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PMID: 33168027 Published · epublish English Journal Article

LncRNA MYLK-AS1 facilitates tumor progression and angiogenesis by targeting miR-424-5p/E2F7 axis and activating VEGFR-2 signaling pathway in hepatocellular carcinoma.

Journal of experimental & clinical cancer research : CR ·Vol. 39 ·No. 1 ·2020-11-09 ·Pages 235

Teng F, Zhang JX, Chang QM, Wu XB, Tang WG, Wang JF, Feng JF, Zhang ZP, Hu ZQ

Abstract

Long non-coding RNAs (lncRNAs) are crucial in the invasion, angiogenesis, progression, and metastasis of hepatocellular carcinoma (HCC). The lncRNA MYLK-AS1 promotes the growth and invasion of HCC through the EGFR/HER2-ERK1/2 signaling pathway. However, the clinical significance of MYLK-AS1 in HCC still needs to be further determined. Bioinformatic analysis was performed to determine the potential relationship among MYLK-AS1, miRNAs and mRNAs. A total of 156 samples of normal liver and paired HCC tissues from HCC patients were used to evaluate MYLK-AS1 expression by qRT-PCR. Human HCC cell lines were used to evaluate the colony formation, cell proliferation, migration, invasion, cell cycle and apoptosis after transfection of lentiviral short-hairpin RNAs (shRNAs) targeting MYLK-AS1 or MYLK-AS1 vectors. The competitive endogenous RNA (ceRNA) mechanism was clarified using fluorescence in situ hybridization (FISH), Western blotting, qPCR, RNA binding protein immunoprecipitation (RIP), and dual luciferase reporter analysis. MYLK-AS1 up-regulation was detected in the HCC tumor tissues and cell lines associated with the enhancement of the angiogenesis and tumor progression. The down-regulation of MYLK-AS1 reversed the effects on angiogenesis, proliferation, invasion and metastasis in the HCC cells and in vivo. MYLK-AS1 acted as ceRNA, capable of regulating the angiogenesis in HCC, while the microRNA miR-424-5p was the direct target of MYLK-AS1. Promoting the angiogenesis and the tumor proliferation, the complex MYLK-AS1/miR-424-5p activated the VEGFR-2 signaling through E2F7, whereas the specific targeting of E2F transcription factor 7 (E2F7) by miR-424-5p, was indicated by the mechanism studies. MYLK-AS1 and E2F7 are closely related to some malignant clinicopathological features and prognosis of HCC, thus the MYLK-AS1/ miR-424-5p/E2F7 signaling pathway might represent a promising treatment strategy to combat HCC.

Keywords
Competing endogenous RNA E2F7 Hepatocellular carcinoma Long non-coding RNAs MYLK-AS1 VEGFR-2 miR-424-5p
MeSH Terms
Calcium-Binding Proteins/genetics Carcinoma, Hepatocellular/blood supply,genetics,metabolism,pathology Disease Progression E2F7 Transcription Factor/metabolism Female Humans Liver Neoplasms/blood supply,genetics,metabolism,pathology Male MicroRNAs/metabolism Middle Aged Myosin-Light-Chain Kinase/genetics Neovascularization, Pathologic/genetics,metabolism,pathology Prognosis RNA, Antisense/genetics,metabolism RNA, Long Noncoding/metabolism Signal Transduction Transfection Vascular Endothelial Growth Factor Receptor-2/metabolism
Chemicals
Calcium-Binding Proteins E2F7 Transcription Factor E2F7 protein, human MIRN424 microrna, human MicroRNAs RNA, Antisense RNA, Long Noncoding Vascular Endothelial Growth Factor Receptor-2 MYLK protein, human Myosin-Light-Chain Kinase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Teng Fei
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. | Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China.
Zhang Ju-Xiang
Shanghai Med-X Engineering Center for Medical Equipment and Technology, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.
Chang Qi-Meng
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. | Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China.
Wu Xu-Bo
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. | Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China.
Tang Wei-Guo
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. | Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China.
Wang Jian-Fa
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. | Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China.
Feng Jin-Feng
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. | Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China.
Zhang Zi-Ping
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. [email protected]. | Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. [email protected].
Hu Zhi-Qiu ORCID
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. [email protected]. | Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People's Republic of China. [email protected].
References (40)
40 references, click to expand
  1. Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional repression.
    J Exp Clin Cancer Res. 2019 Feb 20;38(1):92 PMID: 30786928
  2. Long non-coding RNAs: insights into functions.
    Nat Rev Genet. 2009 Mar;10(3):155-9 PMID: 19188922
  3. Comprehensive analysis of differential expression profiles of mRNAs and lncRNAs and identification of a 14-lncRNA prognostic signature for patients with colon adenocarcinoma.
    Oncol Rep. 2018 May;39(5):2365-2375 PMID: 29565464
  4. E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells.
    Nature. 2009 Dec 17;462(7275):930-4 PMID: 20016602
  5. An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability.
    Nucleic Acids Res. 2018 May 18;46(9):4546-4559 PMID: 29590434
  6. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data.
    Bioinformatics. 2010 Jan 1;26(1):139-40 PMID: 19910308
  7. E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1.
    EMBO J. 2012 Oct 3;31(19):3871-84 PMID: 22903062
  8. miR-424-5p represses the metastasis and invasion of intrahepatic cholangiocarcinoma by targeting ARK5.
    Int J Biol Sci. 2019 Jun 4;15(8):1591-1599 PMID: 31360102
  9. Decade in review-hepatocellular carcinoma: HCC-subtypes, stratification and sorafenib.
    Nat Rev Gastroenterol Hepatol. 2014 Nov;11(11):645-7 PMID: 25245016
  10. A network-biology perspective of microRNA function and dysfunction in cancer.
    Nat Rev Genet. 2016 Dec;17(12):719-732 PMID: 27795564
  11. Long Noncoding RNAs in Cancer Pathways.
    Cancer Cell. 2016 Apr 11;29(4):452-463 PMID: 27070700
  12. Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression.
    Mol Cancer. 2017 Sep 11;16(1):151 PMID: 28893265
  13. Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development.
    Dev Cell. 2008 Jan;14(1):62-75 PMID: 18194653
  14. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
    N Engl J Med. 2006 Dec 14;355(24):2542-50 PMID: 17167137
  15. Distinct and Overlapping Roles for E2F Family Members in Transcription, Proliferation and Apoptosis.
    Curr Mol Med. 2006 Nov;6(7):739-48 PMID: 17100600
  16. Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer.
    Int J Mol Sci. 2019 Apr 29;20(9): PMID: 31035644
  17. The evolution of lncRNA repertoires and expression patterns in tetrapods.
    Nature. 2014 Jan 30;505(7485):635-40 PMID: 24463510
  18. Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response.
    BMC Cancer. 2015 May 12;15:395 PMID: 25962426
  19. Atypical E2Fs: new players in the E2F transcription factor family.
    Trends Cell Biol. 2009 Mar;19(3):111-8 PMID: 19201609
  20. Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.
    Genome Res. 2006 Jan;16(1):55-65 PMID: 16344560
  21. miR-424-5p Regulates Hepatoma Cell Proliferation and Apoptosis.
    Cancer Biother Radiopharm. 2019 Apr;34(3):196-202 PMID: 30676784
  22. MicroRNA-424-5p acts as a potential biomarker and inhibits proliferation and invasion in hepatocellular carcinoma by targeting TRIM29.
    Life Sci. 2019 May 1;224:1-11 PMID: 30876939
  23. miR-424-5p Promotes Proliferation, Migration and Invasion of Laryngeal Squamous Cell Carcinoma.
    Onco Targets Ther. 2019 Nov 29;12:10441-10453 PMID: 31819525
  24. Application of ggplot2 to Pharmacometric Graphics.
    CPT Pharmacometrics Syst Pharmacol. 2013 Oct 16;2:e79 PMID: 24132163
  25. Cytoscape: a software environment for integrated models of biomolecular interaction networks.
    Genome Res. 2003 Nov;13(11):2498-504 PMID: 14597658
  26. Promising roles of mammalian E2Fs in hepatocellular carcinoma.
    Cell Signal. 2014 May;26(5):1075-81 PMID: 24440307
  27. Emerging roles of E2Fs in cancer: an exit from cell cycle control.
    Nat Rev Cancer. 2009 Nov;9(11):785-97 PMID: 19851314
  28. The Role of Angiogenesis in Hepatocellular Carcinoma.
    Clin Cancer Res. 2019 Feb 1;25(3):912-920 PMID: 30274981
  29. Cell proliferation in the absence of E2F1-3.
    Dev Biol. 2011 Mar 1;351(1):35-45 PMID: 21185283
  30. miR-424-5p promotes the proliferation and metastasis of colorectal cancer by directly targeting SCN4B.
    Pathol Res Pract. 2020 Jan;216(1):152731 PMID: 31785995
  31. Wide-ranging functions of E2F4 in transcriptional activation and repression revealed by genome-wide analysis.
    Nucleic Acids Res. 2011 May;39(9):3558-73 PMID: 21247883
  32. MYLK promotes hepatocellular carcinoma progression through regulating cytoskeleton to enhance epithelial-mesenchymal transition.
    Clin Exp Med. 2018 Nov;18(4):523-533 PMID: 29855744
  33. Role and mechanism of circ-PRKCI in hepatocellular carcinoma.
    World J Gastroenterol. 2019 Apr 28;25(16):1964-1974 PMID: 31086464
  34. Linking Long Noncoding RNA Localization and Function.
    Trends Biochem Sci. 2016 Sep;41(9):761-772 PMID: 27499234
  35. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.
    Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16899-903 PMID: 12477932
  36. Angiogenesis in Hepatocellular Carcinoma; Pathophysiology, Targeted Therapy, and Role of Imaging.
    J Hepatocell Carcinoma. 2020 Apr 23;7:77-89 PMID: 32426302
  37. Integrated analysis of a competing endogenous RNA network reveals key long noncoding RNAs as potential prognostic biomarkers for hepatocellular carcinoma.
    J Cell Biochem. 2019 Aug;120(8):13810-13825 PMID: 30989713
  38. MicroRNA-302a/d inhibits the self-renewal capability and cell cycle entry of liver cancer stem cells by targeting the E2F7/AKT axis.
    J Exp Clin Cancer Res. 2018 Oct 16;37(1):252 PMID: 30326936
  39. Long noncoding RNA MYLK-AS1 promotes growth and invasion of hepatocellular carcinoma through the EGFR/HER2-ERK1/2 signaling pathway.
    Int J Biol Sci. 2020 Apr 27;16(11):1989-2000 PMID: 32398965
  40. Drosophila E2F1 has context-specific pro- and antiapoptotic properties during development.
    Dev Cell. 2005 Oct;9(4):463-75 PMID: 16198289
Article Info
Journal
Journal of experimental & clinical cancer research : CR
Abbr.
J Exp Clin Cancer Res
ISSN
1756-9966
DOI
10.1186/s13046-020-01739-z
Email
[email protected]
[email protected]
Published
2020-11-09
Epub
2020-00-09
Pages
235
Language
English
Region
England
NLM ID
8308647
PMCID
PMC7650167
Subset
IM
Grants
Shanghai Minhang Science and Technology Commission (CN) · 2019MHZ079
Fundamental Medical Project of Minhang Hospital of Fudan University Project Foundation · 2019MHJC04
Corrections
ErratumIn
PMID: 33298087
External Links
PubMed source DOI: 10.1186/s13046-020-01739-z PMC Full Text View journal details
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