title: miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis.
abstract: MicroRNAs (miRNAs) play a critical role in regulation of tumor metastasis. However, the role of these molecules in hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we employed miRNA-sequencing and identified 22 miRNAs involved in HCC metastasis. One of these, miR-28-5p, was down-regulated in HCCs. This down-regulation correlated with tumor metastasis, recurrence, and poor survival. Biofunctional investigations revealed that miR-28-5p deficiency promoted tumor growth and metastasis in nude mice without altering the in vitro biological characteristics of HCC cells. Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAM) infiltration. Moreover, we found that TAMs induced by miR-28-5p-IL-34 signaling inhibit miR-28-5p expression on HCC cells by transforming growth factor beta 1, resulting in an miR-28-5p-IL-34-macrophage-positive feedback loop. In clinical HCC samples, miR-28-5p levels were inversely correlated with IL-34 expression and the number of TAMs. Patients with low miR-28-5p expression, high IL-34 levels, and high numbers of TAMs had a poor prognosis with shorter overall survival and time to recurrence.
  
  
  CONCLUSIONS
  A miR-28-5p-IL-34-macrophage feedback loop modulates HCC metastasis and serves as a novel prognostic factor as well as a therapeutic target for HCC.
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
authors.forename: Shao-Lai
authors.initials: SL
authors.lastname: Zhou
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Hu
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
authors.forename: Zheng-Jun
authors.initials: ZJ
authors.lastname: Zhou
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Cancer Research Institute, Central South University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.|Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Huang
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.|Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D025461:Feedback, Physiological; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: C529076:IL34 protein, human; D007378:Interleukins; C570628:MIRN28 microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1