State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P.R. China.
Department of Breast, Longhua Hospital Affiliated to Shanghai University of TCM, Shanghai 200032, P.R. China.
Aging (Albany NY). 2021 Jan 5;13(1):228-240. doi: 10.18632/aging.103669.
Cetuximab resistance is the main obstacle for the treatment of EGFR overexpression cancer, including triple-negative breast cancer (TNBC). MicroRNA (miRNA)-155-5p is upregulated in TNBC cells; thus, the present study explored whether the downregulation of miR-155-5p enhanced the anti-tumor effect of cetuximab in TNBC cells. MDA-MB-231 and MDA-MB-468 cells were infected with lentivirus-epidermal growth factor receptor (EGFR) for 72 h to obtain EGFR-overexpressed cell lines (MDA-MB-231 and MDA-MB-468). The inhibitory effects of cetuximab on the proliferation and migration of EGFR-overexpressed MDA-MB-468 cells were enhanced following transfection with the miR-155-5p antagomir, and miR-155-5p knockdown enhanced the pro-apoptotic effect of cetuximab on EGFR-overexpressed MDA-MB-468 cells. Further, the luciferase reporter assay revealed that gasdermin E (GSDME) was the direct binding target of miR-155-5p. The combination of cetuximab with the miR-155-5p antagomir promoted pyroptosis in EGFR-overexpressed MDA-MB-468 cells via the upregulation of GSDME-N and cleaved caspase-1. Results from the experiments confirmed that the downregulation of miR-155-5p enhanced the anti-tumor effect of cetuximab in an MDA-MB-468 xenograft model and on EGFR-overexpressed TNBC cells via inducing cell apoptosis and pyroptosis. Therefore, cetuximab combination with an miR-155-5p antagomir may be a novel therapeutic strategy for the treatment of TNBC.
西妥昔单抗耐药是 EGFR 过表达癌症（包括三阴性乳腺癌）治疗的主要障碍。miRNA-155-5p 在 TNBC 细胞中上调；因此，本研究探讨了下调 miR-155-5p 是否增强了西妥昔单抗在 TNBC 细胞中的抗肿瘤作用。MDA-MB-231 和 MDA-MB-468 细胞用携带表皮生长因子受体（EGFR）的慢病毒感染 72 h，获得 EGFR 过表达细胞系（MDA-MB-231 和 MDA-MB-468）。转染 miR-155-5p 拮抗剂后，西妥昔单抗对 EGFR 过表达 MDA-MB-468 细胞增殖和迁移的抑制作用增强，miR-155-5p 敲低增强了西妥昔单抗对 EGFR 过表达 MDA-MB-468 细胞的促凋亡作用。进一步的荧光素酶报告基因实验表明，Gasdermin E（GSDME）是 miR-155-5p 的直接结合靶标。西妥昔单抗与 miR-155-5p 拮抗剂联合使用通过上调 GSDME-N 和切割的半胱天冬酶-1 促进 EGFR 过表达 MDA-MB-468 细胞发生细胞焦亡。实验结果证实，下调 miR-155-5p 通过诱导细胞凋亡和细胞焦亡，增强了西妥昔单抗在 MDA-MB-468 异种移植模型和 EGFR 过表达 TNBC 细胞中的抗肿瘤作用。因此，西妥昔单抗与 miR-155-5p 拮抗剂联合使用可能是治疗三阴性乳腺癌的一种新的治疗策略。
