title: STAT3 regulates the migration and invasion of a stem‑like subpopulation through microRNA‑21 and multiple targets in hepatocellular carcinoma.
abstract: Despite advances in the detection and treatment of hepatocellular carcinoma (HCC), the prognosis remains poor partly due to recurrence or extra/intrahepatic metastasis. Stem‑like cancer cells are considered the source of malignant phenotypes including metastasis in various types of cancer. HCC side population (SP), considered as stem‑like cancer cells, plays an important role in the migration and invasion in HCC, while the mechanisms involved remain unknown. In the present study, high levels of STAT3 and phospho‑STAT3 were observed in MHCC97H SP cells compared with the main population (MP) cells. Inhibition of phospho‑STAT3 led to a reduction of miR‑21 expression, an increase of PTEN, RECK, and programmed cell death 4 (PDCD4) expression as well as the migration and invasion of SP cells. A set of rescue experiments was performed using different combinations of STAT3 inhibitor, miR‑21 mimics and siRNAs to observe the expression of miR‑21 targets, cell migration and invasion alterations. Data indicated that the alterations induced by STAT3 inhibition were partly reversed by the upregulation of miR‑21. Additionally, the cells migration and invasion when silencing the targets of miR‑21 were also reversed by STAT3 inhibition. In conclusion, the present study revealed the aberrant expression of STAT3 and miR‑21 in HCC SP cells. Targeting STAT3 may limit HCC migration and invasion, which is likely to involve the regulation of miR‑21 and its targets PTEN, RECK and PDCD4. Strategies directed towards STAT3 may therefore be a novel approach for the treatment of HCC.
authors.affiliation: Institute of Hepatobiliary Surgery and Liver Transplantation Center, China General Hospital of PLA, Beijing 100853, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Institute of Hepatobiliary Surgery and Liver Transplantation Center, China General Hospital of PLA, Beijing 100853, P.R. China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Duan
authors.affiliation: Institute of Hepatobiliary Surgery and Liver Transplantation Center, China General Hospital of PLA, Beijing 100853, P.R. China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Leng
authors.affiliation: Department of General Surgery, The 155 Central Hospital of PLA, Kaifeng, He'nan 471000, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Hepatobiliary Surgery and Liver Transplantation Center, China General Hospital of PLA, Beijing 100853, P.R. China.
authors.forename: Yin-Zhe
authors.initials: YZ
authors.lastname: Xu
authors.affiliation: Institute of Hepatobiliary Surgery and Liver Transplantation Center, China General Hospital of PLA, Beijing 100853, P.R. China.
authors.forename: Xue-Dong
authors.initials: XD
authors.lastname: Wang
authors.affiliation: Institute of Hepatobiliary Surgery and Liver Transplantation Center, China General Hospital of PLA, Beijing 100853, P.R. China.
authors.forename: Ai-Qun
authors.initials: AQ
authors.lastname: Zhang
authors.affiliation: Institute of Hepatobiliary Surgery and Liver Transplantation Center, China General Hospital of PLA, Beijing 100853, P.R. China.
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Dong
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D058851:GPI-Linked Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; C115460:RECK protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014315:Triterpenes; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C038106:cucurbitacin I