HMGB1 induces radioresistance through PI3K/AKT/ATM pathway in esophageal squamous cell carcinoma.
HMGB1 induces radioresistance through PI3K/AKT/ATM pathway in esophageal squamous cell carcinoma.
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HMGB1通过PI3K/AKT/ATM通路诱导食管鳞癌放射抗性
DOI：
10.1007/s11033-022-07989-8
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发表时间：
2022-12
影响因子：
2.8
通讯作者：
Zhu, Shuchai
中科院分区：
文献类型：
--
作者：
Zhang, Xueyuan;Zou, Naiyi;Deng, Wenzhao;Song, Chunyang;Yan, Ke;Shen, Wenbin;Zhu, Shuchai
探讨HMGB1通过调控PI3K/Akt/ATM通路对食管癌细胞放射敏感性的影响。我们用免疫组化染色法观察食管癌活检组织中HMGB1和p-ATM的表达。Western blot和RT-qPCR分别检测PI3K/Akt/ATM通路相关蛋白和RNA。此外，我们用ly294002抑制PI3K/Akt通路，用IGF1激活PI3K/Akt通路，然后分别用transwell、CCK8和流式细胞术研究体外食管癌细胞的侵袭、增殖能力和凋亡情况。在体内，裸鼠建立异种移植瘤模型，研究HMGB1通过PI3K/AKT/ATM信号通路对放射线耐药的影响。HMGB1和p-ATM单阳性/双阴性表达患者的生存率明显高于HMGB1和p-ATM同时阳性表达的患者，HMGB1的缺失联合ly294002显著抑制了细胞的增殖和侵袭能力，而IGF1的加入则使其逆转。同时，HMGB1和ly294002的表达降低Cyclin D1和CDK4的表达，提高P16的表达，促进G0/G1细胞周期的癌细胞凋亡和阻滞。我们进一步在体内验证了这些结果，HMGB1沉默的应用促进了放射后异种移植肿瘤的凋亡，特别是与途径抑制剂ly294002联合使用。HMGB1和p-ATM高表达的食管癌患者放化疗后预后较差。HMGB1的下调可能通过调控PI3K/Akt/ATM通路促进食管癌细胞的放射敏感性。
To explore the effect of HMGB1 on the radio-sensitivity of esophageal cancer cells through regulating the PI3K/Akt/ATM pathway. We observed the expression of HMGB1 and p-ATM in biopsies of esophageal cancer patients with immunohistochemical staining. Western blot and RT-qPCR were applied to detect the protein and RNA related to PI3K/Akt/ATM pathway, respectively. In addition, we inhibited the PI3K/Akt pathway with ly294002 and activated it with IGF1, then we explored the invasion, proliferation ability, and apoptosis of esophageal cancer cells in vitro by transwell, CCK8 assay, and flow cytometry respectively. In vivo, xenograft tumor model was established in nude mice to study the effect of HMGB1 on radioresistance via PI3K/AKT/ATM Signaling Pathway. The survival rate in patients with single positive/double negative expression of HMGB1 and p-ATM was significantly higher than in those with both positive expression of HMGB1 and p-ATM, the depletion of HMGB1 combined with ly294002 significantly inhibited cell proliferation and invasion ability, meanwhile, the addition of IGF1 reversed it. Meanwhile, depletion of HMGB1 and ly294002 promoted apoptosis and arrested the cancer cells in G0/G1 cell cycle with the decreased expression of Cyclin D1 and CDK4 and improved P16. We further validated these results in vivo, the application of HMGB1 silencing promoted apoptosis of xenograft tumors after radiation, especially combined with pathway inhibitor ly294002. Esophageal cancer patients with high expression of HMGB1 and p-ATM have a poor prognosis after chemo-radiotherapy. Down-regulation of HMGB1 may promote the radio-sensitivity of esophageal cancer cells through regulating PI3K/Akt/ATM pathway.
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