Circulating hypoxia marker carbonic anhydrase IX (CA9) in patients with hepatocellular carcinoma and patients with cirrhosis

Abstract

Background and aimsExpression of carbonic anhydrase IX (CA9), an enzyme expressed in response to hypoxia, acidosis and oncogenic alterations, is reported to be a prognostic factor in HCC patients. Here we evaluated serum CA9 levels in HCC and cirrhosis patients.MethodsHCC and cirrhosis patients were prospectively recruited and CA9 levels were determined. CA9 levels were compared to stages of cirrhosis and HCC stages. The association of the CA9 levels and overall survival (OS) was assessed. Furthermore, immunohistochemical CA9 expression in HCC and cirrhosis was evaluated.Results215 patients with HCC were included. The median serum CA9 concentration in patients with HCC was 370 pg/ml and significantly higher than in a healthy cohort. Patients with advanced cancer stages (BCLC and ALBI score) had hid significant higher levels of CA9 in the serum. HCC patients with high serum CA9 concentrations (>400 pg/ml) had an increased mortality risk (hazard ratio (HR) 1.690, 95% confidence interval (CI) 1.017–2.809, P = 0.043). Serum CA9 concentration in cirrhotic patients did not differ significantly from HCC patients. Higher CA9 levels in cirrhotic patients correlated with portal hypertension and esophageal varices. Patients with ethanol induced cirrhosis had the highest CA9 levels in both cohorts. Levels of CA9 did not correlate with immunohistochemical expression.ConclusionsWe conclude that a high CA9 level is a possible prognostic indicator for a poor outcome in HCC patients. The high CA9 levels are probably mainly associated with portal hypertension. Ductular reactions might be a possible source of serum CA9.

Identification of a Subtype of Hepatocellular Carcinoma with Poor Prognosis Based on Expression of Genes within the Glucose Metabolic Pathway

“…By comparing the gene expression profiling between the two subtypes, we found that the aggressive Cluster2 tumors had significantly upregulated expression of stemness-related genes such as CA9, EpCAM, MMP9, KRT19, CD24, and PROM1 (CD133). These are well-known markers of stemness traits and are associated with poorer prognostic outcomes in HCC [18,[59][60][61][62]. Based on integrative analysis of genomic and epigenomic data in liver cancer, Woo et al also identified one aggressive cluster of the HCC subtype (iCl1) with the previously mentioned stemness-related genes being on top of the upregulated genes [17], which is similar to our finding.…”

“…Similar to the findings of Woo et al [17], we found that CA9 was the most upregulated gene in Cluster2 of TCGA data with more than a 20-fold difference ( Figure 7A). As a marker of hypoxia, overexpression of CA9 is a poor prognostic marker in HCC, and its expression is associated with stemness-related phenotypes in HCC [17,18]. Our results also showed that increased CA9 expression was significantly associated with a poor prognosis of OS (p = 0.0002, HR: 1.085 with 95% CI (1.04, 1.132)).…”

A Molecular Subtype Model for Liver HBV-Related Hepatocellular Carcinoma Patients Based on Immune-Related Genes

“…AFP expression mainly occurs in fetal liver cells, and although AFP disappears from the blood about 2 weeks after birth, its overexpression can be detected in liver cancer patients. As a marker of hypoxia, CA9 is also a marker for poor prognosis in HCC, and recent studies show that its expression is related to stem cell phenotypes (44,45). This indicates that molecular subtype C2 may be related to stem cell characteristics.…”

The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

“…Tumorigenic signaling and induced tumor hypoxia in mal-perfused regions of tumors are main features of tumorigenesis. The expression of oncogenic CAs such as CA IX or CA XII is enhanced in hypoxic regions [85][86][87][88][89][90][91]. These enzymes help to maintain an acidic environment and produce HCO3 − to serve HCO3 − transporters.…”