突变的p53激活hnRNPA2B1-AGAP1介导的外泌体形成，促进食管鳞状细胞癌的进展。
Mutant p53 activates hnRNPA2B1-AGAP1-mediated exosome formation to promote esophageal squamous cell carcinoma progression.
发表日期：2023 Apr 07
作者：
Riyue Feng, Yin Yin, Yuge Wei, Yang Li, Lei Li, Rui Zhu, Xiao Yu, Yuhao Liu, Yahui Zhao, Zhihua Liu
来源：
CANCER LETTERS
摘要：
p53基因突变使癌细胞易于发展，增强其存活和转移能力，并导致治疗反应不佳和预后不良。目前尚未有药物获批用于治疗带有p53突变的癌症。本研究对663例食管鳞状细胞癌（ESCC）肿瘤组织和配对正常组织进行了全基因组测序，结果表明，我们的样本中ESCC样本的TP53突变分布更为分散，无义突变的比例更高，而这些在国际癌症研究机构（IARC）数据库中的欧美ESCC样本中并不常见。最常见的p53突变导致抑制正常p53在ESCC中介导的增殖、迁移和侵袭的功能被破坏。此外，p53突变也会改变其蛋白的核质定位和蛋白稳定性。p53 G245S（p53-G245S）突变会与异核核糖核蛋白A2B1（hnRNPA2B1）相互作用，促进磷脂酰肌醇依赖性Arf GAP（AGAP1）的蛋白翻译，并提高AGAP1 mRNA的稳定性。AGAP1通过促进外泌体形成来促进癌细胞的增殖和转移。此外，我们探讨了热休克蛋白90（HSP90）抑制剂HSP90i和AGAP1抑制剂QS11的联合应用可以抑制ESCC细胞的增殖和转移。因此，p53-G245S/hnRNPA2B1/AGAP1轴通过增强外泌体形成来促进ESCC的进展，而同时使用HSP90抑制剂和AGAP1抑制剂可以作为潜在的治疗策略。版权所有©2023 Elsevier B.V.
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.Copyright © 2023. Published by Elsevier B.V.