Abstract
Background
Hepatocellular carcinoma (HCC) is an extremely aggressive malignant tumor associated
with high migratory and invasive potential. The present study intends to explore regulatory
mechanism of p53/microRNA (miR)-29c-3p/A disintegrin and metalloproteinase 12 (ADAM12)
axis in HCC based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated
protein 9 (Cas9) technology.
Methods
Putative miR-29c-3p binding sites on ADAM12 3′UTR were verified by a luciferase assay.
The binding affinity of p53 to miR-29c-3p was assessed based on CRISPR/Cas9 technology
to construct a p53 knockout (p53−/−) HCCLM3 cell line. Furthermore, the effect of p53/miR-29c-3p/ADAM12 was assessed
on maligant phenotypes in vitro and tumor formation and metastasis in nude mice.
Results
ADAM12 was highly expressed but miR-29c-3p was poorly expressed in HCC. miR-29c-3p
inhibited migratory and invasive abilities of HCC cells by targeting ADAM12 expression.
p53 was found to target and upregulate miR-29c-3p, thus downregulating ADAM12 and
conferring inhibitory effect on HCC cell activities. Moreover, ADAM12 knockout or
p53 overexpression reduced HCC tumor formation and metastasis, which were reversed
by further silencing of miR-29c-3p.
Conclusion
The identification of the p53/miR-29c-3p/ADAM12 axis in migration and invasion of
HCC may potentially further our understanding of mechanisms underpinning HCC, and
also bear translational value as novel molecular targets.
Keywords
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References
- Cancer Statistics, 2021.CA Cancer J Clin. 2021; 71: 7-33
- BRD4 induces cell migration and invasion in HCC cells through MMP-2 and MMP-9 activation mediated by the Sonic hedgehog signaling pathway.Oncol Lett. 2015; 10: 2227-2232
- Transforming growth factor-beta1-mediated activation of NF-kappaB contributes to enhanced ADAM-12 expression in mammary carcinoma cells.Mol Cancer Res. 2010; 8: 1261-1270
- Biomarker to distinguish hepatocellular carcinoma from cholangiocarcinoma by serum a disintegrin and metalloprotease 12.Arch Med Sci. 2011; 7: 1013-1016
- Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis.Proc Natl Acad Sci U.S.A. 2021; 118
- Increased ADAM12 expression predicts poor prognosis in cervical cancer patients before general anesthesia.Clin Lab. 2021; 67
- Hepatocellular carcinoma cell-secreted exosomal microRNA-210 promotes angiogenesis in vitro and in vivo.Mol Ther Nucleic Acids. 2018; : 11243-11252
- Sequential alterations of microRNA expression in hepatocellular carcinoma development and venous metastasis.Hepatology. 2012; 55: 1453-1461
- MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma.Oncogene. 2014; 33: 2557-2567
- MicroRNA-22 is down-regulated in hepatitis B virus-related hepatocellular carcinoma.Biomed Pharmacother. 2013; 67: 375-380
- Canonical transforming growth factor-beta signaling regulates disintegrin metalloprotease expression in experimental renal fibrosis via miR-29.Am J Pathol. 2013; 183: 1885-1896
- p53 target miR-29c-3p suppresses colon cancer cell invasion and migration through inhibition of PHLDB2.Biochem Biophys Res Commun. 2017; 487: 90-95
- p53 in survival, death and metabolic health: a lifeguard with a licence to kill.Nat Rev Mol Cell Biol. 2015; 16: 393-405
- Critical roles of p53 in epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma cells.PLoS ONE. 2013; 8: e72846
- CRISPR/Cas9 Immune System as a Tool for Genome Engineering.Arch Immunol Ther Exp (Warsz). 2017; 65: 233-240
- CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice.Proc Natl Acad Sci U S A. 2015; 112: 13982-13987
- Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours.Nat Commun. 2018; 9: 4624
- Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.Methods. 2001; 25: 402-408
- hsa-miR-29c-3p regulates biological function of colorectal cancer by targeting SPARC.Oncotarget. 2017; 8: 104508-104524
- miR-29c-3p inhibits autophagy and cisplatin resistance in ovarian cancer by regulating FOXP1/ATG14 pathway.Cell Cycle. 2020; 19: 193-206
- CRISPR-Cas9 system: a new-fangled dawn in gene editing.Life Sci. 2019; 232116636
- Circular RNA circRHOT1 promotes hepatocellular carcinoma progression by initiation of NR2F6 expression.Mol. Cancer. 2019; 18: 119
- N6-Methyladenosine modification of lincRNA 1281 is critically required for mESC differentiation potential.Nucleic Acids Res. 2018; 46: 3906-3920
- MKL1 regulates hepatocellular carcinoma cell proliferation, migration and apoptosis via the COMPASS complex and NF-kappaB signaling.BMC Cancer. 2021; 21: 1184
- ADAM12 is a novel regulator of tumor angiogenesis via STAT3 Signaling.Mol Cancer Res. 2017; 15: 1608-1622
- Low miR-29c expression is a prognostic marker in hepatocellular carcinoma.Genet Mol Res. 2016; 15
- ADAM12 in human liver cancers: tGF-beta-regulated expression in stellate cells is associated with matrix remodeling.Hepatology. 2003; 37: 1056-1066
- A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion.Oncogene. 2012; 31: 2888-2898
- An ADAM12 and FAK positive feedback loop amplifies the interaction signal of tumor cells with extracellular matrix to promote esophageal cancer metastasis.Cancer Lett. 2018; 422: 118-128
- ADAM12-L confers acquired 5-fluorouracil resistance in breast cancer cells.Sci Rep. 2017; 7: 9687
- MiR-29c suppresses invasion and metastasis by targeting TIAM1 in nasopharyngeal carcinoma.Cancer Lett. 2013; 329: 181-188
- MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of beta-catenin signaling.Ann Oncol. 2014; 25: 2196-2204
- Brown seaweed fucoidan inhibits cancer progression by dual regulation of mir-29c/ADAM12 and miR-17-5p/PTEN axes in human breast cancer cells.J Cancer. 2016; 7: 2408-2419
- p53 in health and disease.Nat Rev Mol Cell Biol. 2007; 8: 275-283
- Long-term disruption of maternal glucose homeostasis induced by prenatal glucocorticoid treatment correlates with miR-29 upregulation.Am J Physiol Endocrinol Metab. 2014; 306: E109-E120
- miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities.Leukemia. 2009; 23: 1159-1163
Article info
Publication history
Published online: July 16, 2022
Accepted:
May 26,
2022
Received:
December 6,
2021
Identification
Copyright
© 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
