BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,includi...BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,including fibrosis,hepatitis viral infection,drug resistance and metastasis.Thus,screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy.Orosomucoid genes(ORMs)encode acute phase plasma proteins,including orosomucoid 1(ORM1)and ORM2.Previous studies showed their upregulation upon inflammation,but the specific function of ORMs has not yet been determined,especially in the development of liver cancer.AIM To determine the expression of ORMs and their potential function in liver cancer.METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project.The expression ratio of ORMs was determined using the HCCDB database,including the ratio between liver cancer and other cancers,normal liver and other normal tissues,liver cancer and adjacent normal liver tissues.Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database.The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data,including GSE36376 and GSE14520.The 10-year overall survival(OS),progression-free survival(PFS)and relapse-free survival(RFS)rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.Gene Set Enrichment Analysis(GSEA)was employed to explore the ORM2-associated signaling network.Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database.The correlation between ORM2 gene levels,tumor-associated macrophage(TAM)markers(including CD68 and TGFβ1)and T cell immunosuppression(including CTLA4 and PD-1)in liver tumor tissues and liver GTEx was determined using the GEPIA database.RESULTS ORM1 and ORM2 were highly expressed in normal liver and liver tumor tissues.ORM1 and ORM2 expression was significantly decreased in liver tumor tissues compared with adjacent normal tissues,and similar results were also noted in cholangiocarcinoma,esophageal carcinoma,and lung squamous cell carcinoma.Further analysis of the Gene Expression Omnibus Database also confirmed the downregulation of ORM1 and ORM2 in liver tumors.Survival analysis showed that the high ORM2 group had better survival rates in OS,PFS and RFS.ORM1 only represented better performance in PFS,but not in OS or RFS.GSEA analysis of ORM2 from The Cancer Genome Atlas liver cancer data identified that ORM2 positively associated with the G2/M checkpoint,E2F target signaling,as well as Wnt/β-catenin and Hedgehog signaling.Moreover,apoptosis,IFN-αresponses,IFN-γresponses and humoral immune responses were upregulated in the ORM2 high group.ORM2 expression was negatively correlated with the macrophage infiltration level,CD68,TGFβ1,CTLA4 and PD-1 levels.CONCLUSION The results showed that ORM1 and ORM2 were highly expressed specifically in liver tissues,whereas ORM1 and ORM2 were downregulated in liver tumor tissues.ORM2 is a better prognostic factor for liver cancer.Furthermore,ORM2 is closely associated with cancer-promoting pathways.展开更多
Background: Porcine adipose tissue expresses orosomucoid(ORM1) mRNA, a protein with anti-inflammatory and immunomodulatory properties. Previous research has demonstrated that porcine ORM1 can reduce insulin stimulated...Background: Porcine adipose tissue expresses orosomucoid(ORM1) mRNA, a protein with anti-inflammatory and immunomodulatory properties. Previous research has demonstrated that porcine ORM1 can reduce insulin stimulated glucose metabolism in porcine adipose tissue in vitro. The present study was designed to examine the preweaning ontogeny of ORM1 m RNA abundance in porcine subcutaneous adipose and to determine if ORM1 can regulate m RNA abundance of inflammatory cytokines that contribute to insulin resistance in primary cultures derived from neonatal porcine subcutaneous adipose tissue. Cultures were differentiated in vitro and subsequently the adipocyte containing cultures were incubated for 24 h with 0–5000 ng porcine ORM1/m L medium. Cultures were then harvested, total RNA extracted for use in reverse transcription and the m RNA abundance of cytokine m RNA quantified by real-time PCR.Results: ORM1 m RNA abundance within neonatal adipose tissue does not change from d 1 to d 21 of age and is a very small fraction relative to liver m RNA abundance. The ORM1 m RNA level in porcine adipocytes and stromalvascular cells are similar(P > 0.05). Treatment with ORM1 did not affect TNFα(tumor necrosis factor α) m RNA level(P > 0.05), while interleukin 6(IL6) m RNA abundance was reduced 32 % at 1,000 ng ORM1/m L(P < 0.01). However,TNFα protein content in the cell culture media was reduced by ORM1 treatment(5,000 ng/m L, P < 0.05), whereas ORM1 had no detectable effect on the media content of IL6(P > 0.05). The reduction of macrophage migration inhibitory factor(MIF) m RNA abundance by ORM1 was dose dependent(P < 0.01). Monocyte chemotactic protein(MCP) m RNA level was reduced 27 % by 1,000 ng ORM1/m L(P < 0.05).Conclusions: The data suggest that ORM1 has limited effects TNFα, IL6, MIF or MCP expression at the concentrations tested. Secondly, these cytokines do not appear to contribute to the reported insulin resistance induced by ORM1 in porcine adipose tissue in vitro as an increase in the abundance of these inflammatory cytokines would be predicted during an insulin resistant state.展开更多
Gender differences in fatigue,manifesting as female more prone to feel exhausted with lower muscle endurance,still remains unclear mechanism.Here,we investigated whether orosomucoid,an endogenous anti-fatigue protein ...Gender differences in fatigue,manifesting as female more prone to feel exhausted with lower muscle endurance,still remains unclear mechanism.Here,we investigated whether orosomucoid,an endogenous anti-fatigue protein which can enhance muscle endurance,is involved in this regulation.Female rats showed lower muscle endurance,and this gender difference was disappeared in orosomucoid 1-deficient mice.Female rats also displayed weaker orosomucoid induction in serum,liver and muscle in response to fatigue when compared to male ones.Ovariectomy in female rats results in elevated orosomucoid level and increased swimming time which was reversed by estrogen replenishment,while exogenous estrogen treatment both in male or female mice produced opposite effects.In vitro C2C12 muscle and Chang liver cells,estrogen decreased orosomucoid expression and its promoter activity,and this effect was abolished when estrogen receptor or MAPK was blocked.Thus,estrogen negatively regulates orosomucoid expression,which is responsible for the weaker muscle endurance in females.展开更多
In this editorial,the roles of orosomucoid(ORM)in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect to the publication by Zhu et al presented in the pre...In this editorial,the roles of orosomucoid(ORM)in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect to the publication by Zhu et al presented in the previous issue of World Journal of Gastroenterology(2020;26(8):840-817).ORM,or alpha-1 acid glycoprotein(AGP),is an acute-phase protein that constitutes 1%to 3%of plasma proteins in humans and is mainly synthesized in the liver.ORM exists in serum as two variants:ORM1 and ORM2.Although the variants share 89.6%sequence identity and have similar biological properties,ORM1 constitutes the main component of serum ORM.An interesting feature of ORM is that its biological effects differ according to variations in glycosylation patterns.This variable feature makes ORM an attractive target for diagnosing and monitoring many diseases,including those of the liver.Recent findings suggest that a sharp decrease in ORM level is an important marker for HBV-associated acute liver failure(ALF),and ORM1 plays an important role in liver regeneration.In viral hepatitis,increases in both ORM and its fucosylated forms and the correlation of these increases with fibrosis progression suggest that this glycoprotein can be used with other markers as a noninvasive method in the follow-up assessment of diseases.In addition,similar findings regarding the level of the asialylated form of ORM,called asialo-AGP(AsAGP),have been reported in a follow-up assessment of fibrosis in chronic liver disease.An increase in ORM in serum has also been shown to improve hepatocellular carcinoma(HCC)diagnosis performance when combined with other markers.In addition,determination of the ORM level has been useful in the diagnosis of HCC with AFP concentrations less than 500 ng/mL.For monitoring patients with AFP-negative HCC,a unique trifucosylated tetra-antennary glycan of ORM may also be used as a new potential marker.The fact that there are very few studies investigating the expression of this glycoprotein and its variants in liver tissues constitutes a potential limitation,especially in terms of revealing all the effects of ORM on carcinogenesis and tumor behavior.Current findings indicate that ORM2 expression is decreased in tumors,and this is related to the aggressive course of the disease.Parallel to this finding,in HCC cell lines,ORM2 decreases HCC cell migration and invasion,supporting reports of its tumor suppressor role.In conclusion,the levels of ORM and its different glycosylated variants are promising additional biomarkers for identifying ALF,for monitoring fibrosis in viral hepatitis,and for diagnosing early HCC.Although there is evidence that the loss of ORM2 expression in HCC is associated with poor prognosis,further studies are needed to support these findings.Additionally,investigations of ORM expression in borderline dysplastic nodules and hepatocellular adenomas,which pose diagnostic problems in the differential diagnosis of HCC,especially in biopsy samples,may shed light on whether ORM can be used in histopathological differential diagnosis.展开更多
Objective Current commercially available immunological tests cannot be used for discriminating active tuberculosis(TB)from latent TB infection.To evaluate the value of biomarker candidates in the diagnosis of active T...Objective Current commercially available immunological tests cannot be used for discriminating active tuberculosis(TB)from latent TB infection.To evaluate the value of biomarker candidates in the diagnosis of active TB,this study aimed to identify differentially expressed genes in peripheral blood mononuclear cells(PBMCs)between patients with active TB and individuals with latent TB infection by transcriptome sequencing.Methods The differentially expressed genes in unstimulated PBMCs and in Mycobacterium tuberculosis(Mtb)antigen-stimulated PBMCs from patients with active TB and individuals with latent TB infection were identified by transcriptome sequencing.Selected candidate genes were evaluated in cohorts consisting of 110 patients with TB,30 individuals with latent TB infections,and 50 healthy controls by quantitative real-time RT-PCR.Receiver operating characteristic(ROC)curve analysis was performed to calculate the diagnostic value of the biomarker candidates.Results Among the differentially expressed genes in PBMCs without Mtb antigen stimulation,interferon-induced protein with tetratricopeptide repeats 3(IFIT3)had the highest area under curve(AUC)value(0.918,95%CI:0.852-0.984,P<0.0001)in discriminating patients with active TB from individuals with latent TB infection,with a sensitivity of 91.86%and a specificity of 84.00%.In Mtb antigen-stimulated PBMCs,orosomucoid 1(ORM1)had a high AUC value(0.833,95%CI:0.752-0.915,P<0.0001),with a sensitivity of 81.94%and a specificity of 70.00%.Conclusion IFIT3 and ORM1 might be potential biomarkers for discriminating active TB from latent TB infection.展开更多
基金Supported by Medicine and Health Science and Technology Plan Projects of Zhejiang Province,No.2018KY569Zhejiang Provincial Natural Science Foundation of China,No.LY17H030002
文摘BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,including fibrosis,hepatitis viral infection,drug resistance and metastasis.Thus,screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy.Orosomucoid genes(ORMs)encode acute phase plasma proteins,including orosomucoid 1(ORM1)and ORM2.Previous studies showed their upregulation upon inflammation,but the specific function of ORMs has not yet been determined,especially in the development of liver cancer.AIM To determine the expression of ORMs and their potential function in liver cancer.METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project.The expression ratio of ORMs was determined using the HCCDB database,including the ratio between liver cancer and other cancers,normal liver and other normal tissues,liver cancer and adjacent normal liver tissues.Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database.The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data,including GSE36376 and GSE14520.The 10-year overall survival(OS),progression-free survival(PFS)and relapse-free survival(RFS)rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.Gene Set Enrichment Analysis(GSEA)was employed to explore the ORM2-associated signaling network.Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database.The correlation between ORM2 gene levels,tumor-associated macrophage(TAM)markers(including CD68 and TGFβ1)and T cell immunosuppression(including CTLA4 and PD-1)in liver tumor tissues and liver GTEx was determined using the GEPIA database.RESULTS ORM1 and ORM2 were highly expressed in normal liver and liver tumor tissues.ORM1 and ORM2 expression was significantly decreased in liver tumor tissues compared with adjacent normal tissues,and similar results were also noted in cholangiocarcinoma,esophageal carcinoma,and lung squamous cell carcinoma.Further analysis of the Gene Expression Omnibus Database also confirmed the downregulation of ORM1 and ORM2 in liver tumors.Survival analysis showed that the high ORM2 group had better survival rates in OS,PFS and RFS.ORM1 only represented better performance in PFS,but not in OS or RFS.GSEA analysis of ORM2 from The Cancer Genome Atlas liver cancer data identified that ORM2 positively associated with the G2/M checkpoint,E2F target signaling,as well as Wnt/β-catenin and Hedgehog signaling.Moreover,apoptosis,IFN-αresponses,IFN-γresponses and humoral immune responses were upregulated in the ORM2 high group.ORM2 expression was negatively correlated with the macrophage infiltration level,CD68,TGFβ1,CTLA4 and PD-1 levels.CONCLUSION The results showed that ORM1 and ORM2 were highly expressed specifically in liver tissues,whereas ORM1 and ORM2 were downregulated in liver tumor tissues.ORM2 is a better prognostic factor for liver cancer.Furthermore,ORM2 is closely associated with cancer-promoting pathways.
文摘Background: Porcine adipose tissue expresses orosomucoid(ORM1) mRNA, a protein with anti-inflammatory and immunomodulatory properties. Previous research has demonstrated that porcine ORM1 can reduce insulin stimulated glucose metabolism in porcine adipose tissue in vitro. The present study was designed to examine the preweaning ontogeny of ORM1 m RNA abundance in porcine subcutaneous adipose and to determine if ORM1 can regulate m RNA abundance of inflammatory cytokines that contribute to insulin resistance in primary cultures derived from neonatal porcine subcutaneous adipose tissue. Cultures were differentiated in vitro and subsequently the adipocyte containing cultures were incubated for 24 h with 0–5000 ng porcine ORM1/m L medium. Cultures were then harvested, total RNA extracted for use in reverse transcription and the m RNA abundance of cytokine m RNA quantified by real-time PCR.Results: ORM1 m RNA abundance within neonatal adipose tissue does not change from d 1 to d 21 of age and is a very small fraction relative to liver m RNA abundance. The ORM1 m RNA level in porcine adipocytes and stromalvascular cells are similar(P > 0.05). Treatment with ORM1 did not affect TNFα(tumor necrosis factor α) m RNA level(P > 0.05), while interleukin 6(IL6) m RNA abundance was reduced 32 % at 1,000 ng ORM1/m L(P < 0.01). However,TNFα protein content in the cell culture media was reduced by ORM1 treatment(5,000 ng/m L, P < 0.05), whereas ORM1 had no detectable effect on the media content of IL6(P > 0.05). The reduction of macrophage migration inhibitory factor(MIF) m RNA abundance by ORM1 was dose dependent(P < 0.01). Monocyte chemotactic protein(MCP) m RNA level was reduced 27 % by 1,000 ng ORM1/m L(P < 0.05).Conclusions: The data suggest that ORM1 has limited effects TNFα, IL6, MIF or MCP expression at the concentrations tested. Secondly, these cytokines do not appear to contribute to the reported insulin resistance induced by ORM1 in porcine adipose tissue in vitro as an increase in the abundance of these inflammatory cytokines would be predicted during an insulin resistant state.
文摘Gender differences in fatigue,manifesting as female more prone to feel exhausted with lower muscle endurance,still remains unclear mechanism.Here,we investigated whether orosomucoid,an endogenous anti-fatigue protein which can enhance muscle endurance,is involved in this regulation.Female rats showed lower muscle endurance,and this gender difference was disappeared in orosomucoid 1-deficient mice.Female rats also displayed weaker orosomucoid induction in serum,liver and muscle in response to fatigue when compared to male ones.Ovariectomy in female rats results in elevated orosomucoid level and increased swimming time which was reversed by estrogen replenishment,while exogenous estrogen treatment both in male or female mice produced opposite effects.In vitro C2C12 muscle and Chang liver cells,estrogen decreased orosomucoid expression and its promoter activity,and this effect was abolished when estrogen receptor or MAPK was blocked.Thus,estrogen negatively regulates orosomucoid expression,which is responsible for the weaker muscle endurance in females.
文摘In this editorial,the roles of orosomucoid(ORM)in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect to the publication by Zhu et al presented in the previous issue of World Journal of Gastroenterology(2020;26(8):840-817).ORM,or alpha-1 acid glycoprotein(AGP),is an acute-phase protein that constitutes 1%to 3%of plasma proteins in humans and is mainly synthesized in the liver.ORM exists in serum as two variants:ORM1 and ORM2.Although the variants share 89.6%sequence identity and have similar biological properties,ORM1 constitutes the main component of serum ORM.An interesting feature of ORM is that its biological effects differ according to variations in glycosylation patterns.This variable feature makes ORM an attractive target for diagnosing and monitoring many diseases,including those of the liver.Recent findings suggest that a sharp decrease in ORM level is an important marker for HBV-associated acute liver failure(ALF),and ORM1 plays an important role in liver regeneration.In viral hepatitis,increases in both ORM and its fucosylated forms and the correlation of these increases with fibrosis progression suggest that this glycoprotein can be used with other markers as a noninvasive method in the follow-up assessment of diseases.In addition,similar findings regarding the level of the asialylated form of ORM,called asialo-AGP(AsAGP),have been reported in a follow-up assessment of fibrosis in chronic liver disease.An increase in ORM in serum has also been shown to improve hepatocellular carcinoma(HCC)diagnosis performance when combined with other markers.In addition,determination of the ORM level has been useful in the diagnosis of HCC with AFP concentrations less than 500 ng/mL.For monitoring patients with AFP-negative HCC,a unique trifucosylated tetra-antennary glycan of ORM may also be used as a new potential marker.The fact that there are very few studies investigating the expression of this glycoprotein and its variants in liver tissues constitutes a potential limitation,especially in terms of revealing all the effects of ORM on carcinogenesis and tumor behavior.Current findings indicate that ORM2 expression is decreased in tumors,and this is related to the aggressive course of the disease.Parallel to this finding,in HCC cell lines,ORM2 decreases HCC cell migration and invasion,supporting reports of its tumor suppressor role.In conclusion,the levels of ORM and its different glycosylated variants are promising additional biomarkers for identifying ALF,for monitoring fibrosis in viral hepatitis,and for diagnosing early HCC.Although there is evidence that the loss of ORM2 expression in HCC is associated with poor prognosis,further studies are needed to support these findings.Additionally,investigations of ORM expression in borderline dysplastic nodules and hepatocellular adenomas,which pose diagnostic problems in the differential diagnosis of HCC,especially in biopsy samples,may shed light on whether ORM can be used in histopathological differential diagnosis.
基金supported by grants from the Thirteen-Fifth Mega-Scientific Project on“Prevention and Treatment of AIDS,Viral Hepatitis and Other Infectious Diseases”(No.2017ZX10201301-007-002)the National Natural Science Foundation of China(No.82072233).
文摘Objective Current commercially available immunological tests cannot be used for discriminating active tuberculosis(TB)from latent TB infection.To evaluate the value of biomarker candidates in the diagnosis of active TB,this study aimed to identify differentially expressed genes in peripheral blood mononuclear cells(PBMCs)between patients with active TB and individuals with latent TB infection by transcriptome sequencing.Methods The differentially expressed genes in unstimulated PBMCs and in Mycobacterium tuberculosis(Mtb)antigen-stimulated PBMCs from patients with active TB and individuals with latent TB infection were identified by transcriptome sequencing.Selected candidate genes were evaluated in cohorts consisting of 110 patients with TB,30 individuals with latent TB infections,and 50 healthy controls by quantitative real-time RT-PCR.Receiver operating characteristic(ROC)curve analysis was performed to calculate the diagnostic value of the biomarker candidates.Results Among the differentially expressed genes in PBMCs without Mtb antigen stimulation,interferon-induced protein with tetratricopeptide repeats 3(IFIT3)had the highest area under curve(AUC)value(0.918,95%CI:0.852-0.984,P<0.0001)in discriminating patients with active TB from individuals with latent TB infection,with a sensitivity of 91.86%and a specificity of 84.00%.In Mtb antigen-stimulated PBMCs,orosomucoid 1(ORM1)had a high AUC value(0.833,95%CI:0.752-0.915,P<0.0001),with a sensitivity of 81.94%and a specificity of 70.00%.Conclusion IFIT3 and ORM1 might be potential biomarkers for discriminating active TB from latent TB infection.
