ABSTRACT
Intersectin 1 (ITSN1) contains two isoforms: ITSN1-S and ITSN1-L, which are highly regulated by alternative splicing. Our previous results showed that the two isoforms of ITSN1 displayed opposite functions: ITSN1-S promoted glioma development, while ITSN1-L exerted an inhibitory role in glioma progression. In this study, our transcriptome analysis using a large glioma cohort indicated that the ratio of ITSN1-S/ITSN1-L was positively correlated with glioma grading and poor prognosis. We identified the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) as an ITSN1 pre-mRNA interaction protein through RNA pull-down assay and RNA immunoprecipitation assay. Knockdown of PTBP1 decreased the ratio of ITSN1-S/ITSN1-L. Minigene reporter assay and mutation analyses further confirmed PTBP1 targeted polypyrimidine sequences on ITSN1 exon 30 (TTGCACTTCAGTATTTT) and promoted the inclusion of ITSN1 exon 30. Subsequently, silencing PTBP1 inhibited glioma cell proliferation, migration, and invasion by down-regulating the ratio of ITSN1-S/ITSN1-L. Taken together, our study provides a novel mechanism that PTBP1 modulates the alternative splicing of ITSN1 and promotes glioma proliferation and motility by up-regulating the ratio of ITSN1-S/ITSN1-L, thereby highlighting that PTBP1 may be an attractive therapeutic target for gliomas.
Subject(s)
Alternative Splicing , Glioma , Adaptor Proteins, Vesicular Transport , Alternative Splicing/genetics , Cell Movement/genetics , Glioma/genetics , Glioma/metabolism , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Humans , Polypyrimidine Tract-Binding Protein/genetics , Polypyrimidine Tract-Binding Protein/metabolism , Protein Isoforms/metabolism , RNA Precursors/metabolism , RNA-Binding Proteins/metabolismABSTRACT
Background: IGSF10 is a member of the immunoglobulin superfamily. Over the previous decade, growing proof has validated definitive correlations between individuals of the immunoglobulin superfamily and human diseases. However, the function of IGSF10 in pan-cancer stays unclear. We aimed to analyze the immunological and prognostic value of IGSF10 in pan-cancer. Methods: We utilized a vary of bioinformatic ways to inspect the function of IGSF10 in pan-cancer, including its correlation with prognosis, immune cell infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), DNA methyltransferases, genetic alteration, drug sensitivity, etc. Results: We noticed low expression of IGSF10 in most cancer types. IGSF10 expression in tumor samples correlates with prognosis in most cancers. In most cancer types, IGSF10 expression was strongly related to immune cells infiltration, immune checkpoints, immune modulators, TMB, MSI, MMR, and DNA methyltransferases, among others. Functional enrichment analyses indicated that IGSF10 expression was involved in lymphocyte differentiation, cell molecules adhesion, etc. Furthermore, low IGSF10 expression could increase the drug sensitivity of many drugs. Conclusion: IGSF10 could serve as a novel prognostic marker and attainable immunotherapy target for several malignancies.
