期刊
ONCOTARGET
卷 8, 期 5, 页码 8342-8355出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14184
关键词
SRSF3; FADS1; miR-1908-5p; NF-kappa B; NKIRAS2
资金
- Mid-career Research Program through National Research Foundation (NRF) - Ministry of Science, ICT, and Future Planning, Republic of Korea [2014R1A2A1A11053130]
- grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)
- National Research Foundation of Korea - Korea government (MSIP) [MRC-2015-009070]
- Ministry of Health & Welfare, Republic of Korea [HI14C3418]
- National Research Foundation of Korea [2014R1A2A1A11053130] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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-kappa B. We observed that miR-1908-5p downregulated NF-kappa B inhibitor interacting Ras-like 2 (NKIRAS2), a negative regulator of the NF-kappa B 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 I kappa B-beta and provoked translocation of NF-kappa B 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.
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