Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

circSFMBT1 promotes pancreatic cancer growth and metastasis via targeting miR-330-5p/PAK1 axis

Cancer Gene Therapy volume 28, pages 234–249 (2021)Cite this article

Subjects

Abstract

Pancreatic cancer (PC) is one of the most common and lethal cancers that affects millions of people around the world. The prognosis of PC is poor with very limited effective treatments. Here, we fully investigated the function and underlying mechanism of circSFMBT1 (hsa_circ_0066147) in PC. Real-time quantitative PCR, Western blotting, and immunohistochemistry were used to examine levels of circSFMBT1, miR-330-5p, PAK1 (p21-activated kinase 1), or proliferation/metastasis-related proteins. Colony formation assay, flow cytometry, and transwell assay detected the roles of circSFMBT1 and miR-330-5p in cell apoptosis, proliferation, migration, and invasion of PC cells, respectively. Dual luciferase assay and RNA immunoprecipitation were used to validate the interactions of circSFMBT1/miR-330-5p and miR-330-5p/PAK1. Fluorescence in situ hybridization was performed to examine the subcellular localization of circSFMBT1 and miR-330-5p. Subcutaneous tumor growth was monitored in nude mice and in vivo metastasis was examined as well following injection of PC cells into the tail vein. This study demonstrated that circSFMBT1 and PAK1 were up-regulated in PC tissues and cells, while miR-330-5p was down-regulated. circSFMBT1 directly bound miR-330-5p and inhibited its expression. In addition, circSFMBT1 promoted proliferation, migration, and invasion of PC cells through up-regulating proliferation-related proteins and down-regulating apoptosis-related proteins via miR-330-5p. miR-330-5p directly bound PAK1 mRNA and suppressed proliferation, migration, invasion, and epithelial–mesenchymal transition process via targeting PAK1 in PC cells. Further, knockdown circSFMBT1 increased miR-330-5p level, but decreased PAK1 expression and repressed tumor growth and metastasis in vivo. Taken together, circSFMBT1 promotes proliferation and metastasis of PC via regulating miR-330-5p/PAK1 pathway as a miR-330-5p sponge.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: circSFMBT1 and PAK1 were up-regulated, while miR-330-5p was down-regulated in PC tissues and cells.
Fig. 2: circSFMBT1 targeted and negatively regulated miR-330-5p.
Fig. 3: circSFMBT1 promoted proliferation but inhibited apoptosis of PC cells through miR-330-5p.
Fig. 4: circSFMBT1 enhanced migration and invasion abilities of PC cells and promoted EMT process via miR-330-5p.
Fig. 5: miR-330-5p directly targeted PAK1.
Fig. 6: miR-330-5p regulated proliferation and apoptosis of PC cells via PAK1.
Fig. 7: miR-330-5p inhibited migration and invasion of PC cells and EMT process via PAK1.
Fig. 8: Knockdown of circSFMBT1 inhibited tumor growth and metastasis in vivo via miR-330-5p/PAK1 pathway.

Similar content being viewed by others

References

  1. Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol. 2019;10:10–27.

    Article  Google Scholar 

  2. Orth M, Metzger P, Gerum S, Mayerle J, Schneider G, Belka C, et al. Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat Oncol. 2019;14:141.

    Article  Google Scholar 

  3. Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388:73–85.

    Article  CAS  Google Scholar 

  4. Grasso C, Jansen G, Giovannetti E. Drug resistance in pancreatic cancer: impact of altered energy metabolism. Crit Rev Oncol Hematol. 2017;114:139–52.

    Article  Google Scholar 

  5. Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675–91.

    Article  CAS  Google Scholar 

  6. Barrett SP, Salzman J. Circular RNAs: analysis, expression and potential functions. Development. 2016;143:1838–47.

    Article  CAS  Google Scholar 

  7. Cocquerelle C, Mascrez B, Hetuin D, Bailleul B. Mis-splicing yields circular RNA molecules. FASEB J. 1993;7:155–60.

    Article  CAS  Google Scholar 

  8. Guo JU, Agarwal V, Guo H, Bartel DP. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014;15:409.

    Article  Google Scholar 

  9. Rong D, Sun H, Li Z, Liu S, Dong C, Fu K, et al. An emerging function of circRNA-miRNAs-mRNA axis in human diseases. Oncotarget. 2017;8:73271–81.

    Article  Google Scholar 

  10. Meng S, Zhou H, Feng Z, Xu Z, Tang Y, Li P, et al. CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer. 2017;16:94.

    Article  Google Scholar 

  11. Qu S, Hao X, Song W, Niu K, Yang X, Zhang X, et al. Circular RNA circRHOT1 is upregulated and promotes cell proliferation and invasion in pancreatic cancer. Epigenomics. 2019;11:53–63.

    Article  CAS  Google Scholar 

  12. Mohr AM, Mott JL. Overview of microRNA biology. Semin Liver Dis. 2015;35:3–11.

    Article  CAS  Google Scholar 

  13. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–22.

    Article  CAS  Google Scholar 

  14. Gong J, Chu Y, Xu M, Huo J, Lv L. Esophageal squamous cell carcinoma cell proliferation induced by exposure to low concentration of cigarette smoke extract is mediated via targeting miR-101-3p/COX-2 pathway. Oncol Rep. 2016;35:463–71.

    Article  CAS  Google Scholar 

  15. Cao J, Liu J, Xu R, Zhu X, Liu L, Zhao X. MicroRNA-21 stimulates epithelial-to-mesenchymal transition and tumorigenesis in clear cell renal cells. Mol Med Rep. 2016;13:75–82.

    Article  CAS  Google Scholar 

  16. Wang S, Zeng Y, Zhou JM, Nie SL, Peng Q, Gong J, et al. MicroRNA-1246 promotes growth and metastasis of colorectal cancer cells involving CCNG2 reduction. Mol Med Rep. 2016;13:273–80.

    Article  CAS  Google Scholar 

  17. Song L, Xie X, Yu S, Peng F, Peng L. MicroRNA126 inhibits proliferation and metastasis by targeting pik3r2 in prostate cancer. Mol Med Rep. 2016;13:1204–10.

    Article  CAS  Google Scholar 

  18. Weber MJ. New human and mouse microRNA genes found by homology search. FEBS J. 2005;272:59–73.

    Article  CAS  Google Scholar 

  19. Mao Y, Chen H, Lin Y, Xu X, Hu Z, Zhu Y, et al. microRNA-330 inhibits cell motility by downregulating Sp1 in prostate cancer cells. Oncol Rep. 2013;30:327–33.

    Article  CAS  Google Scholar 

  20. Li Y, Zhu X, Xu W, Wang D, Yan J. miR-330 regulates the proliferation of colorectal cancer cells by targeting Cdc42. Biochem Biophys Res Commun. 2013;431:560–5.

    Article  CAS  Google Scholar 

  21. Lee KH, Chen YL, Yeh SD, Hsiao M, Lin JT, Goan YG, et al. MicroRNA-330 acts as tumor suppressor and induces apoptosis of prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation. Oncogene. 2009;28:3360–70.

    Article  CAS  Google Scholar 

  22. Feng L, Ma J, Ji H, Liu Y, Hu W. miR-330-5p suppresses glioblastoma cell proliferation and invasiveness through targeting ITGA5. Biosci Rep. 2017;37:BSR20170019.

    Article  CAS  Google Scholar 

  23. Trehoux S, Lahdaoui F, Delpu Y, Renaud F, Leteurtre E, Torrisani J, et al. Micro-RNAs miR-29a and miR-330-5p function as tumor suppressors by targeting the MUC1 mucin in pancreatic cancer cells. Biochim Biophys Acta. 2015;1853:2392–403.

    Article  CAS  Google Scholar 

  24. Rane CK, Minden A. P21 activated kinase signaling in cancer. Semin Cancer Biol. 2019;54:40–9.

    Article  CAS  Google Scholar 

  25. Eswaran J, Li DQ, Shah A, Kumar R. Molecular pathways: targeting p21-activated kinase 1 signaling in cancer-opportunities, challenges, and limitations. Clin Cancer Res. 2012;18:3743–9.

    Article  CAS  Google Scholar 

  26. Shrestha Y, Schafer EJ, Boehm JS, Thomas SR, He F, Du J, et al. PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling. Oncogene. 2012;31:3397–408.

    Article  CAS  Google Scholar 

  27. Symeonidis N, Lambropoulou M, Pavlidis E, Anagnostopoulos C, Tsaroucha A, Kotini A, et al. PAK1 expression in pancreatic cancer: clinicopathological characteristics and prognostic significance. Clin Med Insights Oncol. 2019;13:1179554919831990.

    Article  Google Scholar 

  28. Xie L, Mao M, Xiong K, Jiang B. Circular RNAs: a novel player in development and disease of the central nervous system. Front Cell Neurosci. 2017;11:354.

    Article  Google Scholar 

  29. Yang F, Liu DY, Guo JT, Ge N, Zhu P, Liu X, et al. Circular RNA circ-LDLRAD3 as a biomarker in diagnosis of pancreatic cancer. World J Gastroenterol. 2017;23:8345–54.

    Article  CAS  Google Scholar 

  30. An Y, Cai H, Zhang Y, Liu S, Duan Y, Sun D, et al. circZMYM2 competed endogenously with miR-335-5p to regulate JMJD2C in pancreatic cancer. Cell Physiol Biochem. 2018;51:2224–36.

    Article  CAS  Google Scholar 

  31. Xiao S, Yang M, Yang H, Chang R, Fang F, Yang L. miR-330-5p targets SPRY2 to promote hepatocellular carcinoma progression via MAPK/ERK signaling. Oncogenesis. 2018;7:90.

    Article  Google Scholar 

  32. Yoo HI, Kim BK, Yoon SK. MicroRNA-330-5p negatively regulates ITGA5 expression in human colorectal cancer. Oncol Rep. 2016;36:3023–9.

    Article  CAS  Google Scholar 

  33. Moran Y, Agron M, Praher D, Technau U. The evolutionary origin of plant and animal microRNAs. Nat Ecol Evol. 2017;1:27.

    Article  Google Scholar 

  34. Semenova G, Chernoff J. Targeting PAK1. Biochem Soc Trans. 2017;45:79–88.

    Article  CAS  Google Scholar 

  35. Itakura A, Aslan JE, Kusanto BT, Phillips KG, Porter JE, Newton PK, et al. p21-Activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils. PLoS ONE. 2013;8:e73063.

    Article  CAS  Google Scholar 

  36. Wang Y, Wang S, Lei M, Boyett M, Tsui H, Liu W, et al. The p21-activated kinase 1 (Pak1) signalling pathway in cardiac disease: from mechanistic study to therapeutic exploration. Br J Pharm. 2018;175:1362–74.

    Article  CAS  Google Scholar 

  37. Woo TG, Yoon MH, Hong SD, Choi J, Ha NC, Sun H, et al. Anti-cancer effect of novel PAK1 inhibitor via induction of PUMA-mediated cell death and p21-mediated cell cycle arrest. Oncotarget. 2017;8:23690–701.

    Article  Google Scholar 

  38. Tao J, Oladimeji P, Rider L, Diakonova M. PAK1-Nck regulates cyclin D1 promoter activity in response to prolactin. Mol Endocrinol. 2011;25:1565–78.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81472738).

Author information

Authors and Affiliations

  1. Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, PR China

    Shu Xu, San-Lin Lei, Kui-Jie Liu, Shen-Gen Yi, Zhu-Lin Yang & Hong-Liang Yao

Authors
  1. Shu Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. San-Lin Lei
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Kui-Jie Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Shen-Gen Yi
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Zhu-Lin Yang
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Hong-Liang Yao
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Guarantor of integrity of the entire study: Z-LY, H-LY; study concepts: SX; study design: SX, Z-LY, H-LY; definition of intellectual content: SX; literature research: S-LL; clinical studies: K-JL; experimental studies: SX, S-LL, K-JL, S-GY; data acquisition: SX, S-LL; data analysis: K-JL, Z-LY; statistical analysis: S-GY, H-LY; manuscript preparation: SX; manuscript editing: SX, Z-LY, H-LY; manuscript review: Z-LY, H-LY.

Corresponding authors

Correspondence to Zhu-Lin Yang or Hong-Liang Yao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The study was reviewed and approved by the Ethics Committee of Second Xiangya Hospital of Central South University. All patients were informed of the detailed information about the study and written agreement. All animal experiments and protocols were reviewed and approved by the Animal Care and Use Committee of Second Xiangya Hospital of Central South University.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, S., Lei, SL., Liu, KJ. et al. circSFMBT1 promotes pancreatic cancer growth and metastasis via targeting miR-330-5p/PAK1 axis. Cancer Gene Ther 28, 234–249 (2021). https://doi.org/10.1038/s41417-020-00215-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-020-00215-2

Search

Advanced search

Quick links