Diagnostic Value of Serum Golgi Protein 73 for Liver Inflammation in Patients with Autoimmune Hepatitis and Primary Biliary Cholangitis

Background. There is lack of reliable serum biomarkers to reflect the severity of liver necroinflammation for those who suffer autoimmune liver diseases (AILDs). In this study, a previously established patient cohort was used to explore the potential of serum Golgi protein 73 (GP73) as a noninvasive marker of AILD-related liver necroinflammation. Methods. Serum GP73 concentration was measured in a retrospective cohort of 168 AILD patients, which included 74 patients with autoimmune hepatitis (AIH) and 94 with primary biliary cholangitis (PBC) who had undergone liver biopsy. Spearman’s correlation and multivariate analysis were used to evaluate the relationship between serum GP73 and liver necroinflammation. A receiver operating characteristic curve was constructed to evaluate the value of GP73 for the prediction of moderate or severe liver necroinflammation. The diagnostic value of serum GP73 was also compared with that of alkaline phosphatase (ALP) in patients with PBC. Histologically, immunohistochemical analysis was performed to assess hepatic GP73 expression. Results. Both the serum level and hepatic tissue expression of GP73 protein were aberrantly elevated and correlated well with the severity of necroinflammation in both AIH ( rho = 0.655 , P < 0.001 ) and PBC ( rho = 0.547 , P < 0.001 ) patients. The results here suggested that serum GP73 could be an independent biomarker to reflect the severity of liver necroinflammation. The AUROCs for GP73 to predict moderate necroinflammation (≥G2) and severe necroinflammation (≥G3) in patients with AIH were 0.828 and 0.832, respectively. Moreover, the AUROCs of serum GP73 for the identification of moderate necroinflammation (≥G2) ( AUROC = 0.820 , P < 0.001 ) and severe necroinflammation (≥G3) ( AUROC = 0.803 , P < 0.001 ) were superior to those of ALP (≥G2: AUROC = 0.607 , P = 0.028 and ≥G3: AUROC = 0.559 , P = 0.357 ) in patients with PBC. Mechanically, interlukin-6 (IL-6), the proinflammatory and prohepatic regenerating cytokine, could transcriptionally upregulate GP73 gene expression. Conclusion. Serum GP73 is a potential noninvasive biomarker to evaluate the severity of liver necroinflammation in patients with AILDs.

Assessment of Non-invasive Markers for the Prediction of Esophageal Variceal Hemorrhage

Background: Esophageal variceal (EV) hemorrhage is a life-threatening consequence of portal hypertension in cirrhotic patients. Screening upper endoscopy and endoscopic variceal ligation to identify and treat EVs have contraindications, complications, and high costs. We sought to identify non-invasive tests (NITs) as alternatives to endoscopic EV screening.Methods: In this case-control study, we retrospectively analyzed 286 cirrhotic patients treated for EVs at the Second People's Hospital of Fuyang City, China from January to December 2019. We applied ROC curve analysis to assess the accuracy of various NITs in predicting EV hemorrhage.Results: There were significant differences between the hemorrhage and non-hemorrhage groups in median serum albumin (ALB) (p &lt; 0.001), median bilirubin (TBIL) (p &lt; 0.046), prothrombin (PT) time (p &lt; 0.001), Golgi protein 73 (GP73; p = 0.012) and Child-Pugh (C-P) scores (p &lt; 0.001). For ALB (cutoff &lt;33.2g/L), PT time (cutoff &gt; 14.2 seconds), GP73 (cutoff &gt; 126.4 ng/ml), and C-P scores, the areas under the ROC curves (AUCs) were 73.4% (95% CI: 67.5–79.2), 68.6% (95% CI: 62.4–74.8), 62.2% (95% CI: 52.8–71.5) and 69.8% (95%CI: 63.8–75.8), respectively, with corresponding sensitives of 71.5, 59.8, 69.8, and 92.2% and specificities of 65.6%, 70.1%, 56.5%, and 38.6%. When ALB was combined with GP73, the AUC was 74.3% (95% CI: 66.1–82.5) with a sensitivity of 65.1% and specificity of 76.5%. When ALB, PT, and C-P scores were combined, the AUC was 76.5% (95% CI: 70.9–82.1) with a sensitivity of 79.5% and specificity of 64.3%. When ALB, PT, GP73, and C-P scores were combined, the AUC was 75.2% (95% CI: 67.3–83.1) with a sensitivity of 54.0% and specificity of 86.9%.Conclusion: ALB, TBIL, GP73, and C-P scores, may be used to predict EV hemorrhage in cirrhotic patients. The combination of multiple NITs is better than a single index and can increase diagnostic performance.

Use of GP73 in the diagnosis of non-alcoholic steatohepatitis and the staging of hepatic fibrosis

Objective To evaluate the utility of Golgi protein 73 (GP73) in the diagnosis of non-alcoholic steatohepatitis (NASH) and hepatic fibrosis (HF) staging. Methods Ninety-one patients with non-alcoholic fatty liver disease (NAFLD) were allocated to NAFL (n = 46) and NASH (n = 45) groups according to their NAFLD activity score (NAS), and there were 30 healthy controls. Serum GP73 was measured by ELISA, GP73 protein expression was evaluated using immunohistochemistry, and FibroScan was used to determine liver hardness. Results The serum GP73 concentrations of the NAFL and NASH groups were significantly higher than those of controls. GP73 expression in the liver of the patients gradually progressed from absent or low to moderate or high. Serum GP73 positively correlated with liver expression, and the serum and liver GP73 of the patients positively correlated with FibroScan value and HF stage. There was a strong positive correlation of the combination of alanine aminotransferase, gamma glutamyl transferase and GP73 with NASH. The combination of serum GP73 and FibroScan value was found to predict NASH (NAS > 4) and advanced HF (stage ≥2) in patients with NAFLD using receiver operating characteristic analysis. Conclusion Serum GP73 may be useful in the diagnosis of NASH and the staging of HF.

GP73-mediated secretion of AFP and GP73 promotes proliferation and metastasis of hepatocellular carcinoma cells

Golgi protein 73 (GP73) and alpha fetoprotein (AFP) serve as biomarkers for the diagnosis of hepatocellular carcinoma (HCC), and their serum levels correlate with patients’ outcomes. However, the mechanisms underlying these correlations are unknown. Here we show that GP73 increased the secretion of AFP through direct binding to AFP, thereby promoting the proliferation and metastasis of HCC cells that expressed AFP and its receptor (AFPR). Extracellular GP73 contributed to the proliferation and metastasis of HCC cells independent of AFP and AFPR. Moreover, extracellular AFP and GP73 synergized to enhance the malignant phenotype of HCC cells. Furthermore, extracellular GP73 and AFP inhibited the antitumor effects of sorafenib and synergistically increased the drug resistance of HCC cells. These findings, which reveal the mechanism of GP73-mediated secretion of AFP and its effects on the malignant phenotype of HCC cells, provide a comprehensive theoretical basis for the diagnosis and treatment of HCC and identify potential drug targets.

Meta-QTLs, ortho-MQTLs and candidate genes for thermotolerance in wheat (Triticum aestivum L.)

Meta-QTL analysis for thermotolerance in wheat was conducted to identify robust meta-QTLs (MQTLs). In this study, 441 QTLs related to 31 heat-responsive traits were projected on the consensus map saturated with 50,310 markers. This exercise resulted in the identification of 85 MQTLs with confidence interval (CI) ranging from 0.11 to 34.9 cM with an average of 5.6 cM. This amounted to a 2.96 fold reduction relative to the mean CI (16.5 cM) of the QTLs used. Seventy-seven (77) of these MQTLs were also verified with the results of recent genome-wide association studies (GWAS). These MQTLs included seven MQTLs that are particularly useful for breeding purposes (we called them Breeders’ MQTLs). Seven ortho-MQTLs between wheat and rice genomes were also identified using synteny and collinearity. The MQTLs were used for the identification of 1,704 candidate genes (CGs). In silico expression analysis of these CGs permitted identification of 182 differentially expressed genes (DEGs), which included 36 high-confidence candidate genes (CGs) with known functions previously reported to be important for thermotolerance. These high confidence CGs encoded proteins belonging to the following families: protein kinase, WD40 repeat, glycosyltransferase, ribosomal protein, SNARE associated Golgi protein, GDSL lipase/esterase, SANT/Myb domain, K homology domain, etc. Thus, the present study resulted in the identification of MQTLs (including breeders’ MQTLs), ortho-MQTLs, and underlying CGs, which could prove useful not only for molecular breeding for the development of thermotolerant wheat cultivars but also for future studies focused on understanding the molecular basis of thermotolerance.

Accuracy of Serum Golgi Protein 73 and Alpha Fetoprotein (AFP) to Diagnose Hepatocellular Carcinoma

Background: Hepatocellular Carcinoma (HCC) is one of the most common malignancy in the liver. Modalities of diagnostic are often an obstacle in HCC surveillance. Alpha fetoprotein (AFP) is one of protein that often used in the diagnostic of HCC in chronic liver disease. Golgi protein 73 (GP73), is one of the candidate biomarkers in early diagnostic of HCC and found in biliary epithelial cells but rarely expressed by normal hepatocytes. Expression of GP73 was reported to be increased in a large number of malignancies. Aims of this study to evaluate differences in Golgi protein 73 serum (sGP73) and AFP in diagnosing hepatocellular carcinoma in patients with liver cirrhosis. Materials and Methods: This cross-sectional study was conducted at Haji Adam Malik Hospital in 2020. Serum level of GP73 and others biomarker was detected using enzyme-like immunosorbent assay. Results: From 90 subjects, Liver cirrhosis and HCC group had significantly higher AFP than the control group. AFP was superior in determining HCC to GP73. At a cut off value of > 394.5.00 ng/mL, AFP yielded a sensitivity of 83.3% and specificity of 67%, for discriminating liver cirrhosis and HCC (AUC 0.84), while GP73 with cut off value of > 82.5 ng/mL, sensitivity of 70% and specificity of 57% (AUC 0.74). Conclusion:GP73 was significantly higher in HCC patients in comparison to non-HCC patients and healthy population. Compared with alpha fetoprotein, GP73 was superior in discriminating HCC in healthy population but inferior in group of liver cirrhosis. Keywords: Golgi Protein 73, Alpha Fetoprotein, Hepatocellular carcinoma.

Serum Cartilage Oligomeric Matrix Protein and Golgi Protein-73: New Diagnostic and Predictive Tools for Liver Fibrosis and Hepatocellular Cancer?

The cartilage oligomeric matrix protein (COMP) and Golgi-protein-73 (GP73) have been proposed as markers of liver fibrosis and hepatocellular carcinoma (HCC). Our aim was to assess the performance of the combination of these markers in diagnosing cirrhosis and predicting HCC development. Sera from 288 consecutive patients with chronic liver diseases were investigated by using COMP and GP73-ELISAs. Dual positivity for COMP (>15 U/L) and GP73 (>20 units) was observed in 24 (8.3%) patients, while 30 (10.4%) were GP73(+)/COMP(−), 37/288 (12.8%) GP73(−)/COMP(+), and 197 (68.5%) GP73(−)/COMP(−). Positivity for both markers was associated with cirrhosis [23/24 (95.8%) for GP73(+)/COMP(+) vs. 22/30 (73.3%) for GP73(+)/COMP(−) vs. 25/37 (67.6%) for GP73(−)/COMP(+) vs. 46/197 (23.4%) for GP73(−)/COMP(−); P < 0.001]. The combination of GP73, COMP, the aspartate aminotransferase/platelets ratio index, and the Fibrosis-4 score had even higher diagnostic accuracy to detect the presence of cirrhosis [AUC (95% CI): 0.916 (0.878–0.946)] or significant liver fibrosis (METAVIR ≥ F2) [AUC (95% CI): 0.832 (0.768–0.883)] than each marker alone. Kaplan-Meier analysis showed that positivity for both GP73 and COMP was associated with higher rates of HCC development (P < 0.001) and liver-related deaths (P < 0.001) during follow-up. In conclusion, the combination of GP73 and COMP seems efficient to detect cirrhosis and predict worse outcomes and the development of HCC in patients with chronic liver diseases.