title: Downregulated miR-506 expression facilitates pancreatic cancer progression and chemoresistance via SPHK1/Akt/NF-κB signaling.
abstract: The aberrant expression of microRNAs (miRNAs) has emerged as an important hallmark of cancer. However, the molecular mechanisms underlying the changes in miRNA expression remain unclear. In this study, we discovered a novel epigenetic mechanism of miR-506 regulation and investigated its functional significance in pancreatic cancer. Sequencing analysis revealed that the miR-506 promoter is highly methylated in pancreatic cancer tissues compared with non-cancerous tissues. Reduced miR-506 expression was significantly associated with clinical stage, pathologic tumor status, distant metastasis and decreased survival of pancreatic cancer patients. miR-506 inhibited cell proliferation, induced cell cycle arrest at the G1/S transition and enhanced apoptosis and chemosensitivity of pancreatic cancer cells. Furthermore, we identified sphingosine kinase 1 (SPHK1) as a novel target of miR-506, the expression of which inhibited the SPHK1/Akt/NF-κB signaling pathway, which is activated in pancreatic cancer. High SPHK1 expression was significantly associated with poor survival in a large cohort of pancreatic cancer specimens. Our data suggest that miR-506 acts as a tumor suppressor miRNA and is epigenetically silenced in pancreatic cancer. The newly identified miR-506/SPHK1 axis represents a novel therapeutic strategy for future pancreatic cancer treatment.
authors.affiliation: Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Yin
authors.affiliation: Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: S
authors.initials: S
authors.lastname: Guo
authors.affiliation: Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Institute of Immunology PLA, Third Military Medical University, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Institute of Immunology PLA, Third Military Medical University, Chongqing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ju
authors.affiliation: Department of Pathophysiology and High Altitude Pathology, Third Military Medical University, Chongqing, China.|Institute of Immunology PLA, Third Military Medical University, Chongqing, China.
authors.forename: B
authors.initials: B
authors.lastname: Ni
authors.affiliation: Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D051057:Proto-Oncogene Proteins c-akt; D000099157:Sphingosine Kinase; C561508:MIRN506 microRNA, human