KDM5A silencing transcriptionally suppresses the FXYD3-PI3K/AKT axis to inhibit angiogenesis in hepatocellular cancer via miR-433 up-regulation

Autor: Qi-Fei Zou, Ting-Miao Wu, Pei-Yao Wang, Gao-Ren Wang, Hua Ding, Liu Li, Li-Peng Gu, Fei Yu, Yu-Shui Ma, Yi Shi, Chang-Chun Ling, Bin Qian, Ji-Bin Liu, Lin-Lin Tian, Hui-Min Wang, Yu-Shan Liu, Zhi-Jun Wu, Ming-Ming Fan, Da Fu
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
Angiogenesis
Apoptosis
medicine.disease_cause
migration
miR‐433
Umbilical vein
Phosphatidylinositol 3-Kinases
angiogenesis
0302 clinical medicine
Cell Movement
Tumor Cells
Cultured
Neovascularization
Pathologic
Chemistry
Liver Neoplasms
FXYD domain‐containing ion transport regulator 3
Prognosis
invasion
Neoplasm Proteins
Gene Expression Regulation
Neoplastic
Survival Rate
030220 oncology & carcinogenesis
Molecular Medicine
Female
Original Article
Carcinoma
Hepatocellular
proliferation
microRNA‐433
03 medical and health sciences
Downregulation and upregulation
In vivo
medicine
Biomarkers
Tumor
Gene silencing
Humans
Protein kinase B
PI3K/AKT/mTOR pathway
Aged
Cell Proliferation
PI3K/AKT
Membrane Proteins
Cell Biology
Original Articles
MicroRNAs
030104 developmental biology
Cancer research
Carcinogenesis
Retinoblastoma-Binding Protein 2
FXYD3
Proto-Oncogene Proteins c-akt
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-4934
Popis: Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP‐qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR‐433, while dual luciferase assay was carried out to confirm the targeting relationship between miR‐433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo‐tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A‐miR‐433‐FXYD3‐PI3K‐AKT axis in the progression of HCC after loss‐ and gain‐function assays. KDM5A p‐p85 and p‐AKT were highly expressed but miR‐433 was down‐regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR‐433 by demethylating H3K4me3 on its promoterregion. miR‐433 negatively targeted FXYD3. Depleting miR‐433 or re‐expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down‐regulated miR‐433 and up‐regulated FXYD3‐PI3K‐AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3‐PI3K‐AKT axis to enhance angiogenesis in HCC by suppressing miR‐433.
Databáze: OpenAIRE
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