Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway

Cancer Lett. 2020 Dec 1;494:107-120. doi: 10.1016/j.canlet.2020.08.001. Epub 2020 Aug 16.

Abstract

Pancreatic cancer (PC) is a malignant cancer with high mortality and poor prognosis. In this study, we found that Linc01232 was significantly upregulated in PC tissues and cells and higher Linc01232 expression was associated with poorer prognosis. Linc01232 overexpression promoted and Linc01232 knockdown inhibited the migration and invasion of PC cells. The results of RNA pull-down, RNA Binding Protein Immunoprecipitation (RIP) assays revealed that Linc01232 physically interacted with Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2B1) (680-890 nt fragment with the RNA recognition motif 2 domain) to inhibit its ubiquitin-mediated degradation in PC cells. RNA sequencing was performed to obtain the transcriptional profiles regulated by Linc01232 and we further demonstrated that Linc01232 participated in the alternative splicing of A-Raf by stabilizing HNRNPA2B1 and subsequently regulated the MAPK/ERK signaling pathway. Collected, our study showed that Linc01232/HNRNPA2B1/A-Raf/MAPK axis participated in the progression of PC and provided a potential therapeutic target for PC.

Keywords: Invasion; Long noncoding RNAs; PC; Splicing; Ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism*
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Prognosis
  • Proteolysis
  • Proto-Oncogene Proteins A-raf / genetics
  • Proto-Oncogene Proteins A-raf / metabolism*
  • RNA, Long Noncoding / genetics*
  • Sequence Analysis, RNA
  • Ubiquitin / metabolism*
  • Up-Regulation

Substances

  • HNRNPA3 protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • RNA, Long Noncoding
  • Ubiquitin
  • Proto-Oncogene Proteins A-raf