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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

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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.

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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.

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Funding

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

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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

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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.

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

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The authors declare that they have no conflict of interest.

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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.

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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

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