Mutant p53 activates hnRNPA2B1-AGAP1-mediated exosome formation to promote esophageal squamous cell carcinoma progression. (28th May 2023)

• Record Type: Journal Article
• Authors: Feng, Riyue; Yin, Yin; Wei, Yuge; Li, Yang; Li, Lei; Zhu, Rui; Yu, Xiao; Liu, Yuhao; Zhao, Yahui; Liu, Zhihua
• Is Part Of: Cancer letters. Volume 562(2023)
• Publication Date: 2023-05-28
• Subjects: Exosome -- Esophageal squamous cell carcinoma -- Metastasis -- Proliferation -- Whole-genome sequencing; ESCC Esophageal squamous cell carcinoma -- WGS Whole-genome sequencing; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2023.216154
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: p53 mutations predispose cancer cell development, promote their survival and metastasis, and lead to ineffective therapeutic responses and unfavorable prognosis. No drug that abrogates the oncogenic functions of mutant p53 has been approved for cancer treatment. Here, we performed whole-genome sequencing of 663 esophageal squamous cell carcinoma (ESCC) tumor tissues and paired normal tissues. The results indicated that ESCC samples from our cohort had a more dispersed distribution of TP53 mutants and a higher proportion of nonsense mutants than European and American ESCC samples in the International Agency for Research on Cancer (IARC) database. The most frequent p53 mutations disrupt the inhibition of proliferation, migration, and invasion mediated by wild-type p53 in ESCC. Furthermore, p53 mutations alter its protein nucleoplasmic localization and protein stability. The p53 mutation G245S (p53-G245S) interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) to increase protein translation of phosphatidylinositol-dependent Arf GAP (AGAP1) by promoting AGAP1 mRNA stability. AGAP1 promotes cancer cell proliferation and metastasis by enhancing exosome formation. Furthermore, we explored the combination of the HSP90 inhibitor HSP90i and the AGAP1 inhibitor QS11 could inhibit ESCC cell proliferation and metastasis. Thus, the p53-G245S/hnRNPA2B1/AGAP1 axis promotes ESCC progression by enhancing exosome formation, and the combination of an HSP90 inhibitor and an AGAP1 inhibitor may serve as a potential therapeutic strategy. Highlights: p53-G245S interacted with hnRNPA2B1. hnRNPA2B1 increases AGAP1 protein expression by promoting AGAP1 mRNA stability. p53-G245S/hnRNPA2B1/AGAP1 axis promotes cell proliferation and metastasis by enhancing exosome formation. The combination of HSP90i and QS11 could inhibit ESCC progression.