Expression of circulating annexin A2 in hepatic diseases and hepatocellular carcinoma

Abstract

Background and objectives: Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer related mortality worldwide. The identification of new high-sensitivity and high-specificity markers for HCCis essential. Annexin A2 (ANXA2) plays an important role in the pathogenesis of multiple malignancies particularly HCCs and its expression strongly also affects the outcomes of HCC patients. This study aimed to investigate the clinical utility of hepatic and circulating Annexin A2 expression levels as a novel diagnostic marker of HCC and to correlate its level with alpha fetoprotein (AFP), the current marker ofHCC. Patients and methods: A total number of 40 patients(6 patients with chronic hepatitis, 8 patients with liver fiberosis, 6 patients with liver cirrhosis, 8 patients with early HCC and 12 patients with late HCC). The same number of age and sex matched healthy people was enrolled as a control group. All patients and controls were subjected to full medical history, complete medical examination abdominal sonography, laboratory investigations including liver function tests, AFP, platelet count, Prothrombin time and concentration, HBsAg, anti-HCV and serum HCV RNA quantitation by real time PCR. Liver biopsies were done for all patients. Evaluation of serum ANXA2 level for all patient and controlgroups was detected by using a human ANXA2 ELISA kit. Analyzing the ANXA2 expression at mRNA and protein levels was detected for patient groups by using RT-PCR by immunohistochemistry staining, respectively. Results: Serum ANXA2was significantly increased in all patient groups (except for chronic hepatitis group) compared to the control group (P<0.01). The serological evaluation and expression of ANXA2 levels were significantly increased in early HCC compared to serum AFP. ANXA2 expression was localized in both cell membrane and cytoplasm in HCC tissue, not detected in normal tissues and limited to some hepatocytes in chronic hepatitis patients. Over expression of ANXA2 mRNA levelwas present in HCC tissues compared to other patient groups (P<0.001). There was a significant relation with HCV infection, (P<0.001) when comparing ANXA2 values among positive and negative HCV RNA in HCC patients. No correlations were found between serum ANXA2 levels with serum AST,ALT, platelet count, INR and HBsAgin comparison to controls. Conclusion: Our results demonstrated increased levels of ANXA2 in both of tissues and sera of HCC patients and also in both AFP-positive and-negative cases. Results of serumANXA2 was concomitant with hepatic ANXA2 expression by RT-PCR and immunocytochemistry staining. Remarkably, Combination of conventional serum marker AFP with serumANXA2 may complement and benefit for early HCC detection.

Role of annexin A2 and osteopontin for early diagnosis of hepatocellular carcinoma in hepatitis C virus patients

“…The ROC curve for ANXA2 for detection of HCC was significant, the cutoff point was 10.1 (ng/ml) with sensitivity of 85.0% and specificity of 85.0%. These results are compatible with El-Gezawy et al who reported for early stage HCC, ANXA2 (optimal cutoff of 24.99 IU/ml), higher sensitivity, and specificity (79.34% and 85.56% respectively) than those of AFP (optimal cutoff of 5.96 IU/ml) (67.78% and 59.85% respectively) [18]. The ANXA2 mRNA expression level was obviously, significantly higher and over expressed in HCC tissues rather than in the other patient groups.…”

“…In the present study, ANXA2 level was found to be significantly higher in early HCC patients than chronic hepatitis C patients. These results are compatible with El-Gezawy et al who pastulated that ANXA2 was significantly higher in early HCC patients than cirrhotic patients [18]. Shaker et al also reported that ANXA2 was significantly higher in early HCC patients than chronic liver disease (CLD) patients [24].…”

“…However, no significant correlation was noted between annexin level and other parameters. There was no significant correlation between ANXA2 level and AFP; this agrees with the studies done by El-Gezawy et al [18], Shaker MK et al [24], and Sun et al [13]. The correlation coefficient between serum ANXA2 and AFP values was not significant, indicating that measuring both markers (AFP and ANXA2) in serum can improve the diagnostic value.…”

“…Also, these results were in agreement with that of El-Tayeh et al who explained his results by an increase in the selective transcriptional activation of the AFP gene in malignant hepatocytes, which resulted in the increased secretion of AFP during the development of HCC [17]. On the other hand, these results are incompatible with El-Gezawy et al who postulated that there was a similarity and no significant difference between the early HCC and cirrhotic groups as regards AFP [18].…”

Calcium channel α2δ1 subunit as a novel biomarker for diagnosis of hepatocellular carcinoma

“…Zhang et al 32 who dynamically studied the proteins related to hepatic fibrogenesis in various stages (S0-1, S2, and S3-4) through plasma membrane proteomic technology, found that annexin A2 was highly elevated in S4 compared to that S0-1 and concluded that annexin A2 was a valid biomarker for non-invasive diagnosis of hepatic fibrosis. Elgezawy et al 33 also found that the serum annexin A2 level was significantly elevated in liver fibrosis, liver cirrhosis, early and late HCC, but was not elevated in patients with chronic hepatitis compared with the control group ( P < 0.01).…”