胃癌（GC）化疗的主要挑战之一是多重耐药（MDR）现象。上皮间质转化（EMT）及其关键分子转化生长因子-β（TGFβ）和SMAD2在MDR的发生中发挥着核心作用。他莫昔芬 (TAM) 是一种三苯乙烯衍生物，可以克服人类胃癌的多重耐药性。本研究的目的是探讨 TAM 通过抑制 TGFβ1/SMAD2 信号通路和 EMT 对 GC 5-FU 耐药的影响。 MKN-45 细胞系接受 5-FU、TAM 以及两者的组合处理。 MTT法用于研究5-FU和TAM的细胞毒性作用，DNA梯形技术用于评估DNA断裂和细胞凋亡。实时 RT-PCR 检查 EMT 相关基因（SNAI2、VIM、TGFβ1 和 SMAD2）的基因表达变化。本研究结果表明，TAM处理不仅显着降低了5-FU的IC50（P≤0.05），而且在5-FU中添加TAM还诱导了MKN-45细胞系的凋亡。 TAM和5-FU处理显着抑制MKN-45细胞中TGFβ1和TGFβ1诱导的EMT标志物（VIM和SNAI2）的表达（P≤0.05）。 SMAD2信号通路下游TGFβ1靶标的减少逆转了EMT过程，并显着增加了MKN-45细胞对5-FU的敏感性。本研究的结果表明，使用 TAM 通过 TGFβ1/SMAD 信号通路逆转 EMT 介导的 MDR 可能是克服 GC 化疗期间对 5-FU 化疗耐药的潜在新治疗策略。© 作者。

One of the major challenges in gastric cancer (GC) chemotherapy is the phenomenon of multi-drug resistance (MDR). The epithelial-mesenchymal transition (EMT) and its key molecules, transforming growth factor-β (TGFβ) and SMAD2, play a central role in MDR occurrence. Tamoxifen (TAM), a triphenylethylene derivative, can overcome MDR in human gastric cancers. The aim of this study was to investigate the effect of TAM on 5-FU resistance of GC by suppressing the TGFβ1/SMAD2 signaling pathway and EMT. The MKN-45 cell line was subjected to treatment with 5-FU, TAM and a combination of both. The MTT assay was used to investigate the cytotoxic effects of 5-FU and TAM, and the DNA laddering technique was used to assess DNA fragmentation and apoptosis. Real-time RT-PCR examined the change in gene expression in EMT-related genes (SNAI2, VIM, TGFβ1 and SMAD2). The results of the present study indicated that not only TAM treatment significantly decreased the IC50 of 5-FU (P≤0.05), but also the addition of TAM to 5-FU induced apoptosis in the MKN-45 cell line. Treatment with TAM and 5-FU significantly inhibited TGFβ1 and TGFβ1-induced expression of EMT markers (VIM and SNAI2) in MKN-45 cells (P≤0.05). The reduction of TGFβ1 targets downstream of the SMAD2 signaling pathway reversed the process of EMT and significantly increased the sensitivity of MKN-45 cells to 5-FU. The results of the present study suggested that reversal of EMT-mediated MDR via the TGFβ1/SMAD signaling pathway using TAM may be a potential new therapeutic strategy to overcome chemoresistance to 5-FU during GC chemotherapy.© The Author(s).