miR-3682-3p directly targets FOXO3 and stimulates tumor stemness in hepatocellular carcinoma via a positive feedback loop involving FOXO3/PI3K/AKT/c-Myc

Abstract

BACKGROUND Cancer stem cells (CSCs) have been implicated in tumorigenesis and tumor recurrence and metastasis are key therapeutic targets in cancer treatment. MicroRNAs display therapeutic potential by controlling the properties of CSCs; however, whether an association exists between miR-3682-3p and CSCs is unknown. AIM To investigate the mechanism by which miR-3682-3p promotes stemness maintenance in hepatocellular carcinoma (HCC). METHODS MiR-3682-3p expression in HCC cell lines and 34 pairs of normal and HCC specimens was assayed by quantitative polymerase chain reaction. The functional role of miR-3682-3p was investigated in vitro and in vivo . Dual-luciferase reporter and chromatin immunoprecipitation assays were performed for target asse ssment, and western blotting was utilized to confirm miR-3682-3p/target relationships. RESULTS We found that miR-3682-3p plays a key role in HCC pathogenesis by promoting HCC cell stemness. The upregulation of miR-3682-3p enhanced CSC spheroid-forming ability, side population cell fractions, and the expression of CSC factors in HCC cells in vitro and the tumorigenicity of transplanted HCC cells in vivo . Furthermore, silencing miR-3682-3p prolonged the survival of HCC-bearing mice. Mechanistically, we found that miR-3682-3p targets FOXO3 and enables FOXO3/β-catenin interaction, which promotes c-Myc expression through PI3K/AKT; c-Myc, in turn, activates miR-3682-3p, forming a positive feedback loop. Intriguingly, miR-3682-3p expression was induced by hepatitis B virus X protein (HBx) and was involved in HBx-induced tumor stemness-related pathogenesis. CONCLUSION Our findings reveal a novel mechanism by which miR-3682-3p promotes stemness in HCC stem cells. Silencing miR-3682-3p may represent a novel therapeutic strategy for HCC.

Celestial Insights: Unraveling the Role of miR-3682-3p in Hepatocellular Carcinoma

“…In recent years, several studies on the relationship between miR-3682-3p and liver cancer have been published. These studies primarily focus on which pathways miR-3682-3p regulates in liver cancer, including the RAS-MEK1/2-ERK1/2 pathway ( 18 ), FOXO3/PI3K/AKT/c-Myc pathway ( 19 ), miR-3682-3p-PHLDA1-FAS pathway ( 20 ), and PTEN/PI3K/AKT/beta-catenin pathway ( 21 ). Some researchers have investigated the correlation between miR-3682-3p expression levels in liver cancer tissues and patient survival, concluding that high expression of miR-3682-3p is a poor prognostic factor in HCC patients ( 5 ).…”

Progress in the study of FOXO3a interacting with microRNA to regulate tumourigenesis development

“…MiR-3682-3p directly targets and inhibits FOXO3a expression, and FOXO3a level reduction enhances the downstream signalling pathway PI3K/AKT/β-catenin/c-Myc. c-Myc in turn induces miR-3682-3p expression, forming a PI3K/AKT/β-catenin/c-Myc/miR-3682-3p positive feedback loop that promotes the stemness of hepatocellular carcinoma cells ( 28 ). FOXO3a is a clear tumour suppressor gene that regulates the expression of downstream proapoptotic factors such as p27Kip1 and Bim ( 29 , 30 ).…”

Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma

“…For HBV-HCC patients, several miRNAs from HCC tissues or blood are found to be significantly correlated with overall survival, diseases-free survival (DFS) and progression-free survival (Table 6 ). For tissue miRNAs, higher expression of miR-122[ 54 , 55 ], miR-143[ 55 ], miR-145[ 56 ], miR-193b[ 57 ], miR-203a[ 58 ], miR-216b[ 59 ], miR-375[ 55 , 60 ], and miR-384[ 61 ] is associated with a better prognosis, and higher expression of miR-9-3[ 62 ], miR-10b[ 62 ], miR-21[ 56 ], miR-29a-5p[ 63 ], miR-31[ 62 ], miR-106b[ 64 ], miR-224[ 55 ], miR-371a-5p[ 27 ], miR-519c[ 62 ], miR-522[ 62 , 65 ], miR-523[ 65 ], miR-3188[ 28 ], miR-3682-3p[ 66 ], miR-3660[ 62 ], miR-4784[ 62 ], miR-5188[ 67 ], and miR-6883[ 62 ] is associated with a significantly poorer long-term prognosis. For circulating miRNAs, higher expression of miR-150[ 13 ], miR-223-3p[ 68 ], and miR-768-3p[ 20 ] is associated with a better prognosis, higher expression of miR-24-3p[ 33 ], miR-29a-3p[ 69 ], miR-96[ 34 ], miR-155[ 70 ], miR-192-5p[ 69 ], and miR-487b[ 18 , 19 ] is associated with a significantly poorer long-term prognosis.…”

“…In addition, Jung et al [ 116 ] find that c-Myc mediates HBV-induced miR-17-92 overexpression. c-Myc also binds to the miR-3682-3p promoter, thus HBx may also induce miR-3682-3p expression via c-Myc[ 66 ]. CREB is an essential subset of phosphorylation-dependent transcription factors.…”

“…In addition, miR-3682-3p mediates the oncogenic consequences of HBx-induced PI3K/AKT/c-Myc signaling. HBx increases stemness by elevating miR-3682-3p expression[ 66 ]. Meanwhile, miR-5188 directly targets FOXO1, which inhibits the nuclear translocation of β-catenin and promotes Wnt signaling activation and downstream tumor stemness.…”