MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A

Ohta, Katsuya; Hoshino, Hiromitsu; Wang, Jinhua; Ono, Shigeshi; Iida, Yuuki; Hata, Keisuke; Huang, Sharon K.; Colquhoun, Steven D.; Hoon, Dave S.B.

doi:10.18632/oncotarget.3085

Cited by 149 publications

(128 citation statements)

References 37 publications

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“…However, treatment outcomes are poor due to unfavorable pharmacokinetics, low tumor accumulation and high rates of sorafenib resistance in HCC patients (5). Evidence has shown that, some miRNAs increased sorafenib sensitivity to HCC cells (13,(38)(39)(40). In addition, inhibition of the activation of Akt may be a valid approach to treating human malignancies and overcoming the resistance of cancer cells to chemotherapy (41).…”

Section: Discussionmentioning

confidence: 99%

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

et al. 2015

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Abstract. acts as an oncomiR and is involved in tumor development, progression and metastasis, and confers resistance to chemotherapeutic drugs by targeting a number of molecules in several human cancers. However, the function and underlying molecular mechanism of miR-494 in hepatocellular carcinoma (HCC) has not been totally elucidated. In the present study, we determined the role played by miR-494 in HCC tissues and HCC cell lines using quantitative RT-PCR (RT-qPCR). The results showed that, miR-494 was significantly upregulated in HCC tissues and HCC cell lines. Additionally, a high miR-494 expression positively correlated with tumor differentiation (P<0.01), TNM stage (P<0.01) and lymph node metastasis (P<0.01). Luciferase reporter assays confirmed that miR-494 binds to the 3'-untranslated region (3'-UTR) of the phosphatase and tensin homolog (PTEN) mRNA and represses its translation. Functional analyses indicated that the upregulation of miR-494 promoted cell viability, migration and invasion, decreased cell apoptosis and cell cycle arrest at G1 stage, and conferred sorafenib resistance to HCC cell lines. Underexpression of PTEN by siRNA significantly attenuated the inhibitory effects of anti-miR-494 on the proliferation, migration and invasion of liver cancer cells. Mechanistic investigations revealed that miR-494 suppressed the expression of PTEN but increased the expression of PI3K and p-Akt, which contribute to the promotion of proliferation, migration and invasion, and increased sorafenib resistance to HCC cell lines. These findings suggested that miR-494 is a potential candidate for HCC therapeutics.

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Section: Discussionmentioning

confidence: 99%

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

et al. 2015

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“…miRNA-93 (miR-93) has been reported to be significantly upregulated and to have a promoting role in several cancer types (10,11). For instance, the expression of miR-93 was found to be significantly increased in esophageal squamous cell carcinoma (12).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-93 promotes cell proliferation by directly targeting P21 in osteosarcoma cells

2017

Experimental and Therapeutic Medicine

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Abstract. MicroRNAs (miRNAs) are small, non-coding RNAs that are key regulators of gene expression by directly binding to the 3'-untranslated region of their target mRNAs, resulting in translational repression or degradation of mRNA. It has been demonstrated that miRNAs have key roles in a variety of human malignancies, including osteosarcoma. The present study aimed to assess the molecular mechanism of miR-93 in the regulation of osteosarcoma cell proliferation. Reverse-transcription quantitative PCR and western blot assays were used to examine mRNA and protein expression. An MTT assay and flow cytometry were performed to determine the cell proliferation and cell cycle distribution. A luciferase reporter assay was performed to confirm the direct targeting of cyclin-dependent kinase inhibitor 1A (CDKN1A), also known as P21, by miR-93, which was suggested by a bioinformatics analysis. The results showed that the expression of miR-93 was frequently and significantly increased in a total of 19 osteosarcoma tissues compared to their matched adjacent non-tumor tissues, and the upregulation of miR-93 was associated with the malignant progression of osteosarcoma. Furthermore, miR-93 was also upregulated in the human osteosarcoma cell lines Saos-2, U2OS, SW1353 and MG63 when compared with that in the human osteoblast cell line hFOB1.19. Transfection with miR-93 inhibitor significantly reduced the miR-93 levels and inhibited the proliferation of U2OS and MG63 osteosarcoma cells. The protein levels of P21 were negatively regulated by miR-93 in U2OS and MG63 cells. Knockdown of miR-93 caused cell cycle arrest at G1 stage in U2OS and MG63 cells, identical to the effect of P21 overexpression. Finally, P21 was found to be significantly downregulated in osteosarcoma tissues compared to their matched adjacent non-tumor tissues, suggesting that the inhibition of P21 may be due to increased miR-93 expression in osteosarcoma tissues. In conclusion, the present study demonstrated that miR-93 enhances the proliferation of osteosarcoma cells, at least in part via inhibiting P21 expression and thus promoting cell cycle progression.

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“…It has been well-established that the protein kinase B (AKT) signaling pathway is key in various types of human cancer, including HCC (3,4). An inhibition of AKT signaling effectively suppresses HCC growth (5,6).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN-AKT signaling

Lin²,

et al. 2016

Oncology Letters

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Abstract. Phosphatidylinositol-3,4,5-trisphosphate Rac exchanger 2 (PREX2), a regulator of the small guanosine triphosphatase Rac, demonstrates an inhibitory effect on the activity of phosphatase and tensin homolog (PTEN). Previously, PREX2 was implicated in the regulation of cell invasion in hepatocellular carcinoma (HCC). However, the exact role of PREX2 in the regulation of HCC cell proliferation and migration, as well as the underlying mechanisms, remains unclear. In the present study, reverse transcription-quantitative polymerase chain reaction revealed that PREX2 was upregulated in HCC tissue compared with matched adjacent non-tumorous tissue. In addition, the present study demonstrated that the messenger RNA and protein levels of PREX2 increased in human HCC HepG2, LH86, LMH and PLHC-1 cell lines compared with normal human liver THLE-3 cells. Overexpression of PREX2 significantly enhanced the proliferation and migration of HCC cells, and knockdown of PREX2 expression significantly suppressed the proliferation and migration of HCC cells. Additional investigation revealed that overexpression of PREX2 suppressed the activity of PTEN, leading to an enhancement in the activity of protein kinase B (AKT). By contrast, knockdown of PREX2 expression upregulated the activity of PTEN and suppressed the activity of AKT. Overall, the present study suggests that PREX2 promotes the proliferation and migration of HCC cells by inhibiting PTEN-AKT signaling.

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MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A

Cited by 149 publications

References 37 publications

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

MicroRNA-93 promotes cell proliferation by directly targeting P21 in osteosarcoma cells

Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN-AKT signaling

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