Li Shu-Liang, Wang Pei-Yao, Jia Yang-Pu, Zhang Zhao-Xiong, He Hao-Yu, Chen Peng-Yu, Liu Xin, Liu Bang, Lu Li, Fu Wei-Hua
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China.
Department of Gastrointestinal Surgery, The Second People's Hospital of Liaocheng, Liaocheng 252600, Shandong Province, China.
World J Gastrointest Oncol. 2024 Nov 15;16(11):4436-4455. doi: 10.4251/wjgo.v16.i11.4436.
Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer. However, the emergence of resistance to trastuzumab poses significant challenges.
To identify the key genes associated with trastuzumab resistance. These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes.
High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene and delineate its potential function and pathway regulation. Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between expression and trastuzumab resistance. We established gastric cancer cell lines with both highly expressed and suppressed levels of , followed by comprehensive and experiments to confirm the involvement of in trastuzumab resistance and to elucidate its underlying mechanisms.
In patients with HER2-positive gastric cancer, there is a significant correlation between elevated expression in tumor tissues and higher T stage, tumor node metastasis stage, as well as poor overall survival and progression-free survival. is highly expressed in trastuzumab-resistant gastric cancer cell lines, where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt (PI3K-AKT) pathway in HER2-positive gastric cancer cells, both and .
This study revealed a robust association between high expression and an unfavorable prognosis in patients with HER2-positive gastric cancer. Thus, the high expression of stimulated PI3K-AKT phosphorylation and activation, stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis, ultimately leading to trastuzumab resistance.
曲妥珠单抗靶向治疗目前是晚期人表皮生长因子受体2（HER2）阳性胃癌的标准治疗方法。然而，曲妥珠单抗耐药的出现带来了重大挑战。
确定与曲妥珠单抗耐药相关的关键基因。这些结果为开发应对耐药性的干预措施和改善患者预后提供了依据。
采用高通量测序和生物信息学方法来鉴定差异表达的关键基因，并描绘其潜在功能和通路调控。收集HER2阳性胃癌患者的肿瘤样本，以评估该基因表达与曲妥珠单抗耐药之间的相关性。我们建立了该基因高表达和低表达的胃癌细胞系，随后进行全面的功能和机制实验，以证实该基因参与曲妥珠单抗耐药并阐明其潜在机制。
在HER2阳性胃癌患者中，肿瘤组织中该基因表达升高与更高的T分期、肿瘤淋巴结转移分期以及较差的总生存期和无进展生存期之间存在显著相关性。该基因在曲妥珠单抗耐药的胃癌细胞系中高表达，在HER2阳性胃癌细胞中通过促进磷酸肌醇3激酶-蛋白激酶B（PI3K-AKT）通路的磷酸化和激活来抑制肿瘤细胞凋亡并增强曲妥珠单抗耐药性。
本研究揭示了HER2阳性胃癌患者中该基因高表达与不良预后之间的密切关联。因此，该基因的高表达刺激了PI3K-AKT的磷酸化和激活，促进了HER2阳性肿瘤细胞的增殖并抑制了凋亡，最终导致曲妥珠单抗耐药。
