期刊
BRITISH JOURNAL OF CANCER
卷 111, 期 3, 页码 477-485出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2014.342
关键词
angiogenesis; splicing; melanoma
类别
资金
- Skin Cancer Research Fund
- Richard Bright VEGF Research
- British Heart Foundation [PG11/20/28792]
- MRC [G10002073, MR/K020366/1, MR/K013157/1]
- BBSRC [BB/J007293/1]
- BBSRC [BB/J007293/1, BB/J007293/2] Funding Source: UKRI
- MRC [MR/K020366/1, MR/K013157/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J007293/2, BB/J007293/1] Funding Source: researchfish
- British Heart Foundation [PG/11/20/28792] Funding Source: researchfish
- Medical Research Council [MR/K013157/1, MR/K020366/1] Funding Source: researchfish
Background: Current therapies for metastatic melanoma are targeted either at cancer mutations driving growth (e.g., vemurafenib) or immune-based therapies (e.g., ipilimumab). Tumour progression also requires angiogenesis, which is regulated by VEGF-A, itself alternatively spliced to form two families of isoforms, pro- and anti-angiogenic. Metastatic melanoma is associated with a splicing switch to pro-angiogenic VEGF-A, previously shown to be regulated by SRSF1 phosphorylation by SRPK1. Here, we show a novel approach to preventing angiogenesis-targeting splicing factor kinases that are highly expressed in melanomas. Methods: We used RT-PCR, western blotting and immunohistochemistry to investigate SRPK1, SRSF1 and VEGF expression in tumour cells, and in vivo xenograft assays to investigate SRPK1 knockdown and inhibition in vivo. Results: In both uveal and cutaneous melanoma cell lines, SRPK1 was highly expressed, and inhibition of SRPK1 by knockdown or with pharmacological inhibitors reduced pro-angiogenic VEGF expression maintaining the production of anti-angiogenic VEGF isoforms. Both pharmacological SRPK1 inhibitors and SRPK1 knockdown reduced growth of human melanomas in vivo, but neither affected cell proliferation in vitro. Conclusions: These results suggest that selective blocking of pro-angiogenic isoforms by inhibiting splice-site selection with SRPK1 inhibitors reduces melanoma growth. SRPK1 inhibitors may be used as therapeutic agents.
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