Anti-proliferative and anti-invasive effects of exogenous thermostable MnSOD in gastric cancer associated with p53 and ZEB1 expression.

IF 3.3 3区 医学 Q2 ONCOLOGY
Journal of Cancer Pub Date : 2025-03-03 eCollection Date: 2025-01-01 DOI:10.7150/jca.102600
Hailong Li, Hao Wang, Zong Li, Natalia Kelley, Matt Ouyang, Jia-Wei Wu, Fanguo Meng, Wen-Bin Ou
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Abstract

The incidence of gastric cancer accounts for the first malignant tumor of the digestive tract. Although some progress in gastric cancer treatments has been made, uncontrollable drug resistance makes the development of new targeted drugs and treatment options increasingly urgent. The biological function of endogenous manganese superoxide dismutase (MnSOD) has been widely studied, whereas the anti-tumor growth effects of exogenous thermostable MnSOD in gastric cancer, an oral recombinant protein drug, are still unclear. Here, compared to normal gastric epithelial cell line and enzymatic dead mutant MnSOD H29A, we show that exogenous MnSOD treatment resulted in reduction of cell viability, colony formation, migration, and invasiveness; inhibition of SGC7901 xenograft growth; induction of apoptosis and arrest of G2-phase population in gastric cancer by an enzymatic activity-dependent manner; upregulation of p53, p21, and E-cadherin; and downregulation of cyclin D1 and N-cadherin. Unexpectedly, MnSOD treatment induced zinc finger E-box homeobox 1 (ZEB1) expression in SGC7901 gastric cancer cells, which was associated with a poor five-year survival rate and poor prognosis in gastric cancer patients. However, anti-proliferative effects of exogenous MnSOD were enhanced in SGC7901 after ZEB1 knockdown, whereas attenuated in BGC823 after ZEB1 restoration. These findings indicate that the exogenous thermostable MnSOD inhibited gastric cancer growth associated with p53 and ZEB1 expression levels and highlight that the exogenous thermostable MnSOD as an oral drug warrants evaluation as a novel therapeutic strategy in gastric cancer.

外源性耐热性MnSOD在胃癌中与p53和ZEB1表达相关的抗增殖和抗侵袭作用
胃癌的发病率占消化道恶性肿瘤的第一位。虽然胃癌的治疗已经取得了一些进展,但无法控制的耐药性使得开发新的靶向药物和治疗方案日益紧迫。内源性锰超氧化物歧化酶(MnSOD)的生物学功能已被广泛研究,而外源性热稳定性MnSOD在口服重组蛋白药物胃癌中的抗肿瘤生长作用尚不清楚。在这里,与正常胃上皮细胞系和酶致死亡突变体MnSOD H29A相比,我们发现外源MnSOD处理导致细胞活力、集落形成、迁移和侵袭性降低;抑制SGC7901异种移植物生长;以酶活性依赖的方式诱导胃癌g2期细胞凋亡和阻滞g2期细胞;p53、p21和E-cadherin的上调;cyclin D1和N-cadherin的下调。出乎意料的是,MnSOD处理诱导SGC7901胃癌细胞锌指E-box同源盒1 (ZEB1)表达,与胃癌患者5年生存率差、预后差相关。然而,外源MnSOD的抗增殖作用在ZEB1基因敲除后在SGC7901中增强,而在ZEB1基因恢复后在BGC823中减弱。这些结果表明外源性热稳定性MnSOD抑制胃癌生长与p53和ZEB1表达水平相关,并强调外源性热稳定性MnSOD作为口服药物作为一种新的胃癌治疗策略值得评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Cancer
Journal of Cancer ONCOLOGY-
CiteScore
8.10
自引率
2.60%
发文量
333
审稿时长
12 weeks
期刊介绍: Journal of Cancer is an open access, peer-reviewed journal with broad scope covering all areas of cancer research, especially novel concepts, new methods, new regimens, new therapeutic agents, and alternative approaches for early detection and intervention of cancer. The Journal is supported by an international editorial board consisting of a distinguished team of cancer researchers. Journal of Cancer aims at rapid publication of high quality results in cancer research while maintaining rigorous peer-review process.
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