The oncoprotein SF2/ASF promotes non-small cell lung cancer survival by enhancing survivin expression

摘要

AbstractPurpose: SF2/ASF is a splicing factor recently described as an oncoprotein. In the present work, weexamined the role of SF2/ASF in human non–small cell lung cancer (NSCLC) and analyzed the molecularmechanisms 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 theeffects on proliferation and apoptosis were evaluated. Survivin and SF2/ASF expression in lung tumorswas analyzed by Western blot and immunohistochemistry. Survival curves and log-rank test were used toidentify 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 downregulationof SF2/ASF induced apoptosis in NSCLC cell lines. This effect was associated with a reductionin the expression of survivin, an antiapoptotic protein widely upregulated in cancer. In fact, SF2/ASF specificallybound survivin mRNA and enhanced its translation, via a mammalian target of rapamycin complex1 (mTORC1) pathway-dependent mechanism, through the phosphorylation and inactivation of thetranslational repressor 4E-BP1. Moreover, SF2/ASF promoted the stability of survivin mRNA. A strongcorrelation was observed between the expression of SF2/ASF and survivin in tumor biopsies from NSCLCpatients, 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 ofSF2/ASF-related carcinogenic potential, and shows that SF2/ASF and survivin expression is involved inNSCLC progression.