TMPRSS2 plays a crucial role in facilitating the entry of both the influenza virus and the SARSCoV-2 coronavirus into host cells.Recent studies have identified a guanine-rich sequence in the proximal promoter region o...TMPRSS2 plays a crucial role in facilitating the entry of both the influenza virus and the SARSCoV-2 coronavirus into host cells.Recent studies have identified a guanine-rich sequence in the proximal promoter region of the TMPRSS2 gene,which can form G-quadruplex structures(TMPRSS2-G4s)that are potential targets for small molecules to inhibit TMPRSS2 expression.However,the structural details of the major TMPRSS2-G4 and its complex with small molecules remain unknown,hindering the development of antiviral drugs targeting TMPRSS2-Gquadruplexes(G4s).This study reports the first high-resolution nuclear magnetic resonance(NMR)solution structure of the major TMPRSS2-G4,which consists of a three-tetrad core parallel-stranded G4.Both 3′and 5′flanking regions form well-defined capping structures stabilized by multiple hydrogen bonds.Importantly,we found that berberine,an antiviral alkaloid,strongly binds to the major TMPRSS2-G4 and determined its binding complex structure with TMPRSS2-G4 at a 2∶1 binding stoichiometry.Each berberine molecule recruits an adjacent flanking residue,forming a coplanar structure superimposed on two outer G-tetrads.Moreover,we demonstrated that the major TMPRSS2-G4 can stably form within a longer deoxyribonucleic acid(DNA)context and be targeted by small molecules to inhibit DNA polymerase activity.Overall,this study provides structural insights into the recognition mechanism of small molecules by the major TMPRSS2-G4 and may facilitate the development of novel antiviral therapeutics targeting TMPRSS2-G4.展开更多
The incidence of prostate cancer （PCa） is rising steadily among males in many countries. Serum prostate-specific antigen （PSA） is widely applied to clinical diagnosis and screening of PCa. However, the so-called g...The incidence of prostate cancer （PCa） is rising steadily among males in many countries. Serum prostate-specific antigen （PSA） is widely applied to clinical diagnosis and screening of PCa. However, the so-called grey area of PSA levels 4.0-10.0 ng/mL has a low specificity of 25-40% resulting in a high rate of negative biopsy and overtreatment. So in order to treat PCa patients in early stage, there is an urgent need for new biomarkers in PCa diagnosis. The PCA3 gene, a non-coding RNA （ncRNA） that is highly expressed in prostate cancer （PCa） cells, has been identified as a molecular biomarkers to detect PCa, of which PCA3 has already under clinical application. PCA3 is strongly overexpressed in malignant prostate tissue compared to benign or normal adjacent one. Newly, PCA3 is considered to be a promising biomarker in clinical diagnosis and targeted therapy. The diagnostic significance of PCA3, however, is awaiting further researches. Moreover, it has been demonstrated recently that TMPRSS2-ERG gene fusion is identified as the predominant genetic change in patients diagnosed with PCa. Recent study revealed that combination of the PC43 and TMPRSS2-ERG gene fusion test optimizes PCa detection compared with that of single biomarker, which would lead to a considerable reduction of the number of prostate biopsies. In this review, we focused on the potential use of PCA3 and TMPRSS2-ERG gene fusion detection in the diagnosis of PCa.展开更多
Fusion between the transmembrane protease serine 2 and v-ets erythroblastosis virus E26 oncogene homolog(TMPRSS2-ERG fusion)is a common genetic alteration in prostate cancer among Western populations and has been sugg...Fusion between the transmembrane protease serine 2 and v-ets erythroblastosis virus E26 oncogene homolog(TMPRSS2-ERG fusion)is a common genetic alteration in prostate cancer among Western populations and has been suggested as playing a role in tumorigenesis and progression of prostate cancer.However,the prevalence of TMPRSS2-ERG fusion differs among different ethnic groups,and contradictory results have been reported in Asian patients.We aim to evaluate the prevalence and significance of TMPRSS2-ERG fusion as a molecular subtyping and prognosis indicator of prostate cancer in Asians.We identified the fusion status in 669 samples from prostate biopsy and radical prostatectomy by fluorescence in situ hybridization and/or immunohistochemistry in China.We examined the association of TMPRSS2-ERG fusion with clinicopathological characteristics and biochemical recurrence by Chi-square test and Kaplan–Meier analysis.Finally,a systematic review was performed to investigate the positive rate of the fusion in Asian prostate cancer patients.McNemar’s test was employed to compare the positive rates of TMPRSS2-ERG fusion detected using different methods.The positive rates of TMPRSS2-ERG fusion were 16%in our samples and 27%in Asian patients.In our samples,9.4%and 19.3%of cases were recognized as fusion positive by fluorescence in situ hybridization and immunohistochemistry,respectively.No significant association between the fusion and clinical parameters was observed.TMPRSS2-ERG fusion is not a frequent genomic alteration among Asian prostate cancer patients and has limited significance in clinical practices in China.Besides ethnic difference,detection methods potentially influence the results showing a positive rate of TMPRSS2-ERG fusion.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82322065,82173707,82204241)the Innovation and Entrepreneurship(Shuangchuang)Program of Jiang-su Province(2024)+3 种基金the Natural Science Foundation of Jiangsu Province(No.BK20221039)the Project Program of State Key Laboratory of Natural Medicines(China Pharmaceutical University,No.SKLNMZZ2024JS12)the Fundamental Research Funds for the Central Universities(No.2632025ZD06)the Scientific Research Foundation for High-level Faculty,China Pharmaceutical University(No.3150020065)。
文摘TMPRSS2 plays a crucial role in facilitating the entry of both the influenza virus and the SARSCoV-2 coronavirus into host cells.Recent studies have identified a guanine-rich sequence in the proximal promoter region of the TMPRSS2 gene,which can form G-quadruplex structures(TMPRSS2-G4s)that are potential targets for small molecules to inhibit TMPRSS2 expression.However,the structural details of the major TMPRSS2-G4 and its complex with small molecules remain unknown,hindering the development of antiviral drugs targeting TMPRSS2-Gquadruplexes(G4s).This study reports the first high-resolution nuclear magnetic resonance(NMR)solution structure of the major TMPRSS2-G4,which consists of a three-tetrad core parallel-stranded G4.Both 3′and 5′flanking regions form well-defined capping structures stabilized by multiple hydrogen bonds.Importantly,we found that berberine,an antiviral alkaloid,strongly binds to the major TMPRSS2-G4 and determined its binding complex structure with TMPRSS2-G4 at a 2∶1 binding stoichiometry.Each berberine molecule recruits an adjacent flanking residue,forming a coplanar structure superimposed on two outer G-tetrads.Moreover,we demonstrated that the major TMPRSS2-G4 can stably form within a longer deoxyribonucleic acid(DNA)context and be targeted by small molecules to inhibit DNA polymerase activity.Overall,this study provides structural insights into the recognition mechanism of small molecules by the major TMPRSS2-G4 and may facilitate the development of novel antiviral therapeutics targeting TMPRSS2-G4.
基金supported by the following grants: National Natural Science Foundation of China No. 31571413, 31201037 (to Dr. Yu) and No. 81570180, 81072103 (to Dr. Wang) from the National Natural Science Foundation of China
文摘The incidence of prostate cancer （PCa） is rising steadily among males in many countries. Serum prostate-specific antigen （PSA） is widely applied to clinical diagnosis and screening of PCa. However, the so-called grey area of PSA levels 4.0-10.0 ng/mL has a low specificity of 25-40% resulting in a high rate of negative biopsy and overtreatment. So in order to treat PCa patients in early stage, there is an urgent need for new biomarkers in PCa diagnosis. The PCA3 gene, a non-coding RNA （ncRNA） that is highly expressed in prostate cancer （PCa） cells, has been identified as a molecular biomarkers to detect PCa, of which PCA3 has already under clinical application. PCA3 is strongly overexpressed in malignant prostate tissue compared to benign or normal adjacent one. Newly, PCA3 is considered to be a promising biomarker in clinical diagnosis and targeted therapy. The diagnostic significance of PCA3, however, is awaiting further researches. Moreover, it has been demonstrated recently that TMPRSS2-ERG gene fusion is identified as the predominant genetic change in patients diagnosed with PCa. Recent study revealed that combination of the PC43 and TMPRSS2-ERG gene fusion test optimizes PCa detection compared with that of single biomarker, which would lead to a considerable reduction of the number of prostate biopsies. In this review, we focused on the potential use of PCA3 and TMPRSS2-ERG gene fusion detection in the diagnosis of PCa.
基金This research was funded by the National Nature Science Foundation Youth Project(Grant No.81702514)the National Natural Science Foundation of China(Grant No.81430058)the Clinical Research Project of Shanghai Municipal Commission of Health and Family Planning(Grant No.20184Y0130).
文摘Fusion between the transmembrane protease serine 2 and v-ets erythroblastosis virus E26 oncogene homolog(TMPRSS2-ERG fusion)is a common genetic alteration in prostate cancer among Western populations and has been suggested as playing a role in tumorigenesis and progression of prostate cancer.However,the prevalence of TMPRSS2-ERG fusion differs among different ethnic groups,and contradictory results have been reported in Asian patients.We aim to evaluate the prevalence and significance of TMPRSS2-ERG fusion as a molecular subtyping and prognosis indicator of prostate cancer in Asians.We identified the fusion status in 669 samples from prostate biopsy and radical prostatectomy by fluorescence in situ hybridization and/or immunohistochemistry in China.We examined the association of TMPRSS2-ERG fusion with clinicopathological characteristics and biochemical recurrence by Chi-square test and Kaplan–Meier analysis.Finally,a systematic review was performed to investigate the positive rate of the fusion in Asian prostate cancer patients.McNemar’s test was employed to compare the positive rates of TMPRSS2-ERG fusion detected using different methods.The positive rates of TMPRSS2-ERG fusion were 16%in our samples and 27%in Asian patients.In our samples,9.4%and 19.3%of cases were recognized as fusion positive by fluorescence in situ hybridization and immunohistochemistry,respectively.No significant association between the fusion and clinical parameters was observed.TMPRSS2-ERG fusion is not a frequent genomic alteration among Asian prostate cancer patients and has limited significance in clinical practices in China.Besides ethnic difference,detection methods potentially influence the results showing a positive rate of TMPRSS2-ERG fusion.
