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

Abstract

The STE20-like serine/threonine-protein kinase (SLK), a key regulator of cellular signaling, exhibits remarkable functional heterogeneity through alternative splicing in various cancers. This study investigates the splicing regulation of SLK in hepatocellular carcinoma (HCC), revealing that exon 13 skipping generates functionally antagonistic isoforms: the long isoform (SLK-L, containing exon 13) acts as a tumor suppressor, whereas the short isoform (SLK-S, lacking exon 13) displays oncogenic properties. This splicing imbalance is particularly prominent during HCC metastasis, underscoring the critical role of SLK splicing regulation in tumor progression. Mechanistically, the RNA-binding protein Heterogeneous Nuclear Ribonucleoprotein L (HNRNPL) functions as a "molecular scissor" that specifically recognizes introns 12 and 13 of SLK pre-mRNA to precisely promote SLK-S production. Functional assays demonstrate that SLK-S enhances HCC cell invasion and metastasis by activating the Extracellular signal-Regulated Kinase (ERK) signaling pathway, while SLK-L suppresses these effects through pathway inhibition. Notably, in vivo targeting of the HNRNPL/SLK-S/Rac family small GTPase 1 (Rac1)/ERK axis effectively inhibits HCC metastasis. These findings not only elucidate a novel RNA splicing regulatory mechanism in HCC metastasis but also provide a theoretical foundation and potential therapeutic targets for developing precision treatments based on SLK splicing modulation.