The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma(HCC)is poor because there are few treatment options.Recent research has focused on the identification of novel molecular entiti...The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma(HCC)is poor because there are few treatment options.Recent research has focused on the identification of novel molecular entities that can be targeted to inhibit oncogenic signals that are involved in the carcinogenesis,proliferation and progression of HCC.Among all of the pathways that are involved in the development of HCC,Hedgehog(HH)signalling has demonstrated a substantial role in hepatocarcinogenesis and HCC progression.HH plays a physiological role in embryogenesis,through the induction of the differentiation of hepatocytes from endodermal progenitors.The re-activation of the HH pathway in chronic damaged liver is a mechanism of fibrotic degeneration and is implicated in various stages of HCC development.HH activation sustains the subpopulation of immature liver epithelial cells that are involved in the pathogenesis of cirrhosis and HCC,and HH itself is a mediator of the alcohol-derived malignant transformation of liver cells.High levels of expression of HH protein markers in liver tumour tissues are correlated with aggressive histological and biological features and a poor clinical outcome.In vitro and in vivo inhibition models of the HH pathway confirm that HH is essential in maintaining tumour growth,metastasis and a mesenchymal phenotype.展开更多
The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedge...The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog(Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease(CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelialmesenchymal communication(EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.展开更多
文摘The prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma(HCC)is poor because there are few treatment options.Recent research has focused on the identification of novel molecular entities that can be targeted to inhibit oncogenic signals that are involved in the carcinogenesis,proliferation and progression of HCC.Among all of the pathways that are involved in the development of HCC,Hedgehog(HH)signalling has demonstrated a substantial role in hepatocarcinogenesis and HCC progression.HH plays a physiological role in embryogenesis,through the induction of the differentiation of hepatocytes from endodermal progenitors.The re-activation of the HH pathway in chronic damaged liver is a mechanism of fibrotic degeneration and is implicated in various stages of HCC development.HH activation sustains the subpopulation of immature liver epithelial cells that are involved in the pathogenesis of cirrhosis and HCC,and HH itself is a mediator of the alcohol-derived malignant transformation of liver cells.High levels of expression of HH protein markers in liver tumour tissues are correlated with aggressive histological and biological features and a poor clinical outcome.In vitro and in vivo inhibition models of the HH pathway confirm that HH is essential in maintaining tumour growth,metastasis and a mesenchymal phenotype.
基金supported by the National Natural Science Foundation of China(81130011,81370839,81521003)Guangdong Science Foundation(2014A030312014)+2 种基金Guangzhou Projects Grant(15020025)American Heart Association FTF(16990086)National Institutes of Health Grants(DK064005,DK091239,DK106049)
文摘The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog(Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease(CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelialmesenchymal communication(EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.
