BACKGROUND Colonization with Helicobacter pylori(H.pylori)has a strong correlation with gastric cancer,and the virulence factor CagA is implicated in carcinogenesis.Studies have been conducted using medicinal plants w...BACKGROUND Colonization with Helicobacter pylori(H.pylori)has a strong correlation with gastric cancer,and the virulence factor CagA is implicated in carcinogenesis.Studies have been conducted using medicinal plants with the aim of eliminating the pathogen;however,the possibility of blocking H.pylori-induced cell differentiation to prevent the onset and/or progression of tumors has not been addressed.This type of study is expensive and time-consuming,requiring in vitro and/or in vivo tests,which can be solved using bioinformatics.Therefore,prospective computational analyses were conducted to assess the feasibility of interaction between phenolic compounds from medicinal plants and the CagA oncoprotein.AIM To perform a computational prospecting of the interactions between phenolic compounds from medicinal plants and the CagA oncoprotein of H.pylori.METHODS In this in silico study,the structures of the phenolic compounds(ligands)kaempferol,myricetin,quercetin,ponciretin(flavonoids),and chlorogenic acid(phenolic acid)were selected from the PubChem database.These phenolic compounds were chosen based on previous studies that suggested medicinal plants as non-drug treatments to eliminate H.pylori infection.The three-dimensional structure model of the CagA oncoprotein of H.pylori(receptor)was obtained through molecular modeling using computational tools from the I-Tasser platform,employing the threading methodology.The primary sequence of CagA was sourced from GenBank(BAK52797.1).A screening was conducted to identify binding sites in the structure of the CagA oncoprotein that could potentially interact with the ligands,utilizing the GRaSP online platform.Both the ligands and receptor were prepared for molecular docking using AutoDock Tools 4(ADT)software,and the simulations were carried out using a combination of ADT and AutoDock Vina v.1.2.0 software.Two sets of simulations were performed:One involving the central region of CagA with phenolic compounds,and another involving the carboxy-terminus region of CagA with phenolic compounds.The receptor-ligand complexes were then analyzed using PyMol and BIOVIA Discovery Studio software.RESULTS The structure model obtained for the CagA oncoprotein exhibited high quality(C-score=0.09)and was validated using parameters from the MolProbity platform.The GRaSP online platform identified 24 residues(phenylalanine and leucine)as potential binding sites on the CagA oncoprotein.Molecular docking simulations were conducted with the three-dimensional model of the CagA oncoprotein.No complexes were observed in the simulations between the carboxy-terminus region of CagA and the phenolic compounds;however,all phenolic compounds interacted with the central region of the oncoprotein.Phenolic compounds and CagA exhibited significant affinity energy(-7.9 to-9.1 kcal/mol):CagA/kaempferol formed 28 chemical bonds,CagA/myricetin formed 18 chemical bonds,CagA/quercetin formed 16 chemical bonds,CagA/ponciretin formed 13 chemical bonds,and CagA/chlorogenic acid formed 17 chemical bonds.Although none of the phenolic compounds directly bound to the amino acid residues of the K-Xn-R-X-R membrane binding motif,all of them bound to residues,mostly positively or negatively charged,located near this region.CONCLUSION In silico,the tested phenolic compounds formed stable complexes with CagA.Therefore,they could be tested in vitro and/or in vivo to validate the findings,and to assess interference in CagA/cellular target interactions and in the oncogenic differentiation of gastric cells.展开更多
目的:探讨原癌蛋白18(Oncoprotein 18,Op18)在肝癌侵袭转移过程中的作用机制.方法:采用R N A干扰,抑制人肝癌细胞HCCLM3中Op18的表达,RT-PCR和Westernb l o t评价干扰效率;通过细胞粘附分析、体外Transwell分析法检测Op18表达缺失后对HC...目的:探讨原癌蛋白18(Oncoprotein 18,Op18)在肝癌侵袭转移过程中的作用机制.方法:采用R N A干扰,抑制人肝癌细胞HCCLM3中Op18的表达,RT-PCR和Westernb l o t评价干扰效率;通过细胞粘附分析、体外Transwell分析法检测Op18表达缺失后对HCCLM3细胞粘附、运动和侵袭能力的改变;RT-PCR和免疫组织化学分别在48例未伴转移的肝癌组织和48例伴转移的肝癌组织中解析Op18表达与肝癌侵袭转移的关系.结果:RT-PCR和Western blot结果显示:在HCCLM3细胞中行RNAi后Op18表达被有效抑制,抑制率达到80%以上;Op18表达缺失后,在不同时间点(20、40和60 min)实验组细胞粘附能力(0.616±0.057、0.740±0.0713和1.001±0.083)较阴性对照组(0.944±0.068、1.196±0.115和1.441±0.053)明显下降(P<0.05);Transwell实验结果提示:经RNAi后实验组细胞运动、侵袭能力(运动:0.145±0.011,侵袭0.127±0.008)较阴性对照组(运动:0.206±0.008,侵袭:0.168±0.012)显著降低(P<0.01);分别在伴转移和未伴转移的肝癌组织中检测Op18的表达,RT-PCR(Op18与GAPDH相对比值:0.560±0.128vs 0.414±0.086)和IHC(积分吸光度值为:624.771±100.032 vs 413.786±71.833)实验结果均提示Op18在伴转移的肝癌组织中的表达更高(P<0.01).结论:Op18在肝癌的侵袭转移过程中发挥重要作用.展开更多
Lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the most common extranodal B cell tumor and accounts for 8% of non-Hodgkin’s lymphomas. Gastric MALT lymphoma is the best-studied example an...Lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the most common extranodal B cell tumor and accounts for 8% of non-Hodgkin’s lymphomas. Gastric MALT lymphoma is the best-studied example and is a prototypical neoplasm that occurs in the setting of chronic inflammation brought on by persistent infection or autoimmune disease. Cytogenetic abnormalities are commonly acquired during the course of disease and the most common is chromosomal translocation t(11;18)(q21;q21), which creates the API2-MALT1 fusion oncoprotein. t(11;18)-positive lymphomas can be clinically aggressive and have a higher rate of dissemination than t(11;18)-negative tumors. Many cancers, including MALT lymphomas, characteristically exhibit deregulated over-activation of cellular survival pathways, such as the nuclear factor-κB (NF-κB) pathway. Molecular characterization of API2-MALT1 has revealed it to be a potent activator of NF-κB, which is required for API2-MALT1-induced cellular transformation, however the mechanisms by which API2-MALT1 exerts these effects are only recently becoming apparent. The API2 moiety of the fusion binds tumor necrosis factor (TNF) receptor associated factor (TRAF) 2 and receptor interacting protein 1 (RIP1), two proteins essential for TNF receptor-induced NF-κB activation. By effectively mimicking ligand-bound TNF receptor, API2-MALT1 promotes TRAF2-dependent ubiquitination of RIP1, which then acts as a scaffold for nucleating and activating the canonical NF-κB machinery. Activation occurs, in part, through MALT1 moiety-dependent recruitment of TRAF6, which can directly modify NF-κB essential modulator, the principal downstream regulator of NF-κB. While the intrinsic MALT1 protease catalytic activity is dispensable for this canonical NF-κB signaling, it is critical for non-canonical NF-κB activation. In this regard, API2-MALT1 recognizes NF-κB inducing kinase (NIK), the essential upstream regulator of non-canonical NF-κB, and cleaves it to generate a stable, constitutively active fragment. Thus, API2-MALT1 harnesses multiple unique pathways to achieve deregulated NF-κB activation. Emerging data from our group and others have also detailed additional gain-of-function activities of API2-MALT1 that extend beyond NF-κB activation. Specifically, API2-MALT1 recruits and subverts multiple other signaling factors, including LIM domain and actin-binding protein 1 (LIMA1) and Smac/DIABLO. Like NIK, LIMA1 represents a unique substrate for API2-MALT1 protease activity, but unlike NIK, its cleavage sets in motion a major NF-κB-independent pathway for promoting oncogenesis. In this review, we highlight the most recent results characterizing these unique and diverse gain-of-function activities of API2-MALT1 and how they contribute to lymphomagenesis.展开更多
A comparative molecular dynamics (MD) simulation study was performed on the p53 oncoprotein to investigate the effect of the Arg273His (R273H) mutation on the p53→DNA Binding Domain (DBD). The two p53 dimer structure...A comparative molecular dynamics (MD) simulation study was performed on the p53 oncoprotein to investigate the effect of the Arg273His (R273H) mutation on the p53→DNA Binding Domain (DBD). The two p53 dimer structures of the wild-type and mutant Arg273His (R273H) were simulated with the same thermodynamic and environmental parameters. The obtained results demonstrate that the induced Arg273His mutation has a considerable effect on the p53→DNA close contact interaction and changes the picture of hydrogen formation. The Arg273His mutation, in some cases, destroys the existing native hydrogen bond, but, in other cases, forms a strong p53→DNA hydrogen bond, which is not proper for the native protein. The MD simulation results illustrate some molecular mechanism of the conformational changes of the Arg273His key amino acid residue in the p53→DNA binding domain, which might be important for the understanding of the physiological functioning of the p53 protein and the origin of cancer.展开更多
It is first reported here that estrogen occupied receptor(EoR)and progesterone occupied receptor (RoR)expressed in cancerous tissues (59.57% and 82.98% respectively)and morphologically normal epithlium(50 77.78% and ...It is first reported here that estrogen occupied receptor(EoR)and progesterone occupied receptor (RoR)expressed in cancerous tissues (59.57% and 82.98% respectively)and morphologically normal epithlium(50 77.78% and 70-88.89%respectively) in nasoplharyngeal carcinomas(NPCs)with insignificant difference(P>0.05).Positive rates of EoR and PoR increased greatly in clinical stage Ⅲ and Ⅳ, compared with in Ⅱ(P<0.05), and exhibited insignificant difference between female cases and male ones(P>0.05).Positive rate of C-erbB-2 was 19.15% in cancerous cells, and 9.68% in stage Ⅲand 66.67% in Ⅳin NPCs(P<0.05).Significant difference of C-erbB-2expression was observed between bilateral cervical lymph node metastasis(BCLM)and unilateral ones(P<0.05)but not for EoR or PoR(P>0.05)These findings suggest that EoR or PoR may be correlated with aggravation but not genesis and node metastasis in NPCs and that C-erbB-2may be correlated with aggravation and promotion of formation of node metastasis in NPCs.展开更多
文摘BACKGROUND Colonization with Helicobacter pylori(H.pylori)has a strong correlation with gastric cancer,and the virulence factor CagA is implicated in carcinogenesis.Studies have been conducted using medicinal plants with the aim of eliminating the pathogen;however,the possibility of blocking H.pylori-induced cell differentiation to prevent the onset and/or progression of tumors has not been addressed.This type of study is expensive and time-consuming,requiring in vitro and/or in vivo tests,which can be solved using bioinformatics.Therefore,prospective computational analyses were conducted to assess the feasibility of interaction between phenolic compounds from medicinal plants and the CagA oncoprotein.AIM To perform a computational prospecting of the interactions between phenolic compounds from medicinal plants and the CagA oncoprotein of H.pylori.METHODS In this in silico study,the structures of the phenolic compounds(ligands)kaempferol,myricetin,quercetin,ponciretin(flavonoids),and chlorogenic acid(phenolic acid)were selected from the PubChem database.These phenolic compounds were chosen based on previous studies that suggested medicinal plants as non-drug treatments to eliminate H.pylori infection.The three-dimensional structure model of the CagA oncoprotein of H.pylori(receptor)was obtained through molecular modeling using computational tools from the I-Tasser platform,employing the threading methodology.The primary sequence of CagA was sourced from GenBank(BAK52797.1).A screening was conducted to identify binding sites in the structure of the CagA oncoprotein that could potentially interact with the ligands,utilizing the GRaSP online platform.Both the ligands and receptor were prepared for molecular docking using AutoDock Tools 4(ADT)software,and the simulations were carried out using a combination of ADT and AutoDock Vina v.1.2.0 software.Two sets of simulations were performed:One involving the central region of CagA with phenolic compounds,and another involving the carboxy-terminus region of CagA with phenolic compounds.The receptor-ligand complexes were then analyzed using PyMol and BIOVIA Discovery Studio software.RESULTS The structure model obtained for the CagA oncoprotein exhibited high quality(C-score=0.09)and was validated using parameters from the MolProbity platform.The GRaSP online platform identified 24 residues(phenylalanine and leucine)as potential binding sites on the CagA oncoprotein.Molecular docking simulations were conducted with the three-dimensional model of the CagA oncoprotein.No complexes were observed in the simulations between the carboxy-terminus region of CagA and the phenolic compounds;however,all phenolic compounds interacted with the central region of the oncoprotein.Phenolic compounds and CagA exhibited significant affinity energy(-7.9 to-9.1 kcal/mol):CagA/kaempferol formed 28 chemical bonds,CagA/myricetin formed 18 chemical bonds,CagA/quercetin formed 16 chemical bonds,CagA/ponciretin formed 13 chemical bonds,and CagA/chlorogenic acid formed 17 chemical bonds.Although none of the phenolic compounds directly bound to the amino acid residues of the K-Xn-R-X-R membrane binding motif,all of them bound to residues,mostly positively or negatively charged,located near this region.CONCLUSION In silico,the tested phenolic compounds formed stable complexes with CagA.Therefore,they could be tested in vitro and/or in vivo to validate the findings,and to assess interference in CagA/cellular target interactions and in the oncogenic differentiation of gastric cells.
文摘目的:探讨原癌蛋白18(Oncoprotein 18,Op18)在肝癌侵袭转移过程中的作用机制.方法:采用R N A干扰,抑制人肝癌细胞HCCLM3中Op18的表达,RT-PCR和Westernb l o t评价干扰效率;通过细胞粘附分析、体外Transwell分析法检测Op18表达缺失后对HCCLM3细胞粘附、运动和侵袭能力的改变;RT-PCR和免疫组织化学分别在48例未伴转移的肝癌组织和48例伴转移的肝癌组织中解析Op18表达与肝癌侵袭转移的关系.结果:RT-PCR和Western blot结果显示:在HCCLM3细胞中行RNAi后Op18表达被有效抑制,抑制率达到80%以上;Op18表达缺失后,在不同时间点(20、40和60 min)实验组细胞粘附能力(0.616±0.057、0.740±0.0713和1.001±0.083)较阴性对照组(0.944±0.068、1.196±0.115和1.441±0.053)明显下降(P<0.05);Transwell实验结果提示:经RNAi后实验组细胞运动、侵袭能力(运动:0.145±0.011,侵袭0.127±0.008)较阴性对照组(运动:0.206±0.008,侵袭:0.168±0.012)显著降低(P<0.01);分别在伴转移和未伴转移的肝癌组织中检测Op18的表达,RT-PCR(Op18与GAPDH相对比值:0.560±0.128vs 0.414±0.086)和IHC(积分吸光度值为:624.771±100.032 vs 413.786±71.833)实验结果均提示Op18在伴转移的肝癌组织中的表达更高(P<0.01).结论:Op18在肝癌的侵袭转移过程中发挥重要作用.
文摘Lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the most common extranodal B cell tumor and accounts for 8% of non-Hodgkin’s lymphomas. Gastric MALT lymphoma is the best-studied example and is a prototypical neoplasm that occurs in the setting of chronic inflammation brought on by persistent infection or autoimmune disease. Cytogenetic abnormalities are commonly acquired during the course of disease and the most common is chromosomal translocation t(11;18)(q21;q21), which creates the API2-MALT1 fusion oncoprotein. t(11;18)-positive lymphomas can be clinically aggressive and have a higher rate of dissemination than t(11;18)-negative tumors. Many cancers, including MALT lymphomas, characteristically exhibit deregulated over-activation of cellular survival pathways, such as the nuclear factor-κB (NF-κB) pathway. Molecular characterization of API2-MALT1 has revealed it to be a potent activator of NF-κB, which is required for API2-MALT1-induced cellular transformation, however the mechanisms by which API2-MALT1 exerts these effects are only recently becoming apparent. The API2 moiety of the fusion binds tumor necrosis factor (TNF) receptor associated factor (TRAF) 2 and receptor interacting protein 1 (RIP1), two proteins essential for TNF receptor-induced NF-κB activation. By effectively mimicking ligand-bound TNF receptor, API2-MALT1 promotes TRAF2-dependent ubiquitination of RIP1, which then acts as a scaffold for nucleating and activating the canonical NF-κB machinery. Activation occurs, in part, through MALT1 moiety-dependent recruitment of TRAF6, which can directly modify NF-κB essential modulator, the principal downstream regulator of NF-κB. While the intrinsic MALT1 protease catalytic activity is dispensable for this canonical NF-κB signaling, it is critical for non-canonical NF-κB activation. In this regard, API2-MALT1 recognizes NF-κB inducing kinase (NIK), the essential upstream regulator of non-canonical NF-κB, and cleaves it to generate a stable, constitutively active fragment. Thus, API2-MALT1 harnesses multiple unique pathways to achieve deregulated NF-κB activation. Emerging data from our group and others have also detailed additional gain-of-function activities of API2-MALT1 that extend beyond NF-κB activation. Specifically, API2-MALT1 recruits and subverts multiple other signaling factors, including LIM domain and actin-binding protein 1 (LIMA1) and Smac/DIABLO. Like NIK, LIMA1 represents a unique substrate for API2-MALT1 protease activity, but unlike NIK, its cleavage sets in motion a major NF-κB-independent pathway for promoting oncogenesis. In this review, we highlight the most recent results characterizing these unique and diverse gain-of-function activities of API2-MALT1 and how they contribute to lymphomagenesis.
文摘A comparative molecular dynamics (MD) simulation study was performed on the p53 oncoprotein to investigate the effect of the Arg273His (R273H) mutation on the p53→DNA Binding Domain (DBD). The two p53 dimer structures of the wild-type and mutant Arg273His (R273H) were simulated with the same thermodynamic and environmental parameters. The obtained results demonstrate that the induced Arg273His mutation has a considerable effect on the p53→DNA close contact interaction and changes the picture of hydrogen formation. The Arg273His mutation, in some cases, destroys the existing native hydrogen bond, but, in other cases, forms a strong p53→DNA hydrogen bond, which is not proper for the native protein. The MD simulation results illustrate some molecular mechanism of the conformational changes of the Arg273His key amino acid residue in the p53→DNA binding domain, which might be important for the understanding of the physiological functioning of the p53 protein and the origin of cancer.
文摘It is first reported here that estrogen occupied receptor(EoR)and progesterone occupied receptor (RoR)expressed in cancerous tissues (59.57% and 82.98% respectively)and morphologically normal epithlium(50 77.78% and 70-88.89%respectively) in nasoplharyngeal carcinomas(NPCs)with insignificant difference(P>0.05).Positive rates of EoR and PoR increased greatly in clinical stage Ⅲ and Ⅳ, compared with in Ⅱ(P<0.05), and exhibited insignificant difference between female cases and male ones(P>0.05).Positive rate of C-erbB-2 was 19.15% in cancerous cells, and 9.68% in stage Ⅲand 66.67% in Ⅳin NPCs(P<0.05).Significant difference of C-erbB-2expression was observed between bilateral cervical lymph node metastasis(BCLM)and unilateral ones(P<0.05)but not for EoR or PoR(P>0.05)These findings suggest that EoR or PoR may be correlated with aggravation but not genesis and node metastasis in NPCs and that C-erbB-2may be correlated with aggravation and promotion of formation of node metastasis in NPCs.
