目的:针对前期应用基因芯片(Affymatix Rat 230.2.0)筛选出的大鼠早期肝癌中高表达的人同源基因GDF15(Growth Differentiation Factor15),进一步在人小肝癌组织中检测其表达水平以探讨其作为人小肝癌候选诊断标志物的价值。方法:应用RT-...目的:针对前期应用基因芯片(Affymatix Rat 230.2.0)筛选出的大鼠早期肝癌中高表达的人同源基因GDF15(Growth Differentiation Factor15),进一步在人小肝癌组织中检测其表达水平以探讨其作为人小肝癌候选诊断标志物的价值。方法:应用RT-PCR检测GDF15在大鼠早期肝癌结节中的表达以对芯片结果进行初步验证;进一步采用RT-PCR、实时荧光定量PCR对GDF15在随机配对的正常肝脏组织(n=10)与小肝癌(n=10)中基因转录水平半定量和定量检测,同时用免疫组化鉴定其在正常肝脏组织(n=10),癌旁组织(n=26),小肝癌(n=12)及大肝癌(n=14)中蛋白水平的表达。结果:GDF15在大鼠早期肝癌结节中较正常组织表达显著上调(P<0.05),与芯片结果一致。在人小肝癌,其转录及蛋白水平的表达均明显高于正常肝脏组织(P<0.05)。免疫组化结果显示12例小肝癌中10例表达强阳性,其在细胞中的表达定位于细胞浆与细胞外基质。结论:分泌性蛋白GDF15在人小肝癌组织中高表达,提示其具有潜在的小肝癌筛选价值。展开更多
Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases...Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15(GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.展开更多
文摘目的:针对前期应用基因芯片(Affymatix Rat 230.2.0)筛选出的大鼠早期肝癌中高表达的人同源基因GDF15(Growth Differentiation Factor15),进一步在人小肝癌组织中检测其表达水平以探讨其作为人小肝癌候选诊断标志物的价值。方法:应用RT-PCR检测GDF15在大鼠早期肝癌结节中的表达以对芯片结果进行初步验证;进一步采用RT-PCR、实时荧光定量PCR对GDF15在随机配对的正常肝脏组织(n=10)与小肝癌(n=10)中基因转录水平半定量和定量检测,同时用免疫组化鉴定其在正常肝脏组织(n=10),癌旁组织(n=26),小肝癌(n=12)及大肝癌(n=14)中蛋白水平的表达。结果:GDF15在大鼠早期肝癌结节中较正常组织表达显著上调(P<0.05),与芯片结果一致。在人小肝癌,其转录及蛋白水平的表达均明显高于正常肝脏组织(P<0.05)。免疫组化结果显示12例小肝癌中10例表达强阳性,其在细胞中的表达定位于细胞浆与细胞外基质。结论:分泌性蛋白GDF15在人小肝癌组织中高表达,提示其具有潜在的小肝癌筛选价值。
基金supported by grants from the National Institutes of Health (NIH) U01 CA185148, DOD W81XWH-18-10308 (SKB), DOD W81XWH-21-1-0640 (JAS), and R01 CA218545, R01 CA241752 (MWN)
文摘Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15(GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.
