Hsa_circ_0000069 Knockdown Inhibits Tumorigenesis and Exosomes with Downregulated hsa_circ_0000069 Suppress Malignant Transformation via Inhibition of STIL in Pancreatic Cancer

Int J Nanomedicine. 2020 Dec 7:15:9859-9873. doi: 10.2147/IJN.S279258. eCollection 2020.

Abstract

Background: Circular RNAs (circRNAs) play an important role in the tumorigenesis of pancreatic cancer. However, the expression profiles and roles of circRNAs in pancreatic cancer remain largely unknown.

Methods: To identify differentially expressed circRNAs (DEcircRNAs) between pancreatic cancer and matched normal tissues, bioinformatics analysis was performed. Hsa_circ_0000069 was identified by 0.bioinformatics analysis. In addition, the level of hsa_circ_0000069 in pancreatic cancer tissues and cell lines, and pancreatic cancer cell-derived exosomes were assessed using RT-qPCR assay.

Results: The expression of hsa_circ_0000069 was markedly upregulated in pancreatic cancer tissues and cell lines. SCL/TAL1 interrupting locus (STIL) is the parent gene for hsa_circ_0000069, and its high expression was related to poor overall survival in patients with pancreatic cancer. In addition, downregulation of hsa_circ_0000069 markedly suppressed STIL expression, induced the apoptosis and cell cycle arrest, and inhibited the proliferation, migration and invasion in pancreatic cancer cells. Moreover, hsa_circ_0000069 knockdown inhibited the growth of xenograft pancreatic cancer tumors in vivo. Furthermore, human pancreatic duct epithelial cells (HPDE) are capable of internalizing SW1990 cell-derived exosomes, allowing the transfer of hsa_circ_0000069. Significantly, SW1990 cell-derived exosomes promoted the proliferation, migration and cell cycle progression of HPDE cells, whereas exosomes with downregulated hsa_circ_0000069 suppressed the proliferation, migration and cell cycle progression of HPDE cells, by suppressing STIL expression.

Conclusion: Our results suggest that hsa_circ_0000069 knockdown could inhibit pancreatic cancer tumorigenesis and exosomes with downregulated hsa_circ_0000069 could suppress HPDE cell malignant transformation. Collectively, hsa_circ_0000069 might be a therapeutic target for the treatment of pancreatic cancer.

Keywords: exosomes; hsa_circ_0000069; pancreatic cancer; tumorigenesis.

MeSH terms

  • Apoptosis / genetics
  • Carcinogenesis / genetics*
  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Exosomes / genetics*
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Knockdown Techniques*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology*
  • RNA, Circular / deficiency
  • RNA, Circular / genetics*

Substances

  • Intracellular Signaling Peptides and Proteins
  • RNA, Circular
  • STIL protein, human

Grants and funding

The present study was partially supported by the National Natural Science Foundation of China (no. 81672970), the Natural Science Foundation of Jiangsu Province (no. M2020075), the projects of Suzhou Technology Bureau (nos. SYS201552, SYS2020141 and SYS2018054), found of Suzhou Introduced Team of Clinical Medical Experts (no. SZYJTD201803), Jiangsu Province′s Graduate Student Research Innovation Project (no. KYCX19_1986).