Psoralen Suppresses Cisplatin-Mediated Resistance and Induces Apoptosis of Gastric Adenocarcinoma by Disruption of the miR196a-HOXB7-HER2 Axis

Lei Jin,1,2,* Xue-Mei Ma,1,2,* Ting-Ting Wang,1,2 Yao Yang,1,2 Nan Zhang,2,3 Na Zeng,2,4 Zhi-Gang Bai,1,2 Jie Yin,1,2 Jun Zhang,1,2 Guo-Qian Ding,1,2 Zhong-Tao Zhang1,2 1Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2National Clinical Research Center for Digestive Diseases, Beijing, People’s Republic of China; 3Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Clinical Epidemiology and EBM Center, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guo-Qian Ding; Zhong-Tao Zhang Email dingguoqian@gmail.com; zhangzhongtao@ccmu.edu.cnPurpose: The present study aimed to investigate the impact of psoralen on miR-196a-5p expression and function, and to reveal the mechanism underlying miR-196a-5p-mediated inhibition and the reversal of cisplatin (DDP) resistance.Methods: Serum samples were collected from 50 patients with gastric cancer (GC), and the association between miR-196a-5p expression and the response to chemotherapy was assessed. A DDP-resistant GC cell line was also established to determine the effects of miR-196a-5p and psoralen on DDP resistance. MGC803 cells were transfected with miR-196a-5p mimic and inhibitor vectors for the overexpression and downregulation of miR-196a-5p, respectively.Results: Clinical data analysis showed that the lower expression levels of miR-196a-5p were significantly associated with chemoresistance in patients with GC. Upregulation of miR-196a-5p significantly enhanced the anti-proliferative effect, apoptosis and sensitivity to DDP by regulating the protein expression levels of HOXB7, HER2, Bcl-2 and G1/S-specific cyclin-D1 (CCND1). Furthermore, psoralen reversed miR-196a-5p-induced DDP resistance and reduced the expression levels of HOXB7, HER2, Bcl-2 and CCND1.Conclusion: miR-196a-5p may be a novel biomarker of chemotherapeutic success in patients with GC and may also influence the sensitivity of GC cells to DDP. Moreover, psoralen can increase chemotherapeutic sensitivity by upregulating miR-196a-5p and then downregulating HOXB7-HER2 signaling axis.Keywords: miR-196a-5p, psoralen, chemoresistance, cisplatin, gastric cancer, HOXB7