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Using the E1A Minigene Tool to Study mRNA Splicing Changes
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SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon

Hongda Liu1, Zheng Gong2, Kangshuai Li3

  • 1Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.

Journal of Experimental & Clinical Cancer Research : CR
|February 19, 2021
PubMed
Abstract

Insights

Colon cancer cells show altered splicing of Mnk2 kinase due to SRSF1 regulation, leading to increased MKNK2b and tumor proliferation. This highlights a new therapeutic target for colon adenocarcinoma.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Signal Transduction

Background:

  • The MKNK2 gene encodes Mnk2 kinase, crucial in MAPK signaling and oncogenesis.
  • Human MKNK2 pre-mRNA undergoes alternative splicing, producing MKNK2a and MKNK2b isoforms with distinct protein domains.
  • Previous RNA-sequencing data suggested Mnk2 alternative splicing involvement in colon cancer.

Purpose of the Study:

  • To investigate upstream modulators of Mnk2 alternative splicing in colon adenocarcinoma (CAC).
  • To determine the clinical relevance of Mnk2 alternative splicing in CAC.

Main Methods:

  • Quantitative PCR, Western blotting, and immunohistochemistry (IHC) were used to analyze Mnk2 and related protein expression.
  • Functional studies were conducted in CAC cell lines and xenograft models.
  • Clinical significance was assessed in two independent CAC patient cohorts.

Main Results:

  • CAC tissues exhibited decreased MKNK2a and increased MKNK2b levels compared to adjacent non-tumorous tissues, correlating with KRAS mutation and tumor size.
  • Serine/arginine-rich splicing factor 1 (SRSF1) was identified as the primary splicing factor targeting MKNK2 in CAC.
  • Elevated SRPK1/2 expression or reduced PP1α activity enhanced SRSF1 phosphorylation and nuclear translocation, switching MKNK2 splicing.

Conclusions:

  • Phosphorylation and subcellular localization of SRSF1 are regulated by SRPK1/2 and PP1α in CAC cells.
  • Increased nuclear SRSF1 promotes MKNK2 splicing towards the MKNK2b isoform over MKNK2a.
  • This splicing switch consequently enhances colon adenocarcinoma cell proliferation.
Keywords:
Alternative splicingColon adenocarcinomaMKNK2SRPK1/2SRSF1

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