Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndr...Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.展开更多
研究慢性心力衰竭患者血清赖氨酰氧化酶样蛋白2(lysyl oxidase like 2,LOXL2)水平变化情况,探讨LOXL2在心力衰竭诊断中的应用价值。入选心力衰竭住院患者74例,按纽约心功能分级标准分为心功能Ⅱ级组26例、心功能Ⅲ级组27例、心功能Ⅳ级...研究慢性心力衰竭患者血清赖氨酰氧化酶样蛋白2(lysyl oxidase like 2,LOXL2)水平变化情况,探讨LOXL2在心力衰竭诊断中的应用价值。入选心力衰竭住院患者74例,按纽约心功能分级标准分为心功能Ⅱ级组26例、心功能Ⅲ级组27例、心功能Ⅳ级组21例,并收集38例同期住院非心衰患者作为对照组。采集入选者的临床资料,入院后行心脏彩色超声检查,测定血浆NT-pro BNP水平,采用酶联免疫法测定血清LOXL2浓度。患者血清LOXL2水平在心功能Ⅳ级组(992.1±404.5)pg/mL显著高于心功能Ⅲ,Ⅱ级组[分别为(637.1±125.8)和(467.5±88.7)pg/mL,均P<0.01]及对照组[(314.2±143.5)pg/mL,P<0.01],与对照组相比,各组心衰患者LOXL2水平均显著升高(均P<0.05)。LOXL2浓度与左室舒张末期内径(LVEDd)呈正相关(R^2=0.25,P<0.01)、而与心功能分级(R^2=-0.26,P<0.01)呈负相关。血清LOXL2诊断心力衰竭的ROC曲线下面积(AUC)为0.699,95%可信区间为(0.644~0.894,P<0.001)。心力衰竭患者血清LOXL2水平明显升高,并且升高水平与心力衰竭程度显著相关。LOXL2或可作为NT-pro BNP和超声心动图外的补充手段,对心力衰竭的诊断与鉴别有一定意义。展开更多
基金supported by a National Research Foundation of Korea(NRF)grant funded by the Korean Government,Ministry of Science and ICT(MSIT)(2016R1C1B102207,2022R1A2C1004141 and 2022R1A2C-1091712)the National R&D Program for Cancer Control through the National Cancer Center(NCC)funded by the Ministry of Health&Welfare,Republic of Korea(HA22C0053000022).
文摘Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.
