en Cancer Cancer Original Article Original Article <span style="font-family:Tahoma;"><span style="font-size:12px;"><span style="unicode-bidi:embed"><span style="line-height:107%">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-&beta; (TGF&beta;) and SMAD2, play a central role in MDR occurrence.&nbsp; 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 TGF&beta;1/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, TGF&beta;1 and SMAD2). The results of the present study indicated that not only TAM treatment significantly decreased the IC50 of 5-FU (P&le;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 TGF&beta;1 and TGF&beta;1-induced expression of EMT markers (VIM and SNAI2) in MKN-45 cells (P&le;0.05). The reduction of TGF&beta;1 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 TGF&beta;1/SMAD signaling pathway using TAM may be a potential new therapeutic strategy to overcome chemoresistance to 5-FU during GC chemotherapy.</span></span></span></span> Epithelial-mesenchymal transition, gastric cancer, drug resistance, Tamoxifen, TGFβ1/ SMAD2 signaling pathway 361 371 http://ijmcmed.org/browse.php?a_code=A-10-7926-1&slc_lang=en&sid=1 Zeinab Mahdian mahdian.zeinab0210@gmail.com 100319475328460033910 100319475328460033910 No Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, Iran. Mahdi Pouramir pouramir@yahoo.com 100319475328460033911 100319475328460033911 Yes Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran. Hassan Akrami hassan_akrami@yahoo.com 100319475328460033912 100319475328460033912 No Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Ebrahim Zabihi e_zabihi@yahoo.com 100319475328460033913 100319475328460033913 No Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.