title: Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway.
abstract: The development of chemoresistance and metastasis are the leading causes of death for gastric cancer (GC) patients, however, the molecular mechanisms involved remain unclear. Dysregulation of miRNAs is associated with a variety of disease, including GC. Recently, microarray profiling analysis revealed that miR-939 was dysregulated in human GC samples, but the role of miR-939 in GC has not been intensively investigated.
  
  
  
  In the present study, we firstly examined the expression pattern of miR-939 in two independent cohorts of clinical GC samples: one cohort of 112 GC patients with stage I-III disease who underwent surgery followed by adjuvant chemotherapy; and another cohort of 110 GC patients with stage IV disease who received palliative chemotherapy. A series of in vivo and in vitro assays were then performed to investigate the function of miR-939 in GC.
  
  
  
  We detected that reduced expression of miR-939 was associated with chemoresistance and increased risk of tumor recurrence in GC patients. Further function study demonstrated that overexpression of miR-939 suppressed GC cell growth, and enhanced 5-fluorouracil-induced chemosensitivity by compromising cellular growth and inducing apoptosis in vitro and in vivo. Moreover, miR-939 repressed the migration and invasion of GC cells in vitro, and diminished the occurrence of lung metastasis in vivo. We further identified solute carrier family 34 member 2 (SLC34A2) was a novel target of miR-939. Mechanistically, we elucidated that miR-939 exerted its function mainly through inhibiting SLC34A2/Raf/MEK/ERK pathway, which is activated in GC. Multivariate analysis identified miR-939, SLC34A2, and their combination as independent indicators for poor prognosis and tumor recurrence in GC patients.
  
  
  
  Our data indicate that miR-939 acts as a tumor suppressor miRNA in GC, and miR-939/SLC34A2 axis represents a novel therapeutic strategy for future GC treatment.
authors.affiliation: Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan road II, 510080, Guangzhou, People's Republic of China.|The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, No. 651, Dongfeng Road East, 510060, Guangzhou, People's Republic of China.
authors.forename: Jia-Xing
authors.initials: JX
authors.lastname: Zhang
authors.affiliation: Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan road II, 510080, Guangzhou, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan road II, 510080, Guangzhou, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan road II, 510080, Guangzhou, People's Republic of China.
authors.forename: Cui
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan road II, 510080, Guangzhou, People's Republic of China.
authors.forename: Zhou-San
authors.initials: ZS
authors.lastname: Zheng
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, No. 651, Dongfeng Road East, 510060, Guangzhou, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Yun
authors.affiliation: Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan road II, 510080, Guangzhou, People's Republic of China.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Weng
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, No. 651, Dongfeng Road East, 510060, Guangzhou, People's Republic of China. xiedan@sysucc.org.cn.|Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China. xiedan@sysucc.org.cn.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan road II, 510080, Guangzhou, People's Republic of China. yes20111212@163.com.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ye
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010766:Phosphorylation; D034622:RNA Interference; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D048490:raf Kinases / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C000604729:MIRN939 microRNA, human; D035683:MicroRNAs; C493557:SLC34A2 protein, human; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D048490:raf Kinases
keywords: Chemoresistance; Gastric cancer; Metastasis; SLC34A2; miR-939