NHE1 Mediates 5-Fu Resistance in Gastric Cancer via STAT3 Signaling Pathway

Zhenni Sun,1 Shufang Luan,1 Yasai Yao,1 Tao Qin,1 Xiaomei Xu,1 Zan Shen,2 Ruyong Yao,3 Lu Yue1 1Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong Province 266071, People’s Republic of China; 2Department of Oncology, The Sixth People’s Hospital, Medical College of Shanghai Jiao Tong University, Shanghai 200233, People’s Republic of China; 3Central Laboratory, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong Province 266071, People’s Republic of ChinaCorrespondence: Lu YueDepartment of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Shandong Province 266071, People’s Republic of ChinaTel + 86 18887112038Fax +86 871-68250639Email yuelu191030@yeah.netBackground: Several recent studies have addressed the role of Na+/H+ exchanger isoform 1 (NHE1) in tumor cell growth and apoptosis, including in gastric cancer. However, the role of NHE1 expression related to the 5-Fu resistance in gastric cancer has not been investigated.Methods: The expression of NHE1 was examined by qPCR in the SGC7901/5-FU cell line and its parental cell line. pcDNA3.1-NHE1 and NHE1-siRNA were transfected to SGC7901/5-FU resistance cells and cell apoptosis was detected via TUNEL assay. The upstream activators in NHE1 mediated 5-Fu resistant gastric cancer cells were detected by Western blot and immunofluorescent.Results: A significant increase of the expression of NHE1 was observed in SGC7901 5-FU resistance cells compared to the GES-1 and SGC7901 cell line. NHE1 can suppress the cell apoptosis of SGC7901 5-FU resistance cells and involved in cell cycle. Also, the migration and invasion of SGC7901 5-FU resistance cells were promoted by NHE1. NHE1 also increases the intracellular pH. The results of Western blot analysis showed that NHE1 overexpression induced an increase in the expression of phosphorylated activator transcription factor 3 (pSTAT3). The more obvious phosphorylated level was shown in the phosphorylated STAT3 at pSTAT3tyr705. Further investigations revealed that the constitutive activation of STAT3 may be induced by JAK1 and JAK2, and thus effect the 5-FU resistance by regulating NHE1.Discussion: In summary, our findings provided evidence that NHE1 contributed to 5-Fu resistance in gastric cancer cells by regulating the JAK/STAT3 pathway. Therefore, NHE1 can be a useful marker for predicting and monitoring 5-Fu resistance.Keywords: NHE1, 5-FU resistance, JAK/STAT3 pathway, gastric cancer