MicroRNA-148b-colony-stimulating factor-1 signaling-induced tumor-associated macrophage infiltration promotes hepatocellular carcinoma metastasis

Background: MicroRNAs (miRNAs) are small non-coding molecules that exhibit important regulatory roles in various biological or cellular functions, including tumor metastasis. However, the detailed mechanisms of the expression and functions of miRNAs in hepatocellular carcinoma (HCC) have not yet been completely investigated. Methods: In this study, the levels of miR-148b in HCC cells and patient specimens were determined using qPCR assays. MiR-148b-overexpressing HCC cells were used to investigate the effect of miR-148b in vitro and in vivo. The relationship between the expression of miR-148b and colony stimulating factor-1 (CSF1) in HCC patients and the infiltration of macrophages into the tumor microenvironment were assessed by immunohistochemical staining. Results: MiR-148b expression was decreased in metastatic HCC cells. A positive association between downregulated miR-148b expression and several clinical parameters, including recurrence, metastasis, and poor prognosis, was observed in patients with HCC. The results of bio-functional experiments indicated that the biological characteristics of HCC cells were not affected by miR-148b deficiency in vitro. However, miR-148b deficiency significantly enhanced the progression and metastasis of HCC in nude mice. By analyzing the gene expression profiles, we demonstrated that CSF1 was regulated by miR-148b and that miR-148b deficiency promoted HCC growth and metastasis through CSF1/CSF1 receptor (CSF1R)-mediated tumor-associated macrophage (TAM) infiltration. These results were supported by the negative relationship between miR-148b and CSF1 expression and TAM infiltration in HCC patients. Moreover, HCC patients with low miR-148b levels and high TAM infiltration were associated with poorer prognosis. Conclusion: MiR-148b-CSF1 signaling-induced TAM infiltration promotes HCC metastasis. Therefore, miR-148b plays a suppressor role in HCC and might be a potential prognostic factor and therapeutic candidate for HCC.