N6-methyladenosine-mediated SH3BP5-AS1 upregulation promotes GEM chemoresistance in pancreatic cancer by activating the Wnt signaling pathway

Biol Direct. 2022 Nov 17;17(1):33. doi: 10.1186/s13062-022-00347-5.

Abstract

Background: Pancreatic cancer (PC) is highly malignant. Chemotherapy is the main treatment strategy, especially for patients with advanced PC. However, chemoresistance has always been a frequently encountered bottleneck. Hence, there is an urgent need to enhance the sensitivity of PC to gemcitabine (GEM).

Results: We demonstrated that SH3BP5-AS1 was significantly upregulated in GEM-resistant PC and predicted a poorer prognosis. SH3BP5-AS1 stability was regulated by ALKBH5/IGF2BP1-mediated m6A modification. Loss of SH3BP5-AS1 reduced PC cell migration and invasion and enhanced the sensitivity of PC to GEM, as confirmed by gain- and loss-of-function assays in vitro and in vivo. Bioinformatics analysis revealed that SH3BP5-AS1 acted as a ceRNA against miR-139-5p and directly targeted CTBP1, affecting the biological behavior of PC cells. The mechanistic studies revealed that the upregulation of SH3BP5-AS1 increased CTBP1 expression by directly activating the Wnt signaling pathway, promoting GEM resistance.

Conclusions: This study revealed that SH3BP5-AS1 activated Wnt signaling pathway by sponging miR-139-5p, upregulating CTBP1 expression, and contributing to the sensitivity of PC cells to GEM. SH3BP5-AS1 might be a potential target for PC therapy.

Keywords: Chemoresistance; N6-methyladenosine; Pancreatic cancer; SH3BP5-AS1; Wnt signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Drug Resistance, Neoplasm / genetics
  • Gemcitabine
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs* / metabolism
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / pathology
  • RNA, Long Noncoding* / metabolism
  • Up-Regulation
  • Wnt Signaling Pathway / genetics

Substances

  • RNA, Long Noncoding
  • MicroRNAs
  • SH3BP5 protein, human
  • Adaptor Proteins, Signal Transducing
  • MIRN139 microRNA, human
  • Gemcitabine