Abstract
The decrease of microRNA-452 (miR-452) in gliomas promoted stem-like features and tumorigenesis. However, the role of miR-452, especially in regulating cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) remains ambiguous. We enriched stem-like HCC cells by serial passages of hepatospheres with chemotherapeutic agents. Stem-like characteristics including the capabilities of chemo-resistance, stemness-related gene expression profiling, self-renewal, tumorigenicity and metastasis formation were detected. MiR-452 was markedly increased in the chemo-resistant hepatospheres and human HCC tissues. and the overexpression of miR-452 in HCC patients predicted poor overall survival. MiR-452 significantly promoted stem-like characteristics in vitro and in vivo. Further, Sox7 was identified as the direct target of miR-452, which could physically bind with β-catenin and TCF4 in the nucleus and then inhibit the activity of Wnt/β-catenin signaling pathway. Finally, the combined chemotherapy of doxorubicin and all-trans retinoic acid (ATRA) showed dramatically efficiency in suppressing HCC metastasis. These data suggested that miR-452 promoted stem-like traits of HCC, which might be a potential therapeutic target for HCC. The combination of doxorubicin and ATRA might be a promising therapy in HCC management.
Highlights
Hepatocellular carcinoma (HCC) was one of the most devastating malignancies with extremely high cancer related death worldwide [1]
MiR-452 was overexpressed in HCC cells accumulated by serial passages of hepatospheres combined with chemotherapy in vitro
We revealed these following novel findings: (i) Serial passages of the spheres with doxorubicin and sorafenib could enrich cancer stem cells (CSCs) populations in vitro; (ii) miR-452 was identified to promote stem-like properties of HCC; (iii) Sox7 was a direct and functionally relevant target of miR-452 in HCC; (iv) Combination of doxorubicin and All-trans retinoic acid (ATRA) efficiently suppressed metastasis formation of miR-452 overexpressed HCC
Summary
Hepatocellular carcinoma (HCC) was one of the most devastating malignancies with extremely high cancer related death worldwide [1]. Recent advances speculated that tumor recurrence and metastasis might be due to the existence of cancer stem cells (CSCs) [4,5,6,7], who owned the capabilities of self-renewal, differentiation and chemoresistance, have been identified in various malignancies [5, 8]. MiR-452 was down-regulated in gliomas [12], breast cancer [13], while its expression increased in HCC [14], clear cell renal cell carcinoma [15], esophageal cancer [16], urothelial carcinoma [17] and prostate cancer stem cells [18]. Wnt/ β-catenin signaling was reported to exert crucial roles in the maintenance of self-renewal for stem cells and CSCs [21,22,23]. All-trans retinoic acid (ATRA) had got a great success in treating acute promyelocytic leukemia by inducing naive tumor cells differentiation [24], which might be effective in the treatment of solid tumors
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