CCN1/CYR61(cellular communication network factor 1/cysteine-rich protein 61)是CCN家族成员,是一种重要的分泌基质蛋白。它在胚胎发育过程中对心血管的发育起着至关重要的作用;同时,在生物体成年期,其对炎症反应、血管生成、损伤...CCN1/CYR61(cellular communication network factor 1/cysteine-rich protein 61)是CCN家族成员,是一种重要的分泌基质蛋白。它在胚胎发育过程中对心血管的发育起着至关重要的作用;同时,在生物体成年期,其对炎症反应、血管生成、损伤修复、骨形成及过度纤维化和肿瘤等相关生理、病理过程起着关键作用。本文对CCN1/CYR61在骨再生中的作用作了简要总结,包括其对骨髓间充质干细胞、软骨细胞、成骨细胞及破骨细胞等骨再生相关细胞的调控,以及骨生成过程中必不可少的炎症反应和血管生成等生物学过程。展开更多
Objective:In various cancers,migration and invasion inhibitory protein(MIIP)is expressed at low level and is involved in cancer pathogenesis.Herein,we sought to explore the function of MIIP in clear cell renal cell ca...Objective:In various cancers,migration and invasion inhibitory protein(MIIP)is expressed at low level and is involved in cancer pathogenesis.Herein,we sought to explore the function of MIIP in clear cell renal cell carcinoma(ccRCC).Methods:CCK-8,colony formation,cell cycle,and endothelial cell tube formation assays were performed to evaluate the roles of MIIP in ccRCC proliferation and angiogenesis.To explore the underlyi ng mechanism,we con ducted RNA-sequencing,GSEA,qRT-PCR,Western blot,ELISA,cell transfection,coimmunoprecipitation,and ubiquitination assays in ccRCC cell lines.Furthermore,xenograft tumor growth in nude mice,and Ki-67 and CD31 staining in xenograft tissues were examined.Finally,the association of MIIP expression with clinical pathology and the expression status of HIF-2a and cysteine-rich 61(CYR61)were further analyzed in human RCC tissues through Western blot and immunohistochemistry.Results:Both in vitro and in vivo functional experiments indicated that forced expression of MIIP inhibited ccRCC proliferation and angiogenesis,whereas silencing MIIP either in normal HK-2 cells or in ccRCC cells had the opposite effect(P<0.05).Mechanistically,CYR61 was identified as a gene significantly downregulated by MIIP overexpression,and was required for the suppressive role of MIIP in ccRCC.MIIP was found to promote HSP90 acetylation and thus impair its chaperone function toward HIF-2a.Consequently,RACK1 binds HIF-2a and causes its ubiquitination and proteasomal degradation,thus decreasing the transcription of its target,CYR61.Finally,analyses of clinical samples demonstrated that MIIP is significantly downregulated in cancer vs.normal tissues in RCC cases,and its expression is negatively associated with histological grade,metastasis,the prognosis of patients with RCC,and the expression of HIF-2a and CYR61(P<0.05).Conclusions:MIIP is a novel tumor suppressor in ccRCC via negative regulation of HIF-2a-CYR61 axis.展开更多
文摘CCN1/CYR61(cellular communication network factor 1/cysteine-rich protein 61)是CCN家族成员,是一种重要的分泌基质蛋白。它在胚胎发育过程中对心血管的发育起着至关重要的作用;同时,在生物体成年期,其对炎症反应、血管生成、损伤修复、骨形成及过度纤维化和肿瘤等相关生理、病理过程起着关键作用。本文对CCN1/CYR61在骨再生中的作用作了简要总结,包括其对骨髓间充质干细胞、软骨细胞、成骨细胞及破骨细胞等骨再生相关细胞的调控,以及骨生成过程中必不可少的炎症反应和血管生成等生物学过程。
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.82002686,81872421,81502405,31700667)Science Technology Research and Development Program of Shaanxi Province(Grant No.2008k09-04-05)Basic Research Program of Natural Science of Shaanxi Province(Grant No.2019JM-315).
文摘Objective:In various cancers,migration and invasion inhibitory protein(MIIP)is expressed at low level and is involved in cancer pathogenesis.Herein,we sought to explore the function of MIIP in clear cell renal cell carcinoma(ccRCC).Methods:CCK-8,colony formation,cell cycle,and endothelial cell tube formation assays were performed to evaluate the roles of MIIP in ccRCC proliferation and angiogenesis.To explore the underlyi ng mechanism,we con ducted RNA-sequencing,GSEA,qRT-PCR,Western blot,ELISA,cell transfection,coimmunoprecipitation,and ubiquitination assays in ccRCC cell lines.Furthermore,xenograft tumor growth in nude mice,and Ki-67 and CD31 staining in xenograft tissues were examined.Finally,the association of MIIP expression with clinical pathology and the expression status of HIF-2a and cysteine-rich 61(CYR61)were further analyzed in human RCC tissues through Western blot and immunohistochemistry.Results:Both in vitro and in vivo functional experiments indicated that forced expression of MIIP inhibited ccRCC proliferation and angiogenesis,whereas silencing MIIP either in normal HK-2 cells or in ccRCC cells had the opposite effect(P<0.05).Mechanistically,CYR61 was identified as a gene significantly downregulated by MIIP overexpression,and was required for the suppressive role of MIIP in ccRCC.MIIP was found to promote HSP90 acetylation and thus impair its chaperone function toward HIF-2a.Consequently,RACK1 binds HIF-2a and causes its ubiquitination and proteasomal degradation,thus decreasing the transcription of its target,CYR61.Finally,analyses of clinical samples demonstrated that MIIP is significantly downregulated in cancer vs.normal tissues in RCC cases,and its expression is negatively associated with histological grade,metastasis,the prognosis of patients with RCC,and the expression of HIF-2a and CYR61(P<0.05).Conclusions:MIIP is a novel tumor suppressor in ccRCC via negative regulation of HIF-2a-CYR61 axis.
