Background
Dysregulation of alternative splicing (AS) induced by serine/arginine‐rich proteins has recently been linked to cancer metastasis. Nonetheless, as a member of the serine/arginine‐rich protein family, the involvement of SRSF11 in colorectal cancer (CRC) is unknown.
Methods
The TCGA dataset and clinical samples were used to assess SRSF11 expression levels in CRC. For SRSF11, functional experiments were conducted both in vitro and in vivo. RNA‐seq technology was used to analyze and screen SRSF11‐triggered AS events, which were then confirmed by in vivo UV crosslinking and immunoprecipitation (CLIP) and mini‐gene reporter assays. Jalview software was used to determine the preferential binding motif with relation to exon skipping (ES) events. Furthermore, coimmunoprecipitation (Co‐IP) and Phospho‐tag SDS‐PAGE experiments were used to investigate PAK5‐mediated phosphorylation regulation on SRSF11, and in vitro kinase experiments validated the interaction.
Results
In CRC, SRSF11 was discovered to be overexpressed and associated with a poor prognosis. And SRSF11 played a pro‐metastatic role in vitro and in vivo. By screening SRSF11‐regulated AS events, we identified the binding motif of SRSF11‐triggered splicing‐switching of HSPA12A AS, which specifically regulated HSPA12A AS by directly binding to a motif in exon 2. Mechanistically, the HSPA12A transcript with exon 2 retention increased N‐cadherin expression by promoting RNA stability. Furthermore, the oncogenic kinase PAK5 phosphorylated SRSF11 at serine 287, protecting it from ubiquitination degradation.
Conclusions
SRSF11 exerts pro‐metastatic effects in CRC by inhibiting the AS of HSPA12A pre‐RNA. Our findings point to SRSF11‐regulated HSPA12A splicing as a novel relationship between SRSF11‐regulated splicing and CRC metastasis and suggest a PAK5/SRSF11/HSPA12A axis as a potential therapeutic target and prognostic biomarker in CRC.
Background: Tumors frequently evade immune surveillance through multiple pathways to escape T cell recognition and destruction. Previous studies indicated that lipid metabolism alteration could affect the anti-tumor immunity of cancer cells. Nonetheless, the studies that investigated lipid metabolism-related gene for cancer immunotherapy are still few.Materials and methods: By mining the TCGA database, we screened out carnitine palmitoyltransferase-2 (CPT2), a key enzyme in the fatty acid β-oxidation (FAO) process associated with anti-tumor immunity. We then analyzed the gene expression and clinicopathological features of CPT2 using open-source platforms and databases. Molecular proteins interacting with CPT2 were also identified using web interaction tools. Subsequently, the relationship between CPT2 and survival was analyzed in cancer patients.Results: Our study revealed that CPT2 played a vital role in tumor microenvironment and immune response signaling pathways. We have also demonstrated that increased CPT2 gene expression could enhance the level of tumor immune cell infiltration. Furthermore, high CPT2 expression positively related with overall survival associated with immunotherapy. CPT2 expression was also associated with the prognosis of human cancers, suggesting that CPT2 may be a potential biomarker for predicting the efficacy of cancer immunotherapy.Conclusion: To the best of our knowledge, the relationship between CPT2 and tumor immune microenvironment was first proposed in this study. Therefore, further studies on CPT2 may provide new insights into the development of effective cancer immunotherapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.