title: Knockdown of miR-25 increases the sensitivity of liver cancer stem cells to TRAIL-induced apoptosis via PTEN/PI3K/Akt/Bad signaling pathway.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is considered as a promising anticancer agent, it induced apoptosis in cancer cells selectively without damaging the normal tissue cells. However, the resistance of cancer cells to TRAIL limits its application. Since the cancer stem cells (CSCs) are believed to be responsible for the treatment failure in multiple cancers including hepatocellular carcinoma (HCC), the aim of this study was to investigate the strategies to increase the sensitivity of liver cancer stem cells (LCSCs) to TRAIL. In the present study, we observed significant upregulation of miR-25 in LCSCs compared with the non-CSCs. Furthermore, we found that knockdown of miR-25 by its antisense oligonucleotide (anti‑miR-25) significantly increased the sensitivity of LCSCs to TRAIL-induced apoptosis. The gene of phosphatase and tensin homologue (PTEN), which is a natural inhibitor of PI3K, was found to be directly regulated by miR-25 in HepG2‑CSCs. We demonstrated that knockdown of miR-25 increased the expression of PTEN. Mechanistically, inhibition of Bad phosphorylation, which is regulated by the PTEN/PI3K/AKT pathway, is essential for the functional roles of anti-miR-25 in HepG2-CSCs. In conclusion, our findings indicate that overexpression of miR-25 is associated with the low-sensitivity to TRAIL in LCSCs. Knockdown of miR-25 may represent a potential strategy for increasing the efficacy of TRAIL by targeting the PTEN/PI3K/Akt/Bad signaling pathway.
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of VIP, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Jingjin
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Shi
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: C494819:BAD protein, human; C543351:MIRN25 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051025:bcl-Associated Death Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human