Hypoxia（low oxygen level） is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation...Hypoxia（low oxygen level） is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation of hypoxia-inducible factor 1（HIF-1）.Hypoxia interferes degradation of HIF-1 alpha subunit（HIF-1α）, leading to stabilisation of HIF-1α, heterodimerization with HIF-1 beta subunit（HIF-1β） and subsequent activation of HIF-1 pathway. Apical periodontitis（periapical lesion） is a consequence of endodontic infection and ultimately results in destruction of tooth-supporting tissue, including alveolar bone. Thus far, the role of HIF-1 in periapical lesions has not been systematically examined. In the present study, we determined the role of HIF-1 in a wellcharacterised mouse periapical lesion model using two HIF-1α-activating strategies, dimethyloxalylglycine（DMOG） and adenovirusinduced constitutively active HIF-1α（CA-HIF1 A）. Both DMOG and CA-HIF1 A attenuated periapical inflammation and tissue destruction. The attenuation in vivo was associated with downregulation of nuclear factor-κappa B（NF-κB） and osteoclastic gene expressions. These two agents also suppressed NF-κB activation and subsequent production of proinflammatory cytokines by macrophages. Furthermore, activation of HIF-1α by DMOG specifically suppressed lipopolysaccharide-stimulated macrophage differentiation into M1 cells, increasing the ratio of M2 macrophages against M1 cells. Taken together, our data indicated that activation of HIF-1 plays a protective role in the development of apical periodontitis via downregulation of NF-κB, proinflammatory cytokines, M1 macrophages and osteoclastogenesis.展开更多
Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures...Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.展开更多
OBJECTIVE： To test the hypothesis that modified Shenlingbaizhu decoction （MSD） attenuates the for- mation of intestinal adenomas by regulating activa- tion of CD4＋CD25＋ forkhead box P3 （FoxP3） regu- latory T ce...OBJECTIVE： To test the hypothesis that modified Shenlingbaizhu decoction （MSD） attenuates the for- mation of intestinal adenomas by regulating activa- tion of CD4＋CD25＋ forkhead box P3 （FoxP3） regu- latory T cells （Tregs） by downregulation of hypox- ia-inducible factor la （HIF-la）. METHODS： Chemical fingerprints of ginsenoside Rbl, ginsenoside Rc, paeoniflorin, and dioscin in standard extractions were used as material bases of MSD. Adenomatous polyposis coli multiple intesti- nal neoplasia （ApcM＇n/＋） mice, which harbor a muta- tion in adenomatous polyposis coil, were used to host intestinal adenomas. Peripheral blood and spleen Tregs were analyzed by flow cytometry. Pro- tein expression was analyzed by immunohisto- chemistry and Western blotting. RESULTS： The number and size of intestinal adenomas were significantly reduced by MSD treatment. Mucosal thickening and the spleen size were also substantially decreased by MSD. The carcinogenesis process in Apc^min/＋ mice resembled that of human colorectal cancer. Molecular markers of neoplasms, such as 13-catenin, cyclooxygenase-2, prolif- erating cell nuclear antigen, and p53, were substantially ameliorated by MSD treatment. Moreover, MSD downregulated peripheral and spleen CD4＋ CD25＋FoxP3＋ Tregs and reduced in situ expression of CD4, CD25, and FoxP3 in intestinal adenomas. MSD also suppressed HIF-la expression in the intestinal adenomas, and HIF-la inhibition decreased expression of FoxP3 in Jurkat T cells under hypoxic conditions. CONCLUSION： MSD is a valid prescription to control the formation of intestinal adenomas in Apc^min/＋mice. It exerts anti-cancer effects partially through suppression of HIF-la that induced activation of CD4＋CD25＋FoxP3＋ Tregs in vivo and in vitro.展开更多
Objective To explore the expression level and location of hypoxia-inducible factor 1α(HIF1α)in gastric cancer(GC)tissues and their relationship with clinicopathological features and clinical outcomes.Methods From Ju...Objective To explore the expression level and location of hypoxia-inducible factor 1α(HIF1α)in gastric cancer(GC)tissues and their relationship with clinicopathological features and clinical outcomes.Methods From July to September 2015,27 pairs of fresh paired GC tissues and adjacent normal tissues were gathered from the Eighth Department of General Surgery of展开更多
Background:Increased hypoxia-inducible factor 2α(HIF2α)activation is a common event in clear cell renal cell carcinoma(ccRCC)progression.However,the function and underlying mechanism of HIF2α in ccRCC remains uninv...Background:Increased hypoxia-inducible factor 2α(HIF2α)activation is a common event in clear cell renal cell carcinoma(ccRCC)progression.However,the function and underlying mechanism of HIF2α in ccRCC remains uninvestigated.We conducted this study to access the potential link between junction plakoglobin(JUP)and HIF2αin ccRCC.Methods:Affinity purification and mass spectrometry(AP-MS)screening,glutathione-s-transferase(GST)pull-down and co-immunoprecipitation(Co-IP)assays were performed to detect the interacting proteins of HIF2α.Quantitative PCR(qPCR)and Western blotting were used to detect the expression of JUP in human ccRCC samples.Luciferase reporter assays,chromatin immunoprecipitation(ChIP),cycloheximide chase assays,and ubiquitination assays were conducted to explore the regulation of JUP on the activity of HIF2α.Cell Counting Kit-8(CCK-8)assays,colony formation assays,transwell assays,and xenograft tumor assays were performed to investigate the effect of JUP knockdown or overexpression on the tumorigenicity of renal cancer cells.Results:We identified JUP as a novel HIF2α-binding partner and revealed an important role of JUP in recruiting von Hippel-Lindau(VHL)and histone deacetylases 1/2(HDAC1/2)to HIF2α to regulate its stability and transactivation.JUP knockdown promoted and overexpression suppressed the tumorigenicity of renal cell carcinoma in vitro and in vivo.Importantly,the low expression of JUP was found in clinical ccRCC samples and correlated with enhanced hypoxia scores and poor treatment outcomes.Conclusion:Taken together,these data support a role of JUP in modulating HIF2α signaling during ccRCC progression and identify JUP as a potential therapeutic target.展开更多
Hypoxia is a common phenomenon in hepatocellular carcinoma （HCC）. Hypoxia stabilizes transcription factor, hypoxia-inducible factor （HIF）, to activate gene transcription. Expression of HIF is closely associated wi...Hypoxia is a common phenomenon in hepatocellular carcinoma （HCC）. Hypoxia stabilizes transcription factor, hypoxia-inducible factor （HIF）, to activate gene transcription. Expression of HIF is closely associated with metastasis and poor prognosis in HCC. HIF mediates expression of genes that are involved in every step of HCC metastasis including epithelial-mesenchymal transition, invasion of the extracellular matrix, intravasation, extravasation, and secondary growth of the metastases. Because HIF is the central regulator of HCC metastasis, HIF inhibitors are attractive tools when used alone or as combined treatment to curb HCC metastasis. This review will summarize the current findings on the impact of hypoxia/HIF in HCC, with a particular focus on cancer metastasis.展开更多
基金supported by the National Institute of Dental and Craniofacial Research(NIDCR)the National Center for Research Resources(NCRR)of the National Institutes of Health(NIH)under award numbers R21DE023178,R01DE024796,and S10RR027553
文摘Hypoxia（low oxygen level） is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation of hypoxia-inducible factor 1（HIF-1）.Hypoxia interferes degradation of HIF-1 alpha subunit（HIF-1α）, leading to stabilisation of HIF-1α, heterodimerization with HIF-1 beta subunit（HIF-1β） and subsequent activation of HIF-1 pathway. Apical periodontitis（periapical lesion） is a consequence of endodontic infection and ultimately results in destruction of tooth-supporting tissue, including alveolar bone. Thus far, the role of HIF-1 in periapical lesions has not been systematically examined. In the present study, we determined the role of HIF-1 in a wellcharacterised mouse periapical lesion model using two HIF-1α-activating strategies, dimethyloxalylglycine（DMOG） and adenovirusinduced constitutively active HIF-1α（CA-HIF1 A）. Both DMOG and CA-HIF1 A attenuated periapical inflammation and tissue destruction. The attenuation in vivo was associated with downregulation of nuclear factor-κappa B（NF-κB） and osteoclastic gene expressions. These two agents also suppressed NF-κB activation and subsequent production of proinflammatory cytokines by macrophages. Furthermore, activation of HIF-1α by DMOG specifically suppressed lipopolysaccharide-stimulated macrophage differentiation into M1 cells, increasing the ratio of M2 macrophages against M1 cells. Taken together, our data indicated that activation of HIF-1 plays a protective role in the development of apical periodontitis via downregulation of NF-κB, proinflammatory cytokines, M1 macrophages and osteoclastogenesis.
基金supported by NIH grants AR049510 (TLC) and AR045955 (LDQ)
文摘Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.
基金Supported by The National Science Foundation of China(No.81573848Colorectal Cancer Induces Skeletal Muscle Autophagy and Glycolysis to Cause Spleen-deficiency+5 种基金81774172TAMs Promote Extreme Deficient Macroenvironment to Induce Deeply Rooted Colorectal Cancer Stem Cells)Guangdong Provincial Natural Science Foundation(No.2014A030313323Mechanism Study on Muscle Dystrophy with Spleen-Deficiency Resulting from Colorectal Cancer Induced Skeletal Muscle Autophagy)Specialized Research Fund for the Doctoral Program of Higher Education(No.20134433110007Mechanism of Parthenolide Regulates the Opening of Mitochondrial Membrane Permeability Transition Pore to Induce Cox+/+Colorectal Cancer Necroptosis)
文摘OBJECTIVE： To test the hypothesis that modified Shenlingbaizhu decoction （MSD） attenuates the for- mation of intestinal adenomas by regulating activa- tion of CD4＋CD25＋ forkhead box P3 （FoxP3） regu- latory T cells （Tregs） by downregulation of hypox- ia-inducible factor la （HIF-la）. METHODS： Chemical fingerprints of ginsenoside Rbl, ginsenoside Rc, paeoniflorin, and dioscin in standard extractions were used as material bases of MSD. Adenomatous polyposis coli multiple intesti- nal neoplasia （ApcM＇n/＋） mice, which harbor a muta- tion in adenomatous polyposis coil, were used to host intestinal adenomas. Peripheral blood and spleen Tregs were analyzed by flow cytometry. Pro- tein expression was analyzed by immunohisto- chemistry and Western blotting. RESULTS： The number and size of intestinal adenomas were significantly reduced by MSD treatment. Mucosal thickening and the spleen size were also substantially decreased by MSD. The carcinogenesis process in Apc^min/＋ mice resembled that of human colorectal cancer. Molecular markers of neoplasms, such as 13-catenin, cyclooxygenase-2, prolif- erating cell nuclear antigen, and p53, were substantially ameliorated by MSD treatment. Moreover, MSD downregulated peripheral and spleen CD4＋ CD25＋FoxP3＋ Tregs and reduced in situ expression of CD4, CD25, and FoxP3 in intestinal adenomas. MSD also suppressed HIF-la expression in the intestinal adenomas, and HIF-la inhibition decreased expression of FoxP3 in Jurkat T cells under hypoxic conditions. CONCLUSION： MSD is a valid prescription to control the formation of intestinal adenomas in Apc^min/＋mice. It exerts anti-cancer effects partially through suppression of HIF-la that induced activation of CD4＋CD25＋FoxP3＋ Tregs in vivo and in vitro.
文摘Objective To explore the expression level and location of hypoxia-inducible factor 1α(HIF1α)in gastric cancer(GC)tissues and their relationship with clinicopathological features and clinical outcomes.Methods From July to September 2015,27 pairs of fresh paired GC tissues and adjacent normal tissues were gathered from the Eighth Department of General Surgery of
基金supported by National Natural Science Foundation of China(grant number 81772721,81874089,81602236,81702522)Natural Science Foundation of Jiangxi Province of China(20202BABL216060)National Major Scientific and Technological Special Project for“Significant New Drugs Development”(2017ZX09304022).
文摘Background:Increased hypoxia-inducible factor 2α(HIF2α)activation is a common event in clear cell renal cell carcinoma(ccRCC)progression.However,the function and underlying mechanism of HIF2α in ccRCC remains uninvestigated.We conducted this study to access the potential link between junction plakoglobin(JUP)and HIF2αin ccRCC.Methods:Affinity purification and mass spectrometry(AP-MS)screening,glutathione-s-transferase(GST)pull-down and co-immunoprecipitation(Co-IP)assays were performed to detect the interacting proteins of HIF2α.Quantitative PCR(qPCR)and Western blotting were used to detect the expression of JUP in human ccRCC samples.Luciferase reporter assays,chromatin immunoprecipitation(ChIP),cycloheximide chase assays,and ubiquitination assays were conducted to explore the regulation of JUP on the activity of HIF2α.Cell Counting Kit-8(CCK-8)assays,colony formation assays,transwell assays,and xenograft tumor assays were performed to investigate the effect of JUP knockdown or overexpression on the tumorigenicity of renal cancer cells.Results:We identified JUP as a novel HIF2α-binding partner and revealed an important role of JUP in recruiting von Hippel-Lindau(VHL)and histone deacetylases 1/2(HDAC1/2)to HIF2α to regulate its stability and transactivation.JUP knockdown promoted and overexpression suppressed the tumorigenicity of renal cell carcinoma in vitro and in vivo.Importantly,the low expression of JUP was found in clinical ccRCC samples and correlated with enhanced hypoxia scores and poor treatment outcomes.Conclusion:Taken together,these data support a role of JUP in modulating HIF2α signaling during ccRCC progression and identify JUP as a potential therapeutic target.
文摘Hypoxia is a common phenomenon in hepatocellular carcinoma （HCC）. Hypoxia stabilizes transcription factor, hypoxia-inducible factor （HIF）, to activate gene transcription. Expression of HIF is closely associated with metastasis and poor prognosis in HCC. HIF mediates expression of genes that are involved in every step of HCC metastasis including epithelial-mesenchymal transition, invasion of the extracellular matrix, intravasation, extravasation, and secondary growth of the metastases. Because HIF is the central regulator of HCC metastasis, HIF inhibitors are attractive tools when used alone or as combined treatment to curb HCC metastasis. This review will summarize the current findings on the impact of hypoxia/HIF in HCC, with a particular focus on cancer metastasis.
