|
|||||
|
|
KDM5A silencing transcriptionally suppresses the FXYD3-PI3K/AKT axis to inhibit angiogenesis in hepatocellular cancer via miR-433 up-regulation |
|
| Authors: | Yu-Shui Ma Ting-Miao Wu Bin Qian Yu-Shan Liu Hua Ding Ming-Ming Fan Ji-Bin Liu Fei Yu Hui-Min Wang Yi Shi Li-Peng Gu Liu Li Lin-Lin Tian Pei-Yao Wang Gao-Ren Wang Zhi-Jun Wu Qi-Fei Zou Chang-Chun Ling Da Fu |
| Affiliation: | 1. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Department of Radiology, The Forth Affiliated Hospital of Anhui Medical University, Hefei, China Cancer Institute, Nantong Tumor Hospital, Nantong, China Contribution: Conceptualization (equal), Data curation (lead), Writing - original draft (lead);2. Department of Radiology, The Forth Affiliated Hospital of Anhui Medical University, Hefei, China Contribution: Conceptualization (equal), Software (equal), Writing - original draft (equal);3. Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai, China Contribution: Software (equal), Validation (equal), Writing - review & editing (equal);4. Department of Pathology, Nantong Tumor Hospital, Nantong, China Contribution: Conceptualization (equal), Investigation (equal), Writing - original draft (equal);5. Department of Radiotherapy, Nantong Tumor Hospital, Nantong, China Contribution: Conceptualization (equal), Methodology (equal), Writing - original draft (equal);6. Department of Biliary Surgery IV, Eastern Hepatobiliary Surgery Hospital, Shanghai, China Contribution: Conceptualization (equal), Investigation (equal), Methodology (equal);7. Cancer Institute, Nantong Tumor Hospital, Nantong, China Contribution: Investigation (equal), Methodology (equal);8. Department of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China Contribution: Conceptualization (equal), Software (equal);9. Cancer Institute, Nantong Tumor Hospital, Nantong, China Contribution: Data curation (supporting), Formal analysis (equal);10. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Contribution: Data curation (supporting), Project administration (equal);11. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Contribution: Formal analysis (equal), Resources (equal);12. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Contribution: Formal analysis (equal), Writing - original draft (equal);13. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China Contribution: Validation (equal), Writing - review & editing (equal);14. Department of Radiotherapy, Nantong Tumor Hospital, Nantong, China Contribution: Visualization (equal), Writing - review & editing (equal);15. Department of Oncology, Nantong Second People's Hospital, Nantong, China Contribution: Visualization (equal), Writing - review & editing (equal);16. Department of Biliary Surgery IV, Eastern Hepatobiliary Surgery Hospital, Shanghai, China;17. Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, China;18. Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China |
| Abstract: | 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. |
| Keywords: | angiogenesis FXYD domain-containing ion transport regulator 3 FXYD3 invasion microRNA-433 migration miR-433 PI3K/AKT proliferation |