SRSF10-mediated IL1RAP alternative splicing regulates cervical cancer oncogenesis via mIL1RAP-NF-κB-CD47 axis

Abstract

High-risk human papillomavirus oncoproteins E6 and E7 are the major etiological factors of cervical cancer but are insufficient for malignant transformation of cervical cancer. Dysregulated alternative splicing, mainly ascribed to aberrant splicing factor levels and activities, contributes to most cancer hallmarks. However, do E6 and E7 regulate the expression of splicing factors? Does alternative splicing acts as an “accomplice” of E6E7 to promote cervical cancer progression? Here, we identified that the splicing factor SRSF10, which promotes tumorigenesis of cervix, was upregulated by E6E7 via E2F1 transcriptional activation. SRSF10 modulates the alternate terminator of interleukin-1 receptor accessory protein exon 13 to increase production of the membrane form of interleukin-1 receptor accessory protein. SRSF10-mediated mIL1RAP upregulates the expression of the “don’t eat me” signal CD47 to inhibit macrophage phagocytosis by promoting nuclear factor-κB activation, which is pivotal in inflammatory, immune, and tumorigenesis processes. Altogether, these data reveal a close relationship among HPV infection, alternative splicing and tumor immune evasion, and also suggests that the SRSF10-mIL1RAP-CD47 axis could be an attractive therapeutic target for the treatment of cervical cancer.

IGF2BP3 May Contributes to Lung Tumorigenesis by Regulating the Alternative Splicing of PKM

“…Therefore, understanding the mechanisms by which RBP regulate cancer development is critical to reducing its morbidity and mortality. Since alternative splicing (AS) is a mechanism of post-transcriptional RNA processing that affords a significant evolutionary superiority by producing multiple mRNAs during pre-mRNA maturation, resulting in the production of multiple proteins with different functions from a single gene ( Le et al, 2015 ; Brander et al, 2018 ; Liu et al, 2018 ). Accordingly, we hypothesized IGF2BP3 may also play a role in alternative splicing.…”

Identification of Long Noncoding RNAs as Predictors of Survival in Triple-Negative Breast Cancer Based on Network Analysis

“…BioMed Research International mediate the coexpression network (Figure 9(b)). SRSF10, as a splicing factor, has been found playing important roles in colon and cervical cancer oncogenesis by mediating alternative splicing [56,57]. Whether SRSF10 plays a similar role in breast cancer or not requires more experimental confirmation.…”

The SRSF3-MBNL1-Acin1 circuit constitutes an emerging axis to lessen DNA fragmentation in colorectal cancer via an alternative splicing mechanism

“…In mammalian cells, precise synergism of the spliceosome, transregulators, and corresponding cis- elements specifies spatiotemporal AS events which determine cellular functions [36] . Altered AS events are therefore considered a hallmark of carcinogenesis and are relevant to carcinogenic signatures [37] . In this study, distinct expressions or splicing profiles of MBNL1 and Acin1 transcripts were disclosed using whole-transcriptome analyses, which comprised a CRC-associated circuit involved in DNA fragmentation.…”