Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

Ahead of print

doi: 10.17219/acem/157063

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Cite as:

Cheng Y. Hsa-circ-0000098 promotes the progression of hepatocellular carcinoma by regulation of miR-136-5p/MMP2 axis [published online as ahead of print on March 7, 2023]. Adv Clin Exp Med. 2023. doi:10.17219/acem/157063

Hsa-circ-0000098 promotes the progression of hepatocellular carcinoma by regulation of miR-136-5p/MMP2 axis

Yunfei Cheng1,A,B,C,D,E,F

1 Department of Hepatobiliary Surgery, Xiantao First People’s Hospital, China


Background. Many papers revealed the abnormal expression of circular RNA (circRNA), a kind of non-coding RNA, in mammals. However, the potential functional mechanisms are still unknown.
Objectives. In this paper, we aimed to elucidate the function and mechanisms of hsa-circ-0000098 in hepatocellular carcinoma (HCC).
Material and Methods. Bioinformatics was used to analyze the Gene Expression Omnibus (GEO) database (GSE97332) and predict the targeted gene site of miR-136-5p. The starBase online database was utilized to predict that MMP2 is the downstream target gene of miR-136-5p. The expression of hsa_circ_0000098, miR-136-5p and matrix metalloproteinase 2 (MMP2) in HCC tissues or cells was detected using quantitative real-time polymerase chain reaction (qRT-PCR) method. The migration and invasion abilities of processing cells were measured with transwell assay. The luciferase reporter assay was carried out to verify the targets of hsa_circ_0000098, MMP2 and miR-136-5p. The western blot assay was performed to detect the expression of MMP2, MMP9, E-cadherin, and N-cadherin.
Results. According to the analysis of GEO database of GSE97332, hsa_circ_0000098 had a prominent expression in HCC tissues. A continued analysis of relevant patients has verified that the high expression of hsa_circ_0000098 is present in HCC tissues with relative to poor prognosis. We also proved that the migration and invasion abilities of HCC cell lines can be inhibited by silencing hsa_circ_0000098. In view of the above findings, we continued to study the hsa_circ_0000098 mechanism of action in HCC. The study revealed that hsa_circ_0000098 can sponge miR-136-5p and then regulate MMP2, which is a downstream target gene of miR-136-5p, in order to promote HCC metastasis by regulation of miR-136-5p/MMP2 axis.
Conclusion. Our data showed that has_circ_0000098 facilitates the migration, invasion and malignant progression of HCC. On the other hand, we demonstrated that the mechanism of action of hsa_circ_0000098 in HCC might be due to the regulation of miR-136-5p/MMP2 axis.

Key words

hepatocellular carcinoma, MMP2, miR-136, hsa_circ_0000098

Graphical abstract

Graphical abstracts

References (46)

  1. Zhang H, Deng T, Ge S, et al. Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7. Oncogene. 2019;38(15):2844–2859. doi:10.1038/s41388-018-0619-z
  2. Ziogas IA, Tsoulfas G. Advances and challenges in laparoscopic surgery in the management of hepatocellular carcinoma. World J Gastrointest Surg. 2017;9(12):233–245. doi:10.4240/wjgs.v9.i12.233
  3. Ding H, Ye ZH, Wen DY, et al. Downregulation of miR-136-5p in hepato­cellular carcinoma and its clinicopathological significance. Mol Med Rep. 2017;16(4):5393–5405. doi:10.3892/mmr.2017.7275
  4. Forner A, Bruix J. Hepatocellular carcinoma: Authors’ reply. Lancet. 2012;380(9840):470–471. doi:10.1016/S0140-6736(12)61286-0
  5. Sayiner M, Golabi P, Younossi ZM. Disease burden of hepatocellular carcinoma: A global perspective. Dig Dis Sci. 2019;64(4):910–917. doi:10.1007/s10620-019-05537-2
  6. Yin L, Cai Z, Zhu B, Xu C. Identification of key pathways and genes in the dynamic progression of HCC based on WGCNA. Genes (Basel). 2018;9(2):92. doi:10.3390/genes9020092
  7. Ding J, Zhou W, Li X, Sun M, Ding J, Zhu Q. Tandem DNAzyme for double digestion: A new tool for circRNA suppression. Biol Chem. 2019;400(2):247–253. doi:10.1515/hsz-2018-0232
  8. Gao Y, Zhang J, Zhao F. Circular RNA identification based on multiple seed matching. Brief Bioinform. 2018;19(5):803–810. doi:10.1093/bib/bbx014
  9. Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495(7441):384–388. doi:10.1038/nature11993
  10. Wilusz JE, Sharp PA. A circuitous route to noncoding RNA. Science. 2013;340(6131):440–441. doi:10.1126/science.1238522
  11. Zhang H, Sheng C, Yin Y, et al. PABPC1 interacts with AGO2 and is responsible for the microRNA mediated gene silencing in high grade hepatocellular carcinoma. Cancer Lett. 2015;367(1):49–57. doi:10.1016/j.canlet.2015.07.010
  12. Suzuki H, Tsukahara T. A view of pre-mRNA splicing from RNase R resistant RNAs. Int J Mol Sci. 2014;15(6):9331–9342. doi:10.3390/ijms15069331
  13. Lin X, Chen Y. Identification of potentially functional circRNA-miRNA-mRNA regulatory network in hepatocellular carcinoma by integrated microarray analysis. Med Sci Monit Basic Res. 2018;24:70–78. doi:10.12659/MSMBR.909737
  14. Li X, Ding J, Wang X, Cheng Z, Zhu Q. NUDT21 regulates circRNA cyclization and ceRNA crosstalk in hepatocellular carcinoma. Oncogene. 2020;39(4):891–904. doi:10.1038/s41388-019-1030-0
  15. Xu S, Zhou L, Ponnusamy M, et al. A comprehensive review of circRNA: From purification and identification to disease marker potential. PeerJ. 2018;6:e5503. doi:10.7717/peerj.5503
  16. Han D, Li J, Wang H, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology. 2017;66(4):1151–1164. doi:10.1002/hep.29270
  17. Zhang X, Luo P, Jing W, Zhou H, Liang C, Tu J. circSMAD2 inhibits the epithelial–mesenchymal transition by targeting miR-629 in hepatocellular carcinoma. Onco Targets Ther. 2018;11:2853–2863. doi:10.2147/OTT.S158008
  18. Li P, Chen S, Chen H, et al. Using circular RNA as a novel type of biomarker in the screening of gastric cancer. Clin Chim Acta. 2015;444:132–136. doi:10.1016/j.cca.2015.02.018
  19. Li P, Chen H, Chen S, et al. Circular RNA 0000096 affects cell growth and migration in gastric cancer. Br J Cancer. 2017;116(5):626–633. doi:10.1038/bjc.2016.451
  20. Wang F, Nazarali AJ, Ji S. Circular RNAs as potential biomarkers for cancer diagnosis and therapy. Am J Cancer Res. 2016;6(6):1167–1176. PMID:27429839. PMCID:PMC4937728.
  21. Huang XB, Li J, Zheng L, et al. Bioinformatics analysis reveals potential candidate drugs for HCC. Pathol Oncol Res. 2013;19(2):251–258. doi:10.1007/s12253-012-9576-y
  22. Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: A focus on special subgroups. Gut. 2021;70(1):204–214. doi:10.1136/gutjnl-2020-321702
  23. Garrido A, Djouder N. Cirrhosis: A questioned risk factor for hepatocellular carcinoma. Trends Cancer. 2021;7(1):29–36. doi:10.1016/j.trecan.2020.08.005
  24. Lu L, Jiang J, Zhan M, et al. Targeting neoantigens in hepatocellular carcinoma for immunotherapy: A futile strategy? Hepatology. 2021;73(1):414–421. doi:10.1002/hep.31279
  25. Arnaiz E, Sole C, Manterola L, Iparraguirre L, Otaegui D, Lawrie CH. CircRNAs and cancer: Biomarkers and master regulators. Semin Cancer Biol. 2019;58:90–99. doi:10.1016/j.semcancer.2018.12.002
  26. Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495(7441):333–338. doi:10.1038/nature11928
  27. Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20(11):675–691. doi:10.1038/s41576-019-0158-7
  28. Tsitsipatis D, Grammatikakis I, Driscoll RK, et al. AUF1 ligand circPCNX reduces cell proliferation by competing with p21 mRNA to increase p21 production. Nucleic Acids Res. 2021;49(3):1631–1646. doi:10.1093/nar/gkaa1246
  29. Patop IL, Wüst S, Kadener S. Past, present, and future of circRNAs. EMBO J. 2019;38(16):e100836. doi:10.15252/embj.2018100836
  30. Gasparini S, Licursi V, Presutti C, Mannironi C. The secret garden of neuronal circRNAs. Cells. 2020;9(8):1815. doi:10.3390/cells9081815
  31. Huang G, Liang M, Liu H, et al. CircRNA hsa_circRNA_104348 promotes hepatocellular carcinoma progression through modulating miR-187-3p/RTKN2 axis and activating Wnt/β-catenin pathway. Cell Death Dis. 2020;11(12):1065. doi:10.1038/s41419-020-03276-1
  32. Liu Z, Yu Y, Huang Z, et al. CircRNA-5692 inhibits the progression of hepatocellular carcinoma by sponging miR-328-5p to enhance DAB2IP expression. Cell Death Dis. 2019;10(12):900. doi:10.1038/s41419-019-2089-9
  33. Yu J, Yang M, Zhou B, et al. CircRNA-104718 acts as competing endogenous RNA and promotes hepatocellular carcinoma progression through microRNA-218-5p/TXNDC5 signaling pathway. Clin Sci (Lond). 2019;133(13):1487–1503. doi:10.1042/CS20190394
  34. Shiu TY, Lin HH, Shih YL, et al. CRNDE-h transcript/miR-136-5p axis regulates interleukin enhancer binding factor 2 expression to promote hepatocellular carcinoma cell proliferation. Life Sci. 2021;284:119708. doi:10.1016/j.lfs.2021.119708
  35. Yuan Q, Cao G, Li J, Zhang Y, Yang W. MicroRNA-136 inhibits colon cancer cell proliferation and invasion through targeting liver receptor homolog-1/Wnt signaling. Gene. 2017;628:48–55. doi:10.1016/j.gene.2017.07.031
  36. Niu J, Li Z, Li F. Overexpressed microRNA-136 works as a cancer suppressor in gallbladder cancer through suppression of JNK signaling pathway via inhibition of MAP2K4. Am J Physiol Gastrointest Liver Physiol. 2019;317(5):G670–G681. doi:10.1152/ajpgi.00055.2019
  37. Fayyad-Kazan M, ElDirani R, Hamade E, et al. Circulating miR-29c, miR-30c, miR-193a-5p and miR-885-5p: Novel potential biomarkers for HTLV-1 infection diagnosis. Infect Genet Evol. 2019;74:103938. doi:10.1016/j.meegid.2019.103938
  38. Xiong Y, Kotian S, Zeiger MA, Zhang L, Kebebew E. miR-126-3p inhibits thyroid cancer cell growth and metastasis, and is associated with aggressive thyroid cancer. PLoS One. 2015;10(8):e0130496. doi:10.1371/journal.pone.0130496
  39. Al Rawi N, Elmabrouk N, Abu Kou R, Mkadmi S, Rizvi Z, Hamdoon Z. The role of differentially expressed salivary microRNA in oral squamous cell carcinoma: A systematic review. Arch Oral Biol. 2021;125:105108. doi:10.1016/j.archoralbio.2021.105108
  40. Dong H, Jian P, Yu M, Wang L. Silencing of long noncoding RNA LEF1-AS1 prevents the progression of hepatocellular carcinoma via the crosstalk with microRNA-136-5p/WNK1. J Cell Physiol. 2020;235(10):6548–6562. doi:10.1002/jcp.29503
  41. He W, Zhu X, Tang X, Xiang X, Yu J, Sun H. Circ_0027089 regulates NACC1 by targeting miR-136-5p to aggravate the development of hepatitis B virus-related hepatocellular carcinoma. Anticancer Drugs. 2022;33(1):e336–e348. doi:10.1097/CAD.0000000000001211
  42. Das S, De S, Sengupta S. Post-transcriptional regulation of MMP2 mRNA by its interaction with miR-20a and nucleolin in breast cancer cell lines. Mol Biol Rep. 2021;48(3):2315–2324. doi:10.1007/s11033-021-06261-9
  43. Dorandish S, Williams A, Atali S, et al. Regulation of amyloid-β levels by matrix metalloproteinase-2/9 (MMP2/9) in the media of lung cancer cells. Sci Rep. 2021;11(1):9708. doi:10.1038/s41598-021-88574-0
  44. Khalil HH, Osman HA, Teleb M, et al. Engineered s-triazine-based dendrimer-honokiol conjugates as targeted MMP-2/9 inhibitors for halting hepatocellular carcinoma. ChemMedChem. 2021;16(24):3701–3719. doi:10.1002/cmdc.202100465
  45. Li Y, Zhang T, Qin S, et al. Investigational drugs in HIV: Pros and cons of entry and fusion inhibitors (review). Mol Med Rep. 2019;19(3):1987–1995. doi:10.3892/mmr.2019.9838
  46. Kim CW, Hwang KA, Choi KC. Anti-metastatic potential of resveratrol and its metabolites by the inhibition of epithelial-mesenchymal transition, migration, and invasion of malignant cancer cells. Phytomedicine. 2016;23(14):1787–1796. doi:10.1016/j.phymed.2016.10.016