miR‐28‐5p‐IL‐34‐macrophage feedback loop modulates hepatocellular carcinoma metastasis

• Published in: Hepatology (Baltimore, Md.) Vol. 63; no. 5; pp. 1560 - 1575
• Main Authors: Zhou, Shao‐Lai, Hu, Zhi‐Qiang, Zhou, Zheng‐Jun, Dai, Zhi, Wang, Zheng, Cao, Ya, Fan, Jia, Huang, Xiao‐Wu, Zhou, Jian
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health, Inc 01.05.2016
• Subjects: Animals; Carcinoma, Hepatocellular - secondary; Cell Line, Tumor; Cell Proliferation; Feedback; Feedback, Physiological; Gene expression; Humans; Interleukins - physiology; Liver cancer; Liver Neoplasms - pathology; Macrophages - physiology; Male; Medical prognosis; Metastasis; Mice; Mice, Inbred BALB C; MicroRNAs - physiology; Transforming Growth Factor beta1 - physiology; Tumor Microenvironment
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.28445

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. Conclusion: 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. (Hepatology 2016;63:1560‐1575)