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|The oncoprotein SF2/ASF promotes non-small cell lung cancer survival by enhancing survivin expression|
|Authors: ||Ezponda, T. (T.)|
Pajares, M.J. (María José)
Agorreta, J. (Jacqueline)
Echeveste, J.I. (José I.)
Lopez-Picazo, J.M. (José M.)
Torre, W. (Wenceslao)
Pio, R. (Rubén)
Montuenga, L.M. (Luis M.)
|Keywords: ||The Oncoprotein SF2/ASF|
Cell Lung Cancer
|Issue Date: ||3-Aug-2010|
|Publisher: ||American Association for Cancer Research|
|Publisher version: ||http://dx.doi.org/10.1158/1078-0432.CCR-10-0076|
|Citation: ||Ezponda T, Pajares MJ, Agorreta J, Echeveste JI, Lopez-Picazo JM, Torre W, et al. The oncoprotein SF2/ASF promotes non-small cell lung cancer survival by enhancing survivin expression. Clin Cancer Res 2010 Aug 15;16(16):4113-4125.|
Purpose: SF2/ASF is a splicing factor recently described as an oncoprotein. In the present work, we
examined the role of SF2/ASF in human non–small cell lung cancer (NSCLC) and analyzed the molecular
mechanisms involved in SF2/ASF-related carcinogenesis.
Experimental Design: SF2/ASF protein levels were analyzed in 81 NSCLC patients by immunohistochemistry.
SF2/ASF downregulation cellular models were generated using small interfering RNAs, and the
effects on proliferation and apoptosis were evaluated. Survivin and SF2/ASF expression in lung tumors
was analyzed by Western blot and immunohistochemistry. Survival curves and log-rank test were used to
identify the association between the expression of the proteins and time to progression.
Results: Overexpression of SF2/ASF was found in most human primary NSCLC tumors. In vitro downregulation
of SF2/ASF induced apoptosis in NSCLC cell lines. This effect was associated with a reduction
in the expression of survivin, an antiapoptotic protein widely upregulated in cancer. In fact, SF2/ASF specifically
bound survivin mRNA and enhanced its translation, via a mammalian target of rapamycin complex
1 (mTORC1) pathway-dependent mechanism, through the phosphorylation and inactivation of the
translational repressor 4E-BP1. Moreover, SF2/ASF promoted the stability of survivin mRNA. A strong
correlation was observed between the expression of SF2/ASF and survivin in tumor biopsies from NSCLC
patients, supporting the concept that survivin expression levels are controlled by SF2/ASF. Furthermore,
combined expression of these proteins was associated with prognosis.
Conclusion: This study provides novel data on the mTORC1- and survivin-dependent mechanisms of
SF2/ASF-related carcinogenic potential, and shows that SF2/ASF and survivin expression is involved in
|Permanent link: ||http://hdl.handle.net/10171/12900|
|Appears in Collections:||DA - CIMA - Oncología - Biomarcadores - Artículos de Revista|
DA - Ciencias - HAP - Artículos de revista
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