转录增强相关结构域抑制剂GNE-7883对食管鳞癌细胞恶性表型的影响及其分子机制

doi:10.3969/j.issn.1004-616x.2025.03.001

癌变·畸变·突变 ›› 2025, Vol. 37 ›› Issue (3): 177-182.doi: 10.3969/j.issn.1004-616x.2025.03.001

• 论著 •

转录增强相关结构域抑制剂GNE-7883对食管鳞癌细胞恶性表型的影响及其分子机制

卢晓童, 史建红, 肖雪, 陈思琦, 郝佳洁, 蔡岩, 王明荣, 张钰

国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院, 分子肿瘤学全国重点实验室, 北京 100021

收稿日期:2025-02-25 修回日期:2025-03-26 发布日期:2025-06-13
通讯作者: 张钰
作者简介:卢晓童，E-mail：lxtong9@126.com。
基金资助:
国家自然科学基金(81872279)

Involvement of transcriptional enhanced associate domain inhibitor GNE-7883 on malignant phenotypes in esophageal squamous cell carcinoma

LU Xiaotong, SHI Jianhong, XIAO Xue, CHEN Siqi, HAO Jiajie, CAI Yan, WANG Mingrong, ZHANG Yu

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

Received:2025-02-25 Revised:2025-03-26 Published:2025-06-13

摘要/Abstract

摘要： 目的：探讨Yes相关蛋白-转录增强相关结构域小分子抑制剂GNE-7883对食管鳞癌(ESCC)细胞恶性表型的影响及其分子机制。方法：以DMSO为对照，使用不同浓度(8、16、50和100 μmol/L)的GNE-7883处理ESCC KYSE410和KYSE510细胞24或48 h，检测细胞增殖活力、集落形成能力、迁移能力及凋亡率变化，并用逆转录实时荧光定量PCR(qRT-PCR)和Western blot法检测相关分子及信号通路活性蛋白的表达变化。结果：与对照组相比，50 和 100 μmol/L 的 GNE-7883 可显著抑制 KYSE410 和KYSE510细胞的增殖活力和集落形成能力(均为P<0.01)，并可在血清饥饿条件下诱导KYSE410和KYSE510细胞发生显著凋亡(P<0.05)。同时，在血清饥饿条件下，8和16 μmol/L的GNE-7883可显著抑制KYSE410和KYSE510细胞的迁移能力(P<0.01)。分子水平检测结果显示，与对照组相比，常规培养条件下，50 和 100 μmol/L GNE-7883 处理后，ESCC 细胞中与增殖相关的 CTGF、CYR61、c-Myc、p-ERK和p-AKT蛋白表达水平明显降低(P<0.05)；在血清饥饿条件下，50和100 μmol/L GNE-7883处理后，ESCC细胞中凋亡标志分子cleaved PARP、cleaved Caspase-3的表达水平明显升高(P<0.05)，同时伴随CTGF、CYR61、Bcl-2、Bcl-xL、c-Myc、p-ERK和p-AKT蛋白表达水平的降低(P<0.05)。另外，在血清饥饿条件下，8和16 μmol/L GNE-7883处理后，ESCC细胞中CTGF、CYR61、MMP14及p-ERK蛋白表达水平亦较对照组明显下调(P<0.05)。结论：GNE-7883显著抑制ESCC细胞的增殖、迁移及存活能力，并可明显抑制MAPK/ERK和AKT/mTOR信号通路的活性，GNE-7883有可能成为ESCC治疗的候选药物。

关键词: GNE-7883, 食管鳞癌, 增殖能力, 迁移能力, 细胞凋亡

Abstract: OBJECTIVE： To investigate effects of the Yes-associated protein-transcriptional enhanced associate domain (YAP-TEAD) small-molecule inhibitor GNE-7883 on malignant phenotypes and molecular mechanisms in esophageal squamous cell carcinoma (ESCC) cells. METHODS： KYSE410 and KYSE510 cells were treated with varying concentrations of GNE-7883 (8，16，50，and 100 μmol/L) for 24 or 48 hours，with DMSO as control. Cell proliferation， colony formation， migration， and apoptosis were assessed. Molecular expression changes were analyzed by qPCR and Western blot. RESULTS： Compared to controls，50 and 100 μmol/L of GNE-7883 significantly inhibited proliferation and colony formation in both cell lines (P<0.01)，and induced apoptosis under serum-free conditions (P<0.05). Under serum-free conditions， 8 and 16 μmol/L of GNE-7883 significantly inhibited cell migration (P<0.01). Normal cultures treated with 50 and 100 μmol/L of GNE-7883 reduced CTGF，CYR61，c-Myc，p-ERK and p-AKT levels. Serum-free conditions with 50 and 100 μmol/L of GNE-7883 increased Cleaved PARP and Cleaved Caspase-3，while decreasd CTGF，CYR61， Bcl-2， Bcl-xL， c-Myc， p-ERK and p-AKT. Serum-free conditions with 8 and 16 μmol/L of GNE-7883 down-regulated CTGF， CYR61， MMP14， and p-ERK. CONCLUSION： GNE-7883 significantly suppressed proliferation， migration， and survival of esophageal squamous cell carcinoma (ESCC) cells and markedly inhibited activities of the MAPK/ERK and AKT/mTOR signaling pathways. It could be useful as a therapeutic candidate for ESCC.

Key words: GNE-7883, esophageal squamous cell carcinoma, proliferation, migration, apoptosis

中图分类号:

R735.1

卢晓童, 史建红, 肖雪, 陈思琦, 郝佳洁, 蔡岩, 王明荣, 张钰. 转录增强相关结构域抑制剂GNE-7883对食管鳞癌细胞恶性表型的影响及其分子机制[J]. 癌变·畸变·突变, 2025, 37(3): 177-182.

LU Xiaotong, SHI Jianhong, XIAO Xue, CHEN Siqi, HAO Jiajie, CAI Yan, WANG Mingrong, ZHANG Yu. Involvement of transcriptional enhanced associate domain inhibitor GNE-7883 on malignant phenotypes in esophageal squamous cell carcinoma[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2025, 37(3): 177-182.

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转录增强相关结构域抑制剂GNE-7883对食管鳞癌细胞恶性表型的影响及其分子机制

Involvement of transcriptional enhanced associate domain inhibitor GNE-7883 on malignant phenotypes in esophageal squamous cell carcinoma

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