Feng Riyue, Yin Yin, Wei Yuge, Li Yang, Li Lei, Zhu Rui, Yu Xiao, Liu Yuhao, Zhao Yahui, Liu Zhihua
State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Cancer Lett. 2023 May 28;562:216154. doi: 10.1016/j.canlet.2023.216154. Epub 2023 Apr 7.
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.
p53突变易引发癌细胞的发展，促进其存活和转移，并导致治疗反应无效和预后不良。目前尚无能够消除突变型p53致癌功能的药物获批用于癌症治疗。在此，我们对663例食管鳞状细胞癌（ESCC）肿瘤组织及其配对的正常组织进行了全基因组测序。结果表明，我们队列中的ESCC样本与国际癌症研究机构（IARC）数据库中的欧美ESCC样本相比，TP53突变体的分布更为分散，无义突变的比例更高。ESCC中最常见的p53突变会破坏野生型p53介导的对增殖、迁移和侵袭的抑制作用。此外，p53突变会改变其蛋白质的核质定位和蛋白质稳定性。p53突变体G245S（p53-G245S）与异质性核核糖核蛋白A2B1（hnRNPA2B1）相互作用，通过促进AGAP1 mRNA稳定性来增加磷脂酰肌醇依赖性Arf GAP（AGAP1）的蛋白质翻译。AGAP1通过增强外泌体形成促进癌细胞增殖和转移。此外，我们探究了HSP90抑制剂HSP90i与AGAP1抑制剂QS11联合使用可抑制ESCC细胞增殖和转移。因此，p53-G245S/hnRNPA2B1/AGAP1轴通过增强外泌体形成促进ESCC进展，HSP90抑制剂与AGAP1抑制剂联合使用可能是一种潜在的治疗策略。
