apoptosis [5].

In conclusion, model-based research shows that KHSRP plays essential roles in multiple biological processes and disease conditions. KO mouse models have revealed its oncogenic roles in cancers like PDAC, Wilms tumor, papillary renal cell carcinoma, and breast cancer, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Xu, Zilan, Zhou, Yifan, Liu, Shaoqiu, Zheng, Jian, Zhang, Jialiang. . KHSRP Stabilizes m6A-Modified Transcripts to Activate FAK Signaling and Promote Pancreatic Ductal Adenocarcinoma Progression. In Cancer research, 84, 3602-3616. doi:10.1158/0008-5472.CAN-24-0927. https://pubmed.ncbi.nlm.nih.gov/39120596/

2. Olguin, Sarah L, Patel, Priyanka, Buchanan, Courtney N, Twiss, Jeffery L, Perrone-Bizzozero, Nora I. 2022. KHSRP loss increases neuronal growth and synaptic transmission and alters memory consolidation through RNA stabilization. In Communications biology, 5, 672. doi:10.1038/s42003-022-03594-4. https://pubmed.ncbi.nlm.nih.gov/35798971/

3. Cheng, Cheng, Cai, Yuanxia, Liu, Xiaowei, Wu, Yeming, Wu, Zhixiang. 2022. KHSRP modulated cell proliferation and cell cycle via regulating PPP2CA and p27 expression in Wilms tumor. In Cellular signalling, 100, 110447. doi:10.1016/j.cellsig.2022.110447. https://pubmed.ncbi.nlm.nih.gov/36029941/

4. Song, Wei, Zhang, Heng, Lu, Yi, Wu, Zonglin, Wang, Keyi. 2024. KHSRP knockdown inhibits papillary renal cell carcinoma progression and sensitizes to gemcitabine. In Frontiers in pharmacology, 15, 1446920. doi:10.3389/fphar.2024.1446920. https://pubmed.ncbi.nlm.nih.gov/39439895/

5. Paizula, Xuelaiti, Wulaying, Aliya, Chen, Dong, Ou, Jianghua. 2024. KHSRP has oncogenic functions and regulates the expression and alternative splicing of DNA repair genes in breast cancer MDA-MB-231 cells. In Scientific reports, 14, 14694. doi:10.1038/s41598-024-64687-0. https://pubmed.ncbi.nlm.nih.gov/38926398/