title: MIR506 induces autophagy-related cell death in pancreatic cancer cells by targeting the STAT3 pathway.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and lethal cancer. The role of autophagy in the pathobiology of PDAC is intricate, with opposing functions manifested in different cellular contexts. MIR506 functions as a tumor suppressor in many cancer types through the regulation of multiple pathways. In this study, we hypothesized that MIR506 exerted a tumor suppression function in PDAC by inducing autophagy-related cell death. Our results provided evidence that downregulation of MIR506 expression was associated with disease progression in human PDAC. MIR506 triggered autophagic flux in PDAC cells, which led to autophagy-related cell death through direct targeting of the STAT3 (signal transducer and activator of transcription 3)-BCL2-BECN1 axis. Silencing and inhibiting STAT3 recapitulated the effects of MIR506, whereas forced expression of STAT3 abrogated the effects of MIR506. We propose that the apoptosis-inhibitory protein BCL2, which also inhibits induction of autophagy by blocking BECN1, was inhibited by MIR506 through targeting STAT3, thus augmenting BECN1 and promoting autophagy-related cell death. Silencing BECN1 and overexpression of BCL2 abrogated the effects of MIR506. These findings expand the known mechanisms of MIR506-mediated tumor suppression to activation of autophagy-related cell death and suggest a strategy for using MIR506 as an anti-STAT3 approach to PDAC treatment.
authors.affiliation: a Department of Cancer Biology , Comprehensive Cancer Center of Wake Forest Baptist Medical Center , Winston-Salem , NC , USA.|b Department of Pathology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.|c Department of General Surgery , Tianjin Medical University General Hospital , Tianjin , China.
authors.forename: Longhao
authors.initials: L
authors.lastname: Sun
authors.affiliation: b Department of Pathology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Limei
authors.initials: L
authors.lastname: Hu
authors.affiliation: b Department of Pathology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: David
authors.initials: D
authors.lastname: Cogdell
authors.affiliation: c Department of General Surgery , Tianjin Medical University General Hospital , Tianjin , China.
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.affiliation: a Department of Cancer Biology , Comprehensive Cancer Center of Wake Forest Baptist Medical Center , Winston-Salem , NC , USA.|b Department of Pathology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: c Department of General Surgery , Tianjin Medical University General Hospital , Tianjin , China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Tian
authors.affiliation: c Department of General Surgery , Tianjin Medical University General Hospital , Tianjin , China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: d Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Ya'an
authors.initials: Y
authors.lastname: Kang
authors.affiliation: d Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.affiliation: a Department of Cancer Biology , Comprehensive Cancer Center of Wake Forest Baptist Medical Center , Winston-Salem , NC , USA.|b Department of Pathology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics*; D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C561508:MIRN506 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor
keywords: MIR506; STAT3; autophagy; autophagy-related cell death; pancreatic ductal adenocarcinoma