BACKGROUND Reliable biomarkers of cirrhosis,hepatocellular carcinoma(HCC),or progression of chronic liver diseases are missing.In this context,Golgi protein-73(GP73)also called Golgi phosphoprotein-2,was originally de...BACKGROUND Reliable biomarkers of cirrhosis,hepatocellular carcinoma(HCC),or progression of chronic liver diseases are missing.In this context,Golgi protein-73(GP73)also called Golgi phosphoprotein-2,was originally defined as a resident Golgi type II transmembrane protein expressed in epithelial cells.As a result,GP73 expression was found primarily in biliary epithelial cells,with only slight detection in hepatocytes.However,in patients with acute or chronic liver diseases and especially in HCC,the expression of GP73 is significantly up-regulated in hepatocytes.So far,few studies have assessed GP73 as a diagnostic or prognostic marker of liver fibrosis and disease progression.AIM To assess serum GP73 efficacy as a diagnostic marker of cirrhosis and/or HCC or as predictor of liver disease progression.METHODS GP73 serum levels were retrospectively determined by a novel GP73 ELISA(QUANTA Lite®GP73,Inova Diagnostics,Inc.,Research Use Only)in a large cohort of 632 consecutive patients with chronic viral and non-viral liver diseases collected from two tertiary Academic centers in Larissa,Greece(n=366)and Debrecen,Hungary(n=266).Aspartate aminotransferase(AST)/Platelets(PLT)ratio index(APRI)was also calculated at the relevant time points in all patients.Two hundred and three patients had chronic hepatitis B,183 chronic hepatitis C,198 alcoholic liver disease,28 autoimmune cholestatic liver diseases,15 autoimmune hepatitis,and 5 with other liver-related disorders.The duration of follow-up was 50(57)mo[median(interquartile range)].The development of cirrhosis,liver decompensation and/or HCC during follow-up were assessed according to internationally accepted guidelines.In particular,the surveillance for the development of HCC was performed regularly with ultrasound imaging and alpha-fetoprotein(AFP)determination every 6 mo in cirrhotic and every 12 mo in non-cirrhotic patients.RESULTS Increased serum levels of GP73(>20 units)were detected at initial evaluation in 277 out of 632 patients(43.8%).GP73-seropositivity correlated at baseline with the presence of cirrhosis(96.4%vs 51.5%,P<0.001),decompensation of cirrhosis(60.3%vs 35.5%,P<0.001),presence of HCC(18.4%vs 7.9%,P<0.001)and advanced HCC stage(52.9%vs 14.8%,P=0.002).GP73 had higher diagnostic accuracy for the presence of cirrhosis compared to APRI score[Area under the curve(AUC)(95%CI):0.909(0.885-0.934)vs 0.849(0.813-0.886),P=0.003].Combination of GP73 with APRI improved further the accuracy(AUC:0.925)compared to GP73(AUC:0.909,P=0.005)or APRI alone(AUC:0.849,P<0.001).GP73 levels were significantly higher in HCC patients compared to non-HCC[22.5(29.2)vs 16(20.3)units,P<0.001)and positively associated with BCLC stage[stage 0:13.9(10.8);stage A:17.1(16.8);stage B:19.6(22.3);stage C:32.2(30.8);stage D:45.3(86.6)units,P<0.001]and tumor dimensions[very early:13.9(10.8);intermediate:19.6(18.4);advanced:29.1(33.6)units,P=0.004].However,the discriminative ability for HCC diagnosis was relatively low[AUC(95%CI):0.623(0.570-0.675)].Kaplan-Meier analysis showed that the detection of GP73 in patients with compensated cirrhosis at baseline,was prognostic of higher rates of decompensation(P=0.036),HCC development(P=0.08),and liver-related deaths(P<0.001)during follow-up.CONCLUSION GP73 alone appears efficient for detecting cirrhosis and superior to APRI determination.In combination with APRI,its diagnostic performance can be further improved.Most importantly,the simple GP73 measurement proved promising for predicting a worse outcome of patients with both viral and nonviral chronic liver diseases.展开更多
高尔基体蛋白73(Golgi protein 73,GP73)是位于顺式高尔基体膜上的糖基化跨膜蛋白,其在肿瘤的发展进程中具有重要作用,是肿瘤治疗的潜在靶标。目前研究表明,GP73可作为辅助诊断肝细胞癌(hepatocellular carcinoma,HCC)的血清学标志物。...高尔基体蛋白73(Golgi protein 73,GP73)是位于顺式高尔基体膜上的糖基化跨膜蛋白,其在肿瘤的发展进程中具有重要作用,是肿瘤治疗的潜在靶标。目前研究表明,GP73可作为辅助诊断肝细胞癌(hepatocellular carcinoma,HCC)的血清学标志物。随着GP73的深入研究,与GP73有关的微RNA(microRNA,miRNA)也逐渐被挖掘出来。GP73相关miRNA与多种肿瘤的发生、发展密切相关,其中miR-212、miR-27a等miRNA能抑制HCC的侵袭及转移,GP73与miR-27b、miR-493-5p等能作为HCC患者预后的生物标志物。因此,GP73相关miRNA用于肝癌的诊治是有前景的。本文总结了GP73及其相关miRNA在肝癌发展中的作用以及机制,希望为肝癌的机制研究和诊疗提供思路。展开更多
Background:Hepatic Golgi protein-73(GP73)expression is related to hepatocellular carcinoma(HCC)progression.The aim of this study was to investigate the dynamic expression of GP73 mRNA and protein during hepatocytes ma...Background:Hepatic Golgi protein-73(GP73)expression is related to hepatocellular carcinoma(HCC)progression.The aim of this study was to investigate the dynamic expression of GP73 mRNA and protein during hepatocytes malignant transformation.Methods:Human GP73 expressions in 88 HCC tissues and their self-control surrounding tissues were examined by immunohistochemistry,and survival time of HCC patients was evaluated by the Kaplan-Meier method.HCC model of Sprague-Dawley rats was made by diet containing 2-fluorenylacetamide.The rats were divided into the control,hepatocyte degeneration,precanceration,and HCC groups to observe GP73 protein and mRNA alterations during hepatocytes malignant transformation.Results:The GP73 expression was significantly higher in the cancerous tissues than that in the surrounding tissues,with shorter survival time,and the positive rates of GP73 protein in human HCC tissues were 53.3%at stage I,84.0%at stage II,84.6%at stage III,and 60.0%at stage IV,respectively.The positive rates of hepatic GP73 protein and mRNA in the rat models were none in the control group,66.7%and 44.4%in the hepatocytes degeneration group,88.9%and 77.8%in the hepatocytes precanceration group,and 100%in the HCC group,respectively.There was a positive correlation(r=0.91,P<0.01)between hepatic GP73 and serum GP73 during rat hepatocytes malignant transformation.Conclusions:Abnormal GP73 expression may be a sensitive and valuable biomarker in hepatocarcinogensis.展开更多
Objective: The aim of the present study was to further evaluate the clinical value of single or joint of golgi protein 73 (GP73) and alphafetoprotein (AFP) in diagnosis of hepatocellular (HCC). Methods: One hundred an...Objective: The aim of the present study was to further evaluate the clinical value of single or joint of golgi protein 73 (GP73) and alphafetoprotein (AFP) in diagnosis of hepatocellular (HCC). Methods: One hundred and eighteen, 94 and 47 serum samples from the patients with HCC, chronic liver disease (CLD) and liver cirrhosis (LC) were collected, respectively. Serum levels of AFP and GP73 were assayed with commercial kit according to the manufacturer's instructions. Results: Patients with HCC had higher serum concentration of AFP than that of the patients with CLD (P < 0.01), but was similar to that of the patients with LC. Serum GP73 levels in the patients with CLD or LC were significantly lower than that in the patients from HCC group (P < 0.01). Among 118 HCC patients, the positive rate of GP73 and AFP was 80.5% and 48.3%, respectively (P < 0.001). The ROC curve analysis showed that the AUC value of GP73 was higher than that of serum AFP. Moreover, the sensitivity and the accuracy of GP73 were 77.1% and 82.6%, respectively, which were greater more than that of AFP at 90% specificity (28.8% and 59.8%, respectively). The AUC, the sensitivity and the accuracy of GP73 in combination of AFP (AFP/GP73) were 0.855, 78.0% and 83.0%, respectively, which were similar to that of GP73 alone but were much higher than that of the single marker AFP. Conclusion: For HCC diagnosing, GP73 was more sensitive and specific than AFP. The diagnostic value of AFP/GP73 was similar to GP73 but was much higher than AFP.展开更多
Objective: To study the changes of serum phosphatidylinositol proteinglycan-3 (GPC3) and Golgi protein-73 (GP73) contents in patients with liver cancer and their correlation with angiogenesis and epithelial mesenchyma...Objective: To study the changes of serum phosphatidylinositol proteinglycan-3 (GPC3) and Golgi protein-73 (GP73) contents in patients with liver cancer and their correlation with angiogenesis and epithelial mesenchymal transition. Methods: The patients with liver cancer who underwent surgical resection in our hospital between April 2014 and October 2017 were selected as liver cancer group, healthy subjects who received physical examination during the same period were selected as control group, and the contents of GPC3 and GP73 in serum as well as the contents of GPC3 and GP73, the expression of angiogenesis genes and epithelial mesenchymal transition genes in liver cancer lesions and adjacent lesions of the two groups of subjects were determined. Results: GPC3 and GP73 contents in serum of liver cancer group were significantly higher than those of control group, GPC3 and GP73 contents in liver cancer lesions were significantly higher than those in adjacent lesions, and the GPC3 and GP73 contents in serum of liver cancer group were positively correlated with GPC3 and GP73 contents in liver cancer lesions;SULT2B1, VEGF, Ang-2, Shh, Twist and N-cadherin mRNA expression in liver cancer lesions were significantly higher those in adjacent lesions and positively correlated with the GPC3 and GP73 contents in serum whereas TUM5, Foxg1 and E-cadherin mRNA expression were significantly lower than those in adjacent lesions and negatively correlated with the GPC3 and GP73 contents in serum. Conclusion: The increase of serum GPC3 and GP73 contents in patients with liver cancer is closely related to the aggravation of angiogenesis and epithelial mesenchymal transition in the lesions.展开更多
文摘BACKGROUND Reliable biomarkers of cirrhosis,hepatocellular carcinoma(HCC),or progression of chronic liver diseases are missing.In this context,Golgi protein-73(GP73)also called Golgi phosphoprotein-2,was originally defined as a resident Golgi type II transmembrane protein expressed in epithelial cells.As a result,GP73 expression was found primarily in biliary epithelial cells,with only slight detection in hepatocytes.However,in patients with acute or chronic liver diseases and especially in HCC,the expression of GP73 is significantly up-regulated in hepatocytes.So far,few studies have assessed GP73 as a diagnostic or prognostic marker of liver fibrosis and disease progression.AIM To assess serum GP73 efficacy as a diagnostic marker of cirrhosis and/or HCC or as predictor of liver disease progression.METHODS GP73 serum levels were retrospectively determined by a novel GP73 ELISA(QUANTA Lite®GP73,Inova Diagnostics,Inc.,Research Use Only)in a large cohort of 632 consecutive patients with chronic viral and non-viral liver diseases collected from two tertiary Academic centers in Larissa,Greece(n=366)and Debrecen,Hungary(n=266).Aspartate aminotransferase(AST)/Platelets(PLT)ratio index(APRI)was also calculated at the relevant time points in all patients.Two hundred and three patients had chronic hepatitis B,183 chronic hepatitis C,198 alcoholic liver disease,28 autoimmune cholestatic liver diseases,15 autoimmune hepatitis,and 5 with other liver-related disorders.The duration of follow-up was 50(57)mo[median(interquartile range)].The development of cirrhosis,liver decompensation and/or HCC during follow-up were assessed according to internationally accepted guidelines.In particular,the surveillance for the development of HCC was performed regularly with ultrasound imaging and alpha-fetoprotein(AFP)determination every 6 mo in cirrhotic and every 12 mo in non-cirrhotic patients.RESULTS Increased serum levels of GP73(>20 units)were detected at initial evaluation in 277 out of 632 patients(43.8%).GP73-seropositivity correlated at baseline with the presence of cirrhosis(96.4%vs 51.5%,P<0.001),decompensation of cirrhosis(60.3%vs 35.5%,P<0.001),presence of HCC(18.4%vs 7.9%,P<0.001)and advanced HCC stage(52.9%vs 14.8%,P=0.002).GP73 had higher diagnostic accuracy for the presence of cirrhosis compared to APRI score[Area under the curve(AUC)(95%CI):0.909(0.885-0.934)vs 0.849(0.813-0.886),P=0.003].Combination of GP73 with APRI improved further the accuracy(AUC:0.925)compared to GP73(AUC:0.909,P=0.005)or APRI alone(AUC:0.849,P<0.001).GP73 levels were significantly higher in HCC patients compared to non-HCC[22.5(29.2)vs 16(20.3)units,P<0.001)and positively associated with BCLC stage[stage 0:13.9(10.8);stage A:17.1(16.8);stage B:19.6(22.3);stage C:32.2(30.8);stage D:45.3(86.6)units,P<0.001]and tumor dimensions[very early:13.9(10.8);intermediate:19.6(18.4);advanced:29.1(33.6)units,P=0.004].However,the discriminative ability for HCC diagnosis was relatively low[AUC(95%CI):0.623(0.570-0.675)].Kaplan-Meier analysis showed that the detection of GP73 in patients with compensated cirrhosis at baseline,was prognostic of higher rates of decompensation(P=0.036),HCC development(P=0.08),and liver-related deaths(P<0.001)during follow-up.CONCLUSION GP73 alone appears efficient for detecting cirrhosis and superior to APRI determination.In combination with APRI,its diagnostic performance can be further improved.Most importantly,the simple GP73 measurement proved promising for predicting a worse outcome of patients with both viral and nonviral chronic liver diseases.
文摘高尔基体蛋白73(Golgi protein 73,GP73)是位于顺式高尔基体膜上的糖基化跨膜蛋白,其在肿瘤的发展进程中具有重要作用,是肿瘤治疗的潜在靶标。目前研究表明,GP73可作为辅助诊断肝细胞癌(hepatocellular carcinoma,HCC)的血清学标志物。随着GP73的深入研究,与GP73有关的微RNA(microRNA,miRNA)也逐渐被挖掘出来。GP73相关miRNA与多种肿瘤的发生、发展密切相关,其中miR-212、miR-27a等miRNA能抑制HCC的侵袭及转移,GP73与miR-27b、miR-493-5p等能作为HCC患者预后的生物标志物。因此,GP73相关miRNA用于肝癌的诊治是有前景的。本文总结了GP73及其相关miRNA在肝癌发展中的作用以及机制,希望为肝癌的机制研究和诊疗提供思路。
基金This study was supported by grants from the Ministry of S&T National Key Research and Development Program of China(2018YFC0116902)the National Natural Science Foundation of China(81673241,81702419,31872738,81873915)and Project of Jiangsu Medical Science(BE2016698).
文摘Background:Hepatic Golgi protein-73(GP73)expression is related to hepatocellular carcinoma(HCC)progression.The aim of this study was to investigate the dynamic expression of GP73 mRNA and protein during hepatocytes malignant transformation.Methods:Human GP73 expressions in 88 HCC tissues and their self-control surrounding tissues were examined by immunohistochemistry,and survival time of HCC patients was evaluated by the Kaplan-Meier method.HCC model of Sprague-Dawley rats was made by diet containing 2-fluorenylacetamide.The rats were divided into the control,hepatocyte degeneration,precanceration,and HCC groups to observe GP73 protein and mRNA alterations during hepatocytes malignant transformation.Results:The GP73 expression was significantly higher in the cancerous tissues than that in the surrounding tissues,with shorter survival time,and the positive rates of GP73 protein in human HCC tissues were 53.3%at stage I,84.0%at stage II,84.6%at stage III,and 60.0%at stage IV,respectively.The positive rates of hepatic GP73 protein and mRNA in the rat models were none in the control group,66.7%and 44.4%in the hepatocytes degeneration group,88.9%and 77.8%in the hepatocytes precanceration group,and 100%in the HCC group,respectively.There was a positive correlation(r=0.91,P<0.01)between hepatic GP73 and serum GP73 during rat hepatocytes malignant transformation.Conclusions:Abnormal GP73 expression may be a sensitive and valuable biomarker in hepatocarcinogensis.
基金Supported by a grant from the International Collaboration Program from Nanjing Science and Technology Bureau (No. 201001139)
文摘Objective: The aim of the present study was to further evaluate the clinical value of single or joint of golgi protein 73 (GP73) and alphafetoprotein (AFP) in diagnosis of hepatocellular (HCC). Methods: One hundred and eighteen, 94 and 47 serum samples from the patients with HCC, chronic liver disease (CLD) and liver cirrhosis (LC) were collected, respectively. Serum levels of AFP and GP73 were assayed with commercial kit according to the manufacturer's instructions. Results: Patients with HCC had higher serum concentration of AFP than that of the patients with CLD (P < 0.01), but was similar to that of the patients with LC. Serum GP73 levels in the patients with CLD or LC were significantly lower than that in the patients from HCC group (P < 0.01). Among 118 HCC patients, the positive rate of GP73 and AFP was 80.5% and 48.3%, respectively (P < 0.001). The ROC curve analysis showed that the AUC value of GP73 was higher than that of serum AFP. Moreover, the sensitivity and the accuracy of GP73 were 77.1% and 82.6%, respectively, which were greater more than that of AFP at 90% specificity (28.8% and 59.8%, respectively). The AUC, the sensitivity and the accuracy of GP73 in combination of AFP (AFP/GP73) were 0.855, 78.0% and 83.0%, respectively, which were similar to that of GP73 alone but were much higher than that of the single marker AFP. Conclusion: For HCC diagnosing, GP73 was more sensitive and specific than AFP. The diagnostic value of AFP/GP73 was similar to GP73 but was much higher than AFP.
文摘Objective: To study the changes of serum phosphatidylinositol proteinglycan-3 (GPC3) and Golgi protein-73 (GP73) contents in patients with liver cancer and their correlation with angiogenesis and epithelial mesenchymal transition. Methods: The patients with liver cancer who underwent surgical resection in our hospital between April 2014 and October 2017 were selected as liver cancer group, healthy subjects who received physical examination during the same period were selected as control group, and the contents of GPC3 and GP73 in serum as well as the contents of GPC3 and GP73, the expression of angiogenesis genes and epithelial mesenchymal transition genes in liver cancer lesions and adjacent lesions of the two groups of subjects were determined. Results: GPC3 and GP73 contents in serum of liver cancer group were significantly higher than those of control group, GPC3 and GP73 contents in liver cancer lesions were significantly higher than those in adjacent lesions, and the GPC3 and GP73 contents in serum of liver cancer group were positively correlated with GPC3 and GP73 contents in liver cancer lesions;SULT2B1, VEGF, Ang-2, Shh, Twist and N-cadherin mRNA expression in liver cancer lesions were significantly higher those in adjacent lesions and positively correlated with the GPC3 and GP73 contents in serum whereas TUM5, Foxg1 and E-cadherin mRNA expression were significantly lower than those in adjacent lesions and negatively correlated with the GPC3 and GP73 contents in serum. Conclusion: The increase of serum GPC3 and GP73 contents in patients with liver cancer is closely related to the aggravation of angiogenesis and epithelial mesenchymal transition in the lesions.
