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  • Title: MicroRNA‑9‑5p downregulates Klf4 and influences the progression of hepatocellular carcinoma via the AKT signaling pathway.
    Author: Dong X, Wang F, Xue Y, Lin Z, Song W, Yang N, Li Q.
    Journal: Int J Mol Med; 2019 Mar; 43(3):1417-1429. PubMed ID: 30664155.
    Abstract:
    Krüppel‑like factor 4 (Klf4) is a transcriptional factor involved in the progression of hepatocellular carcinoma (HCC). However, the underlying regulatory mechanisms associated with the Klf4 gene as a tumor suppressor in HCC remain unclear. microRNAs (miRNAs or miRs) are a series of small non‑coding RNAs that serve a vital role in regulating gene expression via their influence on protein translation and the associated degradation of mRNA. The mRNA expression levels of the miRNA, miR‑9‑5p, and Klf4 were measured using reverse transcription‑quantitative polymerase chain reaction. The protein expression levels of Klf4, protein kinase B (AKT), phosphorylated (p‑)AKT, mechanistic target of rapamycin (mTOR), p‑mTOR, B cell lymphoma‑2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax) were determined by western blot analysis. Dual luciferase reporter assay was used to confirm a direct interaction between miR‑9‑5p and the 3'‑untranslated region (3'‑UTR) sequence of Klf4. Cell counting kit‑8 assay, wound healing assay, Transwell migration assay and flow cytometric analysis were performed to evaluate the proliferative, migratory and apoptotic capabilities of the HCC cells. In the present study, miR‑9‑5p was revealed to be overexpressed in HCC as a novel upstream gene of Klf4. miR‑9‑5p expression was inversely associated with Klf4 expression in clinical samples. Additionally, Kaplan‑Meier analysis revealed a markedly poor prognosis of HCC in the miR‑9‑5p high‑expression group. Bioinformatics analysis revealed that miR‑9‑5p bound directly to the 3'‑UTR of Klf4, which reduced the expression levels of Klf4. The miR‑9‑5p/Klf4 axis promoted HCC proliferation and migration, and inhibited HCC apoptosis. Furthermore, miR‑9‑5p upregulated the Bcl‑2/Bax protein ratio and activated AKT/mTOR signaling. Taken together, these data demonstrated that the miR‑9‑5p/Klf4 axis was able to promote HCC progression, which may occur via regulation of the AKT signaling pathway, highlighting a potential novel target in HCC treatment.
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