Abstract
Serine/arginine (SR)-rich proteins that contain RS domains and SR repeats have diverse cellular functions including transcription, polyadenylation, translation, and RNA export. The splicing factor SRSF3, also termed SRp20, is the smallest member of the SR protein family and is a known proto-oncogene. Although it is implicated in the malignant phenotypes of various cancer cells, the molecular mechanism underlying SRSF3-mediated cancer progression is still obscure. We investigated here the oncogenic functions of SRSF3 in osteosarcoma U2OS cells. Knockdown of SRSF3 inhibited proliferation, clonogenicity, and metastatic potential including migration and invasion. It also decreased the level of miR-1908 independent of its host gene FADS1. Although FADS1 was not associated with SRSF3-mediated malignant properties, overexpression of miR-1908-5p increased cell proliferation, migration, and invasion, suggesting that miR-1908-5p is responsible for the oncogenic functions of SRSF3. Knockdown of SRSF3 decreased the expression of miR-1908-5p by inhibiting transactivation of NF-κB. We observed that miR-1908-5p downregulated NF-κB inhibitor interacting Ras-like 2 (NKIRAS2), a negative regulator of the NF-κB pathway by directly binding to the 3’UTR of NKIRAS2 mRNA. Consistent with overexpression of miR-1908-5p, knockdown of NKIRAS2 diminished the expression level of IκB-β and provoked translocation of NF-κB into the nucleus where it transcriptionally activates its target genes including miR-1908-5p expression, thus elevating the proliferation and metastatic potential. Taken together, our results demonstrate that SRSF3 confers the malignant characteristics on cancer cells via the SRSF3/miR-1908-5p/NKIRAS2 axis.
Highlights
Serine/arginine (SR)-rich proteins containing at least one RNA recognition motif (RRM) and one arginine/ serine repeat (RS domain) have diverse cellular functions including transcription, polyadenylation, translation, and RNA export [1]
We found that the NFκB inhibitor interacting Ras-like 2 (NKIRAS2) gene is a novel target of miR-1908-5p and is responsible for the reinforcement of the NF-κB pathway by SRSF3/miR1908-5p/NKIRAS2
Growing evidences demonstrate that several SR proteins including SRSF1 [12], SRSF3 [4], and SRSF6 [13, 14] are classified into oncogenes that are involved in rapid proliferation and metastatic properties
Summary
Serine/arginine (SR)-rich proteins containing at least one RNA recognition motif (RRM) and one arginine/ serine repeat (RS domain) have diverse cellular functions including transcription, polyadenylation, translation, and RNA export [1]. As a critical regulator of RNA metabolism, SR proteins have received attention from oncologists. Several reports have revealed that SR proteins play critical roles in cancer progression [4]. SRSF3 (SR-rich splicing factor 3, termed SRp20) is the smallest member of the SR protein family and is known proto-oncogene [4, 5]. The oncogenic roles of SRSF3 remain largely unknown. SRSF3 has been recently reported to regulate alternative splicing and gene expression of forkhead box M1 (FoxM1), polo-like kinase 1 (PLK1), and cell division cycle 25B (Cdc25B) in U2OS osteosarcoma cells [4]. SRSF3 translationally suppresses the expression of programmed cell death 4 (PDCD4) mRNA through an interaction with 5’ untranslated region (UTR) of its mRNA [9]
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