顺铂是乳腺癌的一线治疗药物，但面临药物耐受性的挑战。本研究探讨了乳腺癌顺铂耐药的新的分子机制。我们分析了TCGA数据库中的测序数据，以确定跨膜emp24蛋白转运区域含2 (TMED2) 与乳腺癌之间的潜在关联。 Western blot、实时PCR、CCK-8和TUNEL测定用于测量TMED2对MCF-7和MDA-MB-231细胞系中顺铂耐药的影响和分子机制。TMED2在乳腺癌中过度表达，并与不良预后相关。 TMED2通过促进Kelch-like ECH-associated protein 1 (KEAP1)泛素化，减轻KEAP1对核因子红细胞2相关因子2 (Nrf2)的抑制，增加下游与耐药相关基因的表达，如血红素氧合酶1（HO-1）和NAD（P）H喹啉醌还原酶1（NQO1），在体内增加了乳腺癌细胞对顺铂的耐药性。我们发现了TMED2影响乳腺癌顺铂耐药性的新的分子机制。我们的结果为未来的临床应用提供理论指导。© 2023. 华中科技大学。

Cisplatin is the first-line treatment for breast cancer, but it faces challenges of drug resistance. This study investigated new molecular mechanisms underlying cisplatin resistance in breast cancer.We analyzed sequencing data from the TCGA database to identify potential associations between transmembrane emp24 protein transport domain containing 2 (TMED2) and breast cancer. Western blotting, real-time PCR, CCK-8, and TUNEL assays were used to measure the effects and molecular mechanism of TMED2 on cisplatin resistance in MCF-7 and MDA-MB-231 cell lines.TMED2 was overexpressed in breast cancer and associated with poor prognosis. TMED2 increased cisplatin resistance in breast cancer cells in vitro via promoting ubiquitination of Kelch-like ECH-associated protein 1 (KEAP1), relieving inhibition of KEAP1 on nuclear factor erythroid 2-related factor 2 (Nrf2), and increasing expression of downstream drug resistance related genes, such as heme oxygenase 1 (HO-1) and NAD (P) H quinone oxidoreductase 1 (NQO1).We identified a new molecular mechanism by which TMED2 affects cisplatin resistance in breast cancer. Our results provide theoretical guidance for future clinical applications.© 2023. Huazhong University of Science and Technology.