Objective:Hepatocellular carcinoma(HCC),the main type of liver cancer,has a high morbidity and mortality,and a poor prognosis.RNA helicase DDX5,which acts as a transcriptional co-regulator,is overexpressed in most mal...Objective:Hepatocellular carcinoma(HCC),the main type of liver cancer,has a high morbidity and mortality,and a poor prognosis.RNA helicase DDX5,which acts as a transcriptional co-regulator,is overexpressed in most malignant tumors and promotes cancer cell growth.Heat shock protein 90(HSP90)is an important molecular chaperone in the conformational maturation and stabilization of numerous proteins involved in cell growth or survival.Methods:DDX5 m RNA and protein expression in surgically resected HCC tissues from 24 Asian patients were detected by quantitative real-time PCR and Western blot,respectively.The interaction of DDX5-HSP90 was determined by molecular docking,immunoprecipitation,and laser scanning confocal microscopy.The autophagy signal was detected by Western blot.The cell functions and signaling pathways of DDX5 were determined in 2 HCC cell lines.Two different murine HCC xenograft models were used to determine the function of DDX5 and the therapeutic effect of an HSP90 inhibitor.Results:HSP90 interacted directly with DDX5 and inhibited DDX5 protein degradation in the AMPK/ULK1-regulated autophagy pathway.The subsequent accumulation of DDX5 protein induced the malignant phenotype of HCC by activating theβ-catenin signaling pathway.The silencing of DDX5 or treatment with HSP90 inhibitor both blocked in vivo tumor growth in a murine HCC xenograft model.High levels of HSP90 and DDX5 protein were associated with poor prognoses.Conclusions:HSP90 interacted with DDX5 protein and subsequently protected DDX5 protein from AMPK/ULK1-regulated autophagic degradation.DDX5 and HSP90 are therefore potential therapeutic targets for HCC.展开更多
In the era of advancement,the entire world continues to remain baffled by the increased rate of progression of cancer.There has been an unending search for novel thera-peutic targets and prognostic markers to curb the...In the era of advancement,the entire world continues to remain baffled by the increased rate of progression of cancer.There has been an unending search for novel thera-peutic targets and prognostic markers to curb the oncogenic scenario.The DEAD-box RNA he-licases are a large family of proteins characterized by their evolutionary conserved D-E-A-D(Asp-Glu-Ala-Asp)domain and merit consideration in the oncogenic platform.They perform multidimensional functions in RNA metabolism and also in the pathology of cancers.Their bio-logical role ranges from ribosome biogenesis,RNA unwinding,splicing,modification of second-ary and tertiary RNA structures to acting as transcriptional coactivators/repressors of various important oncogenic genes.They also play a crucial role in accelerating oncogenesis by pro-moting cell proliferation and metastasis.DDX5(p68)is one of the archetypal members of this family of proteins and has gained a lot of attention due to its oncogenic attribute.It is found to be overexpressed in major cancer types such as colon,brain,breast,and prostate cancer.It exhibits its multifaceted nature by not only coactivating genes implicated in cancers but also mediating crosstalk across major signaling pathways in cancer.Therefore,in this review,we aim to illustrate a comprehensive overview of DEAD-box RNA helicases especially p68 by focusing on their multifaceted roles in different cancers and the various signaling pathways affected by them.Further,we have also briefly discoursed the therapeutic interventional approaches with the DEAD-box RNA helicases as the pharmacological targets for designing in-hibitors to pave way for cancer therapy.展开更多
基金funding support from the National Natural Science Foundation of China(Grant Nos.81672467,81702773,81702389,and 81672368)the Major National R&D Project(Grant Nos.2018ZX10723204,2018ZX10302205,and 2018ZX09J18107)the Natural Science Foundation of Beijing(Grant No.7172207)。
文摘Objective:Hepatocellular carcinoma(HCC),the main type of liver cancer,has a high morbidity and mortality,and a poor prognosis.RNA helicase DDX5,which acts as a transcriptional co-regulator,is overexpressed in most malignant tumors and promotes cancer cell growth.Heat shock protein 90(HSP90)is an important molecular chaperone in the conformational maturation and stabilization of numerous proteins involved in cell growth or survival.Methods:DDX5 m RNA and protein expression in surgically resected HCC tissues from 24 Asian patients were detected by quantitative real-time PCR and Western blot,respectively.The interaction of DDX5-HSP90 was determined by molecular docking,immunoprecipitation,and laser scanning confocal microscopy.The autophagy signal was detected by Western blot.The cell functions and signaling pathways of DDX5 were determined in 2 HCC cell lines.Two different murine HCC xenograft models were used to determine the function of DDX5 and the therapeutic effect of an HSP90 inhibitor.Results:HSP90 interacted directly with DDX5 and inhibited DDX5 protein degradation in the AMPK/ULK1-regulated autophagy pathway.The subsequent accumulation of DDX5 protein induced the malignant phenotype of HCC by activating theβ-catenin signaling pathway.The silencing of DDX5 or treatment with HSP90 inhibitor both blocked in vivo tumor growth in a murine HCC xenograft model.High levels of HSP90 and DDX5 protein were associated with poor prognoses.Conclusions:HSP90 interacted with DDX5 protein and subsequently protected DDX5 protein from AMPK/ULK1-regulated autophagic degradation.DDX5 and HSP90 are therefore potential therapeutic targets for HCC.
基金supported by the Department of Science and Technology(Nano Mission:DST/NM/NT/2018/105(G),SERB:EMR/2017/000992/HS&EMR/2017/001183),CSIR(FBR Project#31-2(274)2020-21),Govt.of India.
文摘In the era of advancement,the entire world continues to remain baffled by the increased rate of progression of cancer.There has been an unending search for novel thera-peutic targets and prognostic markers to curb the oncogenic scenario.The DEAD-box RNA he-licases are a large family of proteins characterized by their evolutionary conserved D-E-A-D(Asp-Glu-Ala-Asp)domain and merit consideration in the oncogenic platform.They perform multidimensional functions in RNA metabolism and also in the pathology of cancers.Their bio-logical role ranges from ribosome biogenesis,RNA unwinding,splicing,modification of second-ary and tertiary RNA structures to acting as transcriptional coactivators/repressors of various important oncogenic genes.They also play a crucial role in accelerating oncogenesis by pro-moting cell proliferation and metastasis.DDX5(p68)is one of the archetypal members of this family of proteins and has gained a lot of attention due to its oncogenic attribute.It is found to be overexpressed in major cancer types such as colon,brain,breast,and prostate cancer.It exhibits its multifaceted nature by not only coactivating genes implicated in cancers but also mediating crosstalk across major signaling pathways in cancer.Therefore,in this review,we aim to illustrate a comprehensive overview of DEAD-box RNA helicases especially p68 by focusing on their multifaceted roles in different cancers and the various signaling pathways affected by them.Further,we have also briefly discoursed the therapeutic interventional approaches with the DEAD-box RNA helicases as the pharmacological targets for designing in-hibitors to pave way for cancer therapy.
