Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a h...Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a hallmark of cancer.Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy.In this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.Methods:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC.Squalene epoxidase(SQLE)was identified to be highly upregulated in CRC patients.The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor growth.Themolecularmechanism of SQLE functionwas explored by combining transcriptome and untargeted metabolomics analysis.Western blotting and realtime PCR were used to assess MAPK signaling activation by SQLE.Results:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis.SQLE promoted CRC growth in vitro and in vivo.Inhibition of SQLE reduced the levels of calcitriol(active form of vitamin D3)and CYP24A1,followed by an increase in intracellular Ca2+concentration.Subsequently,MAPK signaling was suppressed,resulting in the inhibition of CRC cell growth.Consistently,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor growth.Conclusions:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.展开更多
Hepatocytes are responsible for diverse metabolic activities in a liver. Proper ribosome biogenesis is essential to sustain the function of hepatocytes. There are approximately 200 factors involved in ribosome biogene...Hepatocytes are responsible for diverse metabolic activities in a liver. Proper ribosome biogenesis is essential to sustain the function of hepatocytes. There are approximately 200 factors involved in ribosome biogenesis;however, few studies have focused on the role of these factors in maintaining liver homeostasis. The digestive organ expansion factor(def) gene encodes a nucleolar protein Def that participates in ribosome biogenesis. In addition, Def forms a complex with cysteine protease Calpain3(Capn3) and recruits Capn3 to the nucleolus to cleave protein targets. However, the function of Def has not been characterized in the mammalian digestive organs. In this report, we show that conditional knockout of the mouse def gene in hepatocytes causes cell morphology abnormality and constant infiltration of inflammatory cells in the liver. As age increases, the def conditional knockout liver displays multiple tissue damage foci and biliary hyperplasia. Moreover, partial hepatectomy leads to sudden acute death to the def conditional knockout mice and this phenotype is rescued by intragastric injection of the anti-inflammation drug dexamethasone one day before hepatectomy. Our results demonstrate that Def is essential for maintaining the liver homeostasis and liver regeneration capacity in mammals.展开更多
Craniosynostosis is a rare disease in which one or more of the cranial sutures in an infant skull prematurely fuses by turning into bone,with a prevalence of 1 in 2,000—2,500 individuals from reports in Western count...Craniosynostosis is a rare disease in which one or more of the cranial sutures in an infant skull prematurely fuses by turning into bone,with a prevalence of 1 in 2,000—2,500 individuals from reports in Western countries(Wilkie et al.,2017).It may restrict the growth of the brain,leading to some degree of morphological and functional abnormalities,and may affect the neurocognitive function of infants(Lattanzi et al.,2017).Genetic variants underlying craniosynostosis have been identified in cohort studies in Western populations.展开更多
基金National Natural Science Foundation of China,Grant/Award Numbers:31630047,81874201,81725014Natural Science Foundation of Shanghai,Grant/AwardNumber:20ZR1452300+1 种基金Shanghai Municipal Health Bureau,Grant/Award Number:201840359The National Key Research and Development Program of China,Grant/Award Numbers:2020YFA0509000,2017YFA0503600。
文摘Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a hallmark of cancer.Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy.In this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.Methods:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC.Squalene epoxidase(SQLE)was identified to be highly upregulated in CRC patients.The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor growth.Themolecularmechanism of SQLE functionwas explored by combining transcriptome and untargeted metabolomics analysis.Western blotting and realtime PCR were used to assess MAPK signaling activation by SQLE.Results:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis.SQLE promoted CRC growth in vitro and in vivo.Inhibition of SQLE reduced the levels of calcitriol(active form of vitamin D3)and CYP24A1,followed by an increase in intracellular Ca2+concentration.Subsequently,MAPK signaling was suppressed,resulting in the inhibition of CRC cell growth.Consistently,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor growth.Conclusions:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.
基金supported by the National Key Research and Development Program of China (2018YFA0800502)。
文摘Hepatocytes are responsible for diverse metabolic activities in a liver. Proper ribosome biogenesis is essential to sustain the function of hepatocytes. There are approximately 200 factors involved in ribosome biogenesis;however, few studies have focused on the role of these factors in maintaining liver homeostasis. The digestive organ expansion factor(def) gene encodes a nucleolar protein Def that participates in ribosome biogenesis. In addition, Def forms a complex with cysteine protease Calpain3(Capn3) and recruits Capn3 to the nucleolus to cleave protein targets. However, the function of Def has not been characterized in the mammalian digestive organs. In this report, we show that conditional knockout of the mouse def gene in hepatocytes causes cell morphology abnormality and constant infiltration of inflammatory cells in the liver. As age increases, the def conditional knockout liver displays multiple tissue damage foci and biliary hyperplasia. Moreover, partial hepatectomy leads to sudden acute death to the def conditional knockout mice and this phenotype is rescued by intragastric injection of the anti-inflammation drug dexamethasone one day before hepatectomy. Our results demonstrate that Def is essential for maintaining the liver homeostasis and liver regeneration capacity in mammals.
基金supported by the foundation of Shanghai municipal commission of Health and Family Planning(20174Y0088)the Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)+1 种基金the CAS Interdisciplinary Innovation Team Projectthe NIHR Oxford Biomedical Research Centre Programme。
文摘Craniosynostosis is a rare disease in which one or more of the cranial sutures in an infant skull prematurely fuses by turning into bone,with a prevalence of 1 in 2,000—2,500 individuals from reports in Western countries(Wilkie et al.,2017).It may restrict the growth of the brain,leading to some degree of morphological and functional abnormalities,and may affect the neurocognitive function of infants(Lattanzi et al.,2017).Genetic variants underlying craniosynostosis have been identified in cohort studies in Western populations.