miR-500a-3p promotes cancer stem cells properties via STAT3 pathway in human hepatocellular carcinoma

Abstract

BackgroundmiR-500a-3p has been demonstrated to be involved in the development, progression and metastasis in several human cancers. Constitutive activation of JAK/STAT3 signaling pathway has been reported to play an important role in the development and progression of hepatocellular carcinoma (HCC).The purpose of this study was to determine the biological roles and clinical significance of miR-500a-3p in HCC and to identify whether miR-500a-3p has an effect on the activity of JAK/STAT3 signaling in HCC.MethodsmiR-500a-3p expression was examined by real-time PCR in 8 paired HCC tissues and individual 120 HCC tissues respectively. Statistical analysis was performed to explore the clinical correlation between miR-500a-3p expression and clinicopathological features and overall and relapse-free survival in HCC patients. In vitro and in vivo assays were performed to investigate the biological roles of miR-500a-3p in HCC. The bioinformatics analysis, real-time PCR, western blot and luciferase reporter assay were performed to discern and examine the relationship between miR-500a-3p and its potential targets. Clinical correlation of miR-500a-3p with its targets was examined in HCC tissues.ResultsmiR-500a-3p is dramatically elevated in HCC tissues and cells and high expression of miR-500a-3p correlates with poor overall and relapse-free survival in HCC patients. Upregulating miR-500a-3p enhances, while silencing miR-500a-3p suppresses, the spheroid formation ability, fraction of side population and expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further reveal miR-500a-3p promotes the cancer stem cell characteristics via targeting multiple negative regulators of JAK/STAT3 signaling pathway, including SOCS2, SOCS4 and PTPN11, leading to constitutive activation of STAT3 signaling. Moreover, the inhibitory effects of anti-miR-500a-3p on cancer stem cell phenotypes and activity of STAT3 signaling were reversed by silencing SOCS2, SOCS4 and PTPN11 in miR-500a-3p-downexpressing cells, respectively. Clinical correlation of miR-500a-3p with the targets was examined in human HCC tissues.Conclusionour results uncover a novel mechanism by which miR-500a-3p promotes the stemness maintenance of cancer stem cell in HCC, suggesting that silencing miR-500a-3p may serve as a new therapeutic strategy in the treatment of hepatocellular carcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0568-3) contains supplementary material, which is available to authorized users.

Targeting cancer stem cell pathways for cancer therapy

“…314 Several lines of evidence show that constitutive activation of JAK2 and STAT3 in the absence of any stimulating ligand occurs in polycythemia vera. 317,318 Moreover, studies have also found aberrant activation of STATs in human cancers, such as head and neck cancer, 319 endometrial cancer, 320 breast cancer, diffuse large B cell lymphoma, 321 HCC, 322 colorectal cancer, glioma, 323 and colon cancer. 324 Furthermore, aberrant STAT5 signaling has been found in the pathogenesis of hematologic and solid organ malignancies.…”

“…For example, miR-500a-3p targets multiple negative regulators of the JAK2/STAT3 signaling pathway, such as SOCS2, SOCS4, and PTPN, in HCC stem cells, leading to constitutive activation of STAT3 signaling. 322 MiR-30 targets SOCS3 in glioma stem cells. 337 Mir-93 downregulates the expression of JAK1 and STAT3 to induce the differentiation of breast CSCs.…”

hsa‐miR‐500a‐3P alleviates kidney injury by targeting MLKL‐mediated necroptosis in renal epithelial cells

“…Of these miRNAs, only miR-500a-3P was significantly reduced after toxic and hypoxic insults. miR-500a-3p appears to play roles in breast cancer, hepatocellular carcinoma, and endometriosis (23)(24)(25). A previous study also showed that miR-500 induces gastric cancer cell proliferation while preventing apoptosis, indicating that it is involved in the regulation of cell death (26).…”

MicroRNA-500a Promotes the Progression of Hepatocellular Carcinoma by Post-Transcriptionally Targeting BID

“…For miR-500a, it was suggested that it was increased in the sera of HCC patients and returned to normal after surgical resection; thus, it may be a diagnostic marker for human HCC [22]. It was also suggested that miR-500a may be important for the maintenance of cancer stem cell properties [23]. In the present study, we found that miR-500a was significantly increased in HCC tissues, and high miR-500a expression predicted poor prognosis, thus suggesting that miR-500a may be a potential prognostic and therapeutic target of HCC.…”