PDF(Pubmed)
Abstract：
Gastric cancer results in great cancer mortality worldwide, and inducing ferroptosis dramatically improves the malignant phenotypes of gastric cancer. DNA polymerase epsilon subunit 2 (POLE2) plays indispensable roles in tumorigenesis; however, its involvement and molecular basis in ferroptosis and gastric cancer are not clear. Human gastric cancer cells were infected with lentiviral vectors to knock down or overexpress POLE2, and cell ferroptosis was detected. To further validate the involvement of nuclear factor erythroid 2-related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4), lentiviral vectors were used. POLE2 expression was elevated in human gastric cancer cells and tissues and closely correlated with clinicopathological features in gastric cancer patients. POLE2 knockdown was induced, while POLE2 overexpression inhibited ferroptosis of human gastric cancer cells, thereby modulating the malignant phenotypes of gastric cancer. Mechanistic studies revealed that POLE2 overexpression elevated NRF2 expression and activity and subsequently activated GPX4, which then prevented lipid peroxidation and ferroptosis in human gastric cancer cells. In contrast, either NRF2 or GPX4 silence significantly prevented POLE2 overexpression-mediated inductions of cell proliferation, migration, invasion and inhibition of ferroptosis. POLE2 overexpression inhibits ferroptosis in human gastric cancer cells through activating NRF2/GPX4 pathway, and inhibiting POLE2 may be a crucial strategy to treat gastric cancer.
摘要：
胃癌导致世界范围内巨大的癌症死亡率，诱导铁凋亡能显著改善胃癌的恶性表型。DNA聚合酶ε亚基2（POLE2）在肿瘤发生中起着不可或缺的作用；然而，其在铁凋亡和胃癌中的参与和分子基础尚不清楚。用慢病毒载体感染人胃癌细胞以敲除或过表达POLE2，并检测细胞铁凋亡。为了进一步验证核因子红系2相关因子2（NRF2）和谷胱甘肽过氧化物酶4（GPX4）的参与，使用慢病毒载体。POLE2在人胃癌细胞和组织中表达升高，并与胃癌患者的临床病理特征密切相关。POLE2敲低被诱导，而POLE2过表达抑制人胃癌细胞的铁凋亡，从而调节胃癌的恶性表型。机制研究表明，POLE2过表达可提高NRF2的表达和活性，并随后激活GPX4，从而阻止人胃癌细胞的脂质过氧化和铁凋亡。相比之下,NRF2或GPX4沉默显著阻止POLE2过表达介导的细胞增殖诱导，迁移,铁凋亡的侵袭和抑制。POLE2过表达通过激活NRF2/GPX4通路抑制人胃癌细胞铁凋亡,而抑制POLE2可能是治疗胃癌的重要策略。
