Objectives:SLFN11(Schlafen-11)enhances sensitivity to DNA-damaging agents(DDAs)and DNA damage response(DDR)inhibitors in various cancer types.However,its function in pancreatic cancer(PC)remains largely unknown.This r...Objectives:SLFN11(Schlafen-11)enhances sensitivity to DNA-damaging agents(DDAs)and DNA damage response(DDR)inhibitors in various cancer types.However,its function in pancreatic cancer(PC)remains largely unknown.This research aims to investigate the expression patterns of SLFN11 and other SLFN family members in PC and their correlation with drug sensitivity.Methods:SLFN11 expression and genetic alterations were analyzed using publicly available datasets(TCGA and GTEx).Functional studies,including cell cycle,apoptosis assays,and proliferation assays,were performed in SLFN11-knockdown and SLFN11-knockout(KO)PC cells.The relationship between SLFN11 expression and drug responsiveness was assessed via the CellMiner Cross-Database.Results:Analysis of multiple public datasets demonstrated that elevated SLFN11 expression is significantly linked with poor survival outcomes in PC,supporting its function as a predictive marker.Functional assays in PC cell lines demonstrated that SLFN11 knockdown disrupted G1 phase progression and increased apoptosis,indicating its involvement in tumor cell survival.Moreover,while elevated SLFN11 expression correlated with improved sensitivity to gemcitabine in some cell lines,CRISPR/Cas9-mediated SLFN11 knockout resulted in notable gemcitabine resistance.Importantly,this resistance was partially reversed when gemcitabine was combined with cisplatin and DDR inhibitors(Poly(ADP-ribose)polymerase(PARP),ataxia telangiectasia and Rad3 related(ATR),and Wee1 inhibitors),suggesting that SLFN11 modulates the reaction to both DNA-damaging agents and DDR-targeted therapies.Conclusion:Our findings indicate that SLFN11 plays a dual role in PC:as a prognostic marker,with high expression linked to poor clinical outcomes,and as a predictor of drug sensitivity,where its presence is associated with increased gemcitabine efficacy.However,the development of chemoresistance upon SLFN11 loss(and its partial reversal by DDR inhibitors)highlights the complexity of its function.These results underscore that SLFN11 expression alone may not fully determine gemcitabine response,and additional factors are likely involved.Further clinical validation is therefore essential to establish SLFN11 as a reliable biomarker for guiding DDR-targeted therapeutic strategies in PC.展开更多
基金supported by the 8th AstraZeneca-KHIDI(Korea Health Industry Development Institute)oncology research programa research grant was supported by AstraZeneca and by Grant No.02-2022-0020 from the Seoul National University Hospital(SNUBH)Research Fund.
文摘Objectives:SLFN11(Schlafen-11)enhances sensitivity to DNA-damaging agents(DDAs)and DNA damage response(DDR)inhibitors in various cancer types.However,its function in pancreatic cancer(PC)remains largely unknown.This research aims to investigate the expression patterns of SLFN11 and other SLFN family members in PC and their correlation with drug sensitivity.Methods:SLFN11 expression and genetic alterations were analyzed using publicly available datasets(TCGA and GTEx).Functional studies,including cell cycle,apoptosis assays,and proliferation assays,were performed in SLFN11-knockdown and SLFN11-knockout(KO)PC cells.The relationship between SLFN11 expression and drug responsiveness was assessed via the CellMiner Cross-Database.Results:Analysis of multiple public datasets demonstrated that elevated SLFN11 expression is significantly linked with poor survival outcomes in PC,supporting its function as a predictive marker.Functional assays in PC cell lines demonstrated that SLFN11 knockdown disrupted G1 phase progression and increased apoptosis,indicating its involvement in tumor cell survival.Moreover,while elevated SLFN11 expression correlated with improved sensitivity to gemcitabine in some cell lines,CRISPR/Cas9-mediated SLFN11 knockout resulted in notable gemcitabine resistance.Importantly,this resistance was partially reversed when gemcitabine was combined with cisplatin and DDR inhibitors(Poly(ADP-ribose)polymerase(PARP),ataxia telangiectasia and Rad3 related(ATR),and Wee1 inhibitors),suggesting that SLFN11 modulates the reaction to both DNA-damaging agents and DDR-targeted therapies.Conclusion:Our findings indicate that SLFN11 plays a dual role in PC:as a prognostic marker,with high expression linked to poor clinical outcomes,and as a predictor of drug sensitivity,where its presence is associated with increased gemcitabine efficacy.However,the development of chemoresistance upon SLFN11 loss(and its partial reversal by DDR inhibitors)highlights the complexity of its function.These results underscore that SLFN11 expression alone may not fully determine gemcitabine response,and additional factors are likely involved.Further clinical validation is therefore essential to establish SLFN11 as a reliable biomarker for guiding DDR-targeted therapeutic strategies in PC.
