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Abstract
Aberrant expression of microRNA-155 (miR-155) has been reported in several human cancers and is associated with prognosis of patients. However, the clinical significance of miR‑155 and its underlying mechanisms involved in hepatocarcinogenesis remain to be determined. In this study, we demonstrated that the expression of miR-155 was elevated in both hepatocellular carcinoma (HCC) tissues and cell lines. Clinical association analysis revealed that high expression of miR-155 was correlated with malignant clinicopathological characteristics including large tumor size, high Edmondson-Steiner grading and TNM tumor stage. Furthermore, its high expression conferred a reduced 5-year overall survival and disease-free survival of HCC patients. Gain- and loss-of function studies revealed that miR‑155 promoted cell cycle progression, cell proliferation and inhibited apoptosis. Mechanistically, we identified AT-rich interactive domain 2 (ARID2) as a direct downstream target and functional mediator of miR‑155 in HCC cells. Notably, alterations of ARID2 expression abrogated the effects of miR‑155 on HCC cell proliferation, cell cycle and apoptosis. Moreover, we demonstrated that Akt phosphorylation is essential for the functional roles of miR‑155 through altering CyclinD1 and p27, which were key components of cell cycle machinery. Finally, we disclosed that the downregulation of miR‑155 suppressed tumor growth of HCC by inhibiting Akt signaling pathway. In conclusion, our results indicate that miR‑155 promotes tumor growth of HCC by targeting ARID2-mediated Akt phosphorylation pathway, and potentially serves as a novel prognostic biomarker and therapeutic target for HCC.
Highlights
Hepatocellular carcinoma (HCC) is the dominant pathologic type of primary liver cancer, which is the third leading cause of cancer-related death worldwide [1]
We demonstrated that the expression of miR‐155 was upregulated in HCC tissues and its high expression was associated with poor clinicopathological features and the reduced survival of HCC patients. miR‐155 promoted cell proliferation, cell cycle and apoptosis resistance in vitro
Lerner et al indicated that miR‐155 was upregulated in blood, tissue and cell lines of head and neck squamous cell carcinoma and could serve as an independent prognosis predictor for patients and promoted the cell proliferation and migration [25]
Summary
Hepatocellular carcinoma (HCC) is the dominant pathologic type of primary liver cancer, which is the third leading cause of cancer-related death worldwide [1]. Despite recent advances in the diagnosis and treatment of HCC, including hepatectomy and liver transplantation, the prognosis for HCC patients remains poor due to the high recurrence rate and early metastasis [2]. The detailed mechanism underlying the development and progression of HCC is still not clear [3]. It is urgent to clarify the molecular mechanisms of HCC and identify novel prognostic biomarkers to provide potential therapeutic targets for the patients with HCC. Increasing evidence suggests that microRNAs (miRNAs), a class of non-coding RNAs composed of ~22 nucleotides, can act as suitable biomarkers with diagnostic, prognostic, and predictive potential [4]. MiRNAs have shown high stability in tissues and body fluids, which reveal their potential as tumor markers.
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