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Exon 13 skipping mediated by HNRNPL facilitates truncated SLK-induced metastasis in hepatocellular carcinoma

Zhongxue Guo1, Peining Yu1, Liu Yu1

  • 1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Genomic Medicine, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China.

Biochemical Pharmacology
|October 4, 2025
PubMed

Insights

Alternative splicing of STE20-like serine/threonine-protein kinase (SLK) in liver cancer generates tumor-suppressing (SLK-L) and oncogenic (SLK-S) forms. Heterogeneous Nuclear Ribonucleoprotein L (HNRNPL) drives SLK-S production, promoting metastasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • RNA Splicing

Background:

  • STE20-like serine/threonine-protein kinase (SLK) is crucial for cellular signaling and exhibits functional diversity via alternative splicing in cancers.
  • Aberrant splicing of SLK contributes to tumor progression, particularly in hepatocellular carcinoma (HCC).

Purpose of the Study:

  • To investigate the role of SLK alternative splicing in HCC metastasis.
  • To elucidate the regulatory mechanism of SLK splicing and its functional consequences in HCC.

Main Methods:

  • Analysis of SLK splicing patterns in HCC tissues.
  • Identification of RNA-binding proteins involved in SLK splicing using RNA immunoprecipitation and minigene assays.
  • Functional studies using cell invasion and metastasis assays.
  • In vivo xenograft models to evaluate therapeutic targeting.

Main Results:

  • Exon 13 skipping in SLK generates antagonistic isoforms: SLK-L (tumor suppressor) and SLK-S (oncogene).
  • Splicing imbalance favoring SLK-S is associated with HCC metastasis.
  • Heterogeneous Nuclear Ribonucleoprotein L (HNRNPL) promotes SLK-S formation by recognizing SLK pre-mRNA introns.
  • SLK-S activates the Extracellular signal-Regulated Kinase (ERK) pathway, enhancing HCC cell invasion and metastasis.
  • SLK-L inhibits these metastatic processes.
  • Targeting the HNRNPL/SLK-S/Rac1/ERK pathway suppressed HCC metastasis in vivo.

Conclusions:

  • A novel RNA splicing regulatory mechanism involving HNRNPL controls SLK isoform balance in HCC metastasis.
  • SLK-S promotes HCC metastasis via the Rac1/ERK pathway, while SLK-L acts as a suppressor.
  • Modulating SLK splicing presents a potential therapeutic strategy for HCC treatment.
Keywords:
Alternative splicingCancer metastasisHNRNPLHepatocellular carcinomaSLK

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