PREX2, or Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2, is a key regulator that interacts with the PTEN protein and is involved in the PI3K signaling pathway. It can affect cell migration, proliferation, and apoptosis, thus being of great importance in tumor-related biological processes [3,4,5,6,7,8]. Genetic models, such as gene knockout mouse models, can be valuable in studying its functions.

In colorectal cancer, PREX2 was found to be upregulated in radioresistant cells. It enhanced radioresistance by facilitating DNA repair, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration via the cGAS/STING/IFNs pathway. Blocking PREX2 in vivo improved the efficacy of ionizing radiation therapy, suggesting it could be a biomarker and therapeutic target [1]. In pancreatic cancer, chromosomal rearrangements can disrupt PREX2, and in melanoma, truncating PREX2 mutations activate its Rac1 guanine nucleotide exchange factor activity, alter gene expression, and promote tumor development through the PI3K/PTEN/Akt pathway [2,5]. In hepatocellular carcinoma, a gain-of-function mutation (S1113R) in PREX2 enhanced protein stability, promoted cell proliferation, and was linked to aggressiveness [3].

In conclusion, PREX2 is intricately involved in the regulation of multiple cellular processes relevant to cancer development, especially in colorectal, pancreatic, melanoma, and hepatocellular carcinoma. Studies using gene-based models, such as KO mouse models in melanoma, have revealed its role in tumor-related signaling pathways, providing potential therapeutic directions for these cancers.

References:

1. Li, Mingzhou, Xiao, Jianbiao, Song, Shasha, Zhu, Qin, Liang, Li. 2024. PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer. In BMC medicine, 22, 154. doi:10.1186/s12916-024-03375-2. https://pubmed.ncbi.nlm.nih.gov/38609982/

2. Waddell, Nicola, Pajic, Marina, Patch, Ann-Marie, Biankin, Andrew V, Grimmond, Sean M. . Whole genomes redefine the mutational landscape of pancreatic cancer. In Nature, 518, 495-501. doi:10.1038/nature14169. https://pubmed.ncbi.nlm.nih.gov/25719666/

3. Yang, Ming-Hui, Yen, Chia-Hung, Chen, Yen-Fu, Teh, Bin Tean, Chen, Yi-Ming Arthur. 2019. Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma. In Scientific reports, 9, 2552. doi:10.1038/s41598-018-36810-5. https://pubmed.ncbi.nlm.nih.gov/30796242/

4. Hedayati, Manouchehr Ahmadi, Ahmadi, Sanaz, Servatyari, Karo, Sheikhesmaeili, Farshad. . PREX2 gene's expression in gastric antral epithelial cells of patients with H. pylori infection. In Arquivos de gastroenterologia, 58, 353-358. doi:10.1590/S0004-2803.202100000-59. https://pubmed.ncbi.nlm.nih.gov/34705970/

5. Lissanu Deribe, Yonathan, Shi, Yanxia, Rai, Kunal, Garraway, Levi A, Chin, Lynda. 2016. Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma. In Proceedings of the National Academy of Sciences of the United States of America, 113, E1296-305. doi:10.1073/pnas.1513801113. https://pubmed.ncbi.nlm.nih.gov/26884185/

6. Li, Chung-Hsien, Yen, Chia-Hung, Chen, Yen-Fu, Lin, Hui-Kuan, Arthur Chen, Yi-Ming. . Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma. In International journal of cancer, 140, 2284-2297. doi:10.1002/ijc.30652. https://pubmed.ncbi.nlm.nih.gov/28205209/

7. Mense, Sarah M, Barrows, Douglas, Hodakoski, Cindy, Hibshoosh, Hanina, Parsons, Ramon. 2015. PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion. In Science signaling, 8, ra32. doi:10.1126/scisignal.2005840. https://pubmed.ncbi.nlm.nih.gov/25829446/

8. Yang, Jianyi, Gong, Xuejun, Ouyang, Lu, Xiao, Rou, Tan, Li. 2016. PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway. In Oncology letters, 12, 1139-1143. doi:. https://pubmed.ncbi.nlm.nih.gov/27446408/