title: MicroRNA 23b regulates autophagy associated with radioresistance of pancreatic cancer cells.
abstract: OBJECTIVE
  Tumor resistance to radiation is a challenge in the treatment of patients with pancreatic cancer. Improving our understanding of the mechanisms of radioresistance could lead to strategies to increase patients' response to therapy. We investigated the roles of microRNAs (miRNAs) involved in radioresistance of pancreatic cancer cells.
  
  
  METHODS
  We established radioresistant pancreatic cancer cell lines and used array analysis to compare levels of different miRNAs between radioresistant cell lines and the parental cell lines from which they were derived. We transfected pancreatic cancer cells with miRNA mimics or inhibitors and evaluated their effects on cell radiosensitivity using a clonogenic survival assay. The effects of miRNA on autophagy were determined by transmission electron microscopy and immunoblot analysis. We used a luciferase reporter assay to identify messenger RNA targets of specific miRNAs.
  
  
  RESULTS
  Radioresistant pancreatic cancer cells had reduced levels of the miRNA miR-23b and increased autophagy compared with cells that were not radioresistant. Overexpression of miR-23b inhibited radiation-induced autophagy, whereas an inhibitor of miR-23b promoted autophagy in pancreatic cancer cells. Overexpression of miR-23b sensitized pancreatic cancer cells to radiation. The target of miR-23b, ATG12, was overexpressed in radioresistant cells; levels of ATG12 protein correlated with the occurrence of autophagy. Expression of miR-23b blocked radiation-induced autophagy and sensitized pancreatic cancer cells to radiation. We observed an inverse correlation between the level of miR-23b and autophagy in human pancreatic cancer tissue samples.
  
  
  CONCLUSIONS
  In pancreatic cancer cells, reduced levels of the miRNA miR-23b increase levels of ATG12 and autophagy to promote radioresistance. miR-23b might be used to increase the sensitivity of pancreatic cancer cells to radiation therapy.
authors.affiliation: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhengfei
authors.initials: Z
authors.lastname: Zhu
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.forename: Lianyu
authors.initials: L
authors.lastname: Chen
authors.forename: Liping
authors.initials: L
authors.lastname: Zhuang
authors.forename: Jianmin
authors.initials: J
authors.lastname: Luo
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Luming
authors.initials: L
authors.lastname: Liu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Meng
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology* / Q000532:radiotherapy; D001343:Autophagy / Q000502:physiology* / Q000528:radiation effects; D000071192:Autophagy-Related Protein 12; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D010179:Pancreas / Q000473:pathology / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000502:physiology*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000502:physiology; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: C466624:ATG12 protein, human; D000071192:Autophagy-Related Protein 12; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D025841:Small Ubiquitin-Related Modifier Proteins
keywords: ANOVA; ATG12; CQ; IR; NC; Pancreatic Cancer; RR; Radioresistance; UTR; analysis of variance; chloroquine; ionizing radiation; mRNA; messenger RNA; miRNA; microRNA; negative control; qPCR; quantitative real-time polymerase chain reaction; radioresistant; untranslated region