Altered Serum Annexin A2 Might Be a New Potential Diagnostic Biomarker in Human Colorectal Cancer.

OBJECTIVE: Annexin A2 is a calcium dependent phospholipid binding protein that is a biomarker in cancers. However, the value of serum Annexin A2 in the diagnosis of colorectal cancer (CRC) is not clear. This study aimed to investigate clinical utility of serum Annexin A2 as a potential biomarker for CRC. METHODS: Annexin A2 was analyzed in 20 cases of CRC tissues and 20 controls of normal adjacent paired tissues. Serum Annexin A2 was calculated in 59 CRC patients and 44 healthy subjects. Receiver operating characteristic (ROC) curve and logistic regression were utilized to evaluate the diagnostic effectiveness and construct diagnostic model. RESULTS: Annexin A2 in CRC tissues was slightly higher than in normal adjacent paired tissues (χ2=6.0652, p<0.05). Serum Annexin A2 in CRC patients was significantly lower than in healthy controls (p<0.05). Besides, the levels of serum Annexin A2 were lower in patients with poor tumor differentiation than in well or moderate tumor differentiation (p=0.0111). ROC analysis indicated the diagnostic efficacy of serum Annexin A2 was better than carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA199) for CRC. Furthermore, joint detection of Annexin A2 and CEA had the maximum area under the ROC curve (AUC) in discriminating CRC from healthy controls (AUC 0.931, sensitivity 86.4%, specificity 84.7%, positive predictive value 87.9%, and negative predictive value 82.2%). CONCLUSIONS: Serum Annexin A2 may be a non-invasive and promising biomarker for the diagnosis of CRC, and the joint detection of Annexin A2 and CEA may have been favorable clinical applied value in the diagnosis of CRC.

Circulating annexin A2 as a biomarker in patients with pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a highly lethal malignancy. There are only few predictive or prognostic markers for PC. This study was conducted to investigate the serum levels of annexin A2 (AnxA2) in patients with PC and its relationship with tumor progression and known prognostic parameters. MATERIALS AND METHODS: Serum samples were obtained on the first admission before any treatment. Serum AnxA2 levels were determined using enzyme-linked immunosorbent assay. Age- and sex-matched healthy controls were included in the analysis. All statistical tests were carried out using two-sided test, and P ≤ 0.05 was considered statistically significant. RESULTS: The median age at diagnosis was 59 years. The most common metastatic site was liver in 23 patients with metastasis (n = 19, 83%). At the end of the observation period, thirty-two patients (97%) were dead. Thirty-nine percent of 23 metastatic patients who received palliative chemotherapy (CTx) were CTx responsive. Median overall survival of the whole group was 41.3 ± 8.3 weeks (95% confidence interval = 25-58 weeks). The baseline serum AnxA2 levels were significantly higher in patients with PC than in the control group (P = 0.01). Serum AnxA2 levels were significantly higher in the patients with high erythrocyte sedimentation rate (P = 0.04). Conversely, serum AnxA2 concentration had no prognostic role on survival (P = 0.18). CONCLUSIONS: AnxA2 is identified as a novel secretory biomarker for PC, but it has no role as a prognostic or predictive marker.

[Serum annexin A2 level is significantly elevated in patients with coronary heart disease].

OBJECTIVE: To analyze the correlation of annexin A2 with coronary atherosclerotic heart disease (CAD) and the severity of CAD. METHODS: We collected data from a total of 200 inpatients admitted in our department between August, 2017 and August, 2019. According to the. RESULTS: of coronary angiography, the patients were divided into CAD group (n=150) and non-CAD (n=50), and the CAD patients was further divided, according to their clinical stability, into stable angina (SAP) group and acute coronary syndrome (ACS) group. Serum levels of annexin A2, MPO and PON1 were detected in all these patients, and their correlations with CAD, disease severity, and degree of coronary artery stenosis were analyzed.ResultsThe levels of annexin A2 and MPO were significantly higher in CAD patients than in non-CAD patients (P < 0.05). Among the CAD patients, those with ACS had significantly higher levels of annexin A2 (P < 0.05) and lower levels of PON-1 (P < 0.05) than those with SAP, but annexin A2 level was not significantly correlated with coronary lesion count, Gensini score, or the co-morbidity of diabetes. CONCLUSIONS: Annexin A2 is significantly elevated in patients with CAD, especially in those with ACS, and can be used as a predictor of clinical instability.

Serum exosomal-annexin A2 is associated with African-American triple-negative breast cancer and promotes angiogenesis.

BACKGROUND: Limited information is available on biomarker(s) for triple-negative breast cancer (TNBC) that can address the higher incidence and aggressiveness of TNBC in African-American (AA) women. Our previous studies have demonstrated annexin A2 (AnxA2) association with exosomes which promotes angiogenesis and metastasis. Therefore, our goal was to examine the expression and function of exosomal-annexin A2 (exo-AnxA2) derived from the serum samples of breast cancer patients. METHODS: The expression of serum exo-AnxA2 and its association with clinicopathological features of the breast cancer patients were determined. The role of serum exo-AnxA2 to promote angiogenesis was determined by an in vivo Matrigel plug assay. RESULTS: Our results show that the expression of serum exo-AnxA2 in breast cancer patients (n = 169; 83.33 ± 2.040 ng/mL, P < 0.0001) is high compared to non-cancer females (n = 68; 34.21 ± 2.238 ng/mL). High expression of exo-AnxA2 levels in breast cancer was significantly associated with tumor grade (P < 0.0001), poor overall survival (hazard ratio (HR) 2.802; 95% confidence intervals (CI) = 1.030-7.620; P = 0.0353), and poor disease-free survival (HR 7.934; 95% CI = 1.778-35.398; P = 0.0301). The expression of serum exo-AnxA2 levels was significantly elevated in TNBC (n = 68; 109.1 ± 2.905 ng/mL; P < 0.0001) in comparison to ER+ (n = 50; 57.35 ± 1.545 ng/mL), HER2+ (n = 59; 78.25 ± 1.146 ng/mL), and non-cancer females (n = 68; 34.21 ± 2.238 ng/mL). Exo-AnxA2 showed diagnostic values with a maximum AUC as 1.000 for TNBC, 0.8304 for ER+, and 0.9958 for HER2+ compared to non-cancer females. The expression of serum exo-AnxA2 was significantly elevated in AA women with TNBC (n = 29; 118.9 ± 4.086 ng/mL, P < 0.0001) in comparison to Caucasian-American TNBC (n = 27; 97.60 ± 3.298 ng/mL) patients. Our in vivo results suggest a role of serum exo-AnxA2 in angiogenesis and its association with aggressiveness of TNBC in AA women. CONCLUSIONS: Our results demonstrated that the expression of serum exo-AnxA2 is high in AA women with TNBC and promotes angiogenesis. These findings suggest that exo-AnxA2 holds promise as a potential prognosticator of TNBC and may lead to an effective therapeutic option.

The S100A10 Pathway Mediates an Occult Hyperfibrinolytic Subtype in Trauma Patients.

OBJECTIVE: To determine the characteristics of trauma patients with low levels of fibrinolysis as detected by viscoelastic hemostatic assay (VHA) and explore the underlying mechanisms of this subtype. BACKGROUND: Hyperfibrinolysis is a central component of acute traumatic coagulopathy but a group of patients present with low levels of VHA-detected fibrinolysis. There is concern that these patients may be at risk of thrombosis if empirically administered an antifibrinolytic agent. METHODS: A prospective multicenter observational cohort study was conducted at 5 European major trauma centers. Blood was drawn on arrival, within 2 hours of injury, for VHA (rotation thromboelastometry [ROTEM]) and fibrinolysis plasma protein analysis including the fibrinolytic mediator S100A10. An outcomes-based threshold for ROTEM hypofibrinolysis was determined and patients grouped by this and by D-dimer (DD) levels. RESULTS: Nine hundred fourteen patients were included in the study. The VHA maximum lysis (ML) lower threshold was determined to be <5%. Heterogeneity existed among patients with low ML, with survivors sharing similar clinical and injury characteristics to patients with normal ML values (5-15%). Those who died were critically injured with a preponderance of traumatic brain injury and had a 7-fold higher DD level (died vs. survived: 103,170 vs. 13,672 ng/mL, P < 0.001). Patients with low ML and high DD demonstrated a hyperfibrinolytic biomarker profile, low tissue plasminogen activator levels but high plasma levels of S100A10. S100A10 was negatively correlated with %ML (r = -0.26, P < 0.001) and caused a significant reduction in %ML when added to whole blood ex-vivo. CONCLUSIONS: Patients presenting with low ML and low DD levels have low injury severity and normal outcomes. Conversely, patients with low ML but high DD levels are severely injured, functionally coagulopathic and have poor clinical outcomes. These patients have low tissue plasminogen activator levels and are not detectable by ROTEM. S100A10 is a cell surface plasminogen receptor which may drive the hyperfibrinolysis in these patients and which when shed artificially lowers %ML ex-vivo.

Reciprocal regulation of pro-inflammatory Annexin A2 and anti-inflammatory Annexin A1 in the pathogenesis of rheumatoid arthritis.

Annexin A2 has been implicated in several immune modulated diseases including Rheumatoid arthritis (RA) pannus formation. The most relied treatment option for RA pathogenesis is glucocorticoids. Glucocorticoids regulate the synthesis, phosphorylation and cellular deposition of Annexin A1. This annexin mediates the anti-inflammatory actions of glucocorticoids. These two first characterized members of annexin superfamily proteins acts reciprocally, one as an anti-inflammatory and the other proinflammatory in nature. The possibility of these molecules as soluble biomarkers and as an upstream regulator of major cytokine devastation at RA microenvironment has not been previously explored. Current study elucidates the reciprocal regulation of these two annexins in RA pathogenesis. These Annexin A2/A1 and downstream cytokines in RA serum were analysed by ELISA. Western blot, Immunocytochemistry, immunoprecipitation and Immunohistochemistry were adapted to analyse these molecules in tissue and synovial fibroblasts and also in different experimental conditions. Significant increase in the level of Annexin A2 was noticed in naïve RA patients compared to controls (14.582 ± 1.766 ng/ml vs. 7.37 ± 1.450 ng/ml; p ≤ 0.001). In remission cases significant low levels was detected. On the contrary, significant decrease in the level of Annexin A1 was noticed in naïve RA patients compared to healthy controls (12.322 ± 2.91 vs. 16.998 ± 4.298 ng/ml; p ≤ 0.001), wherein remission cases serum Annexin A1 was significantly high. The knockdown of proinflammatory Annexin A2 by siRNA/antibody treatment could mimic the glucocorticoid treatment as which induced cellular Annexin A1 and membrane translocation resulting in the terminal action. Current data elucidating the regulatory interplay between Annexin A2 and Annexin A1 in RA pathogenesis.

The Role of Serum Caspase 3 Levels in Prediction of Endometriosis Severity.

BACKGROUND/AIMS: To identify the role of serum caspase 3, Annexin A2 (ANXA2), and Soluble Fas Ligand (sFasL) levels in the prediction of endometriosis severity. METHODS: The study was performed on 90 women who were candidates for laparoscopic surgery due to endometrioma or any other benign ovarian cysts detected by ultrasound examination, pelvic pain, or infertility. The control group comprised 29  patients. The second group comprised 29 patients with stage I-II endometriosis and the third group comprised 30 patients with stage III-IV endometriosis. RESULTS: Significant differences were detected between the control and stage III-IV endometriosis groups and between stage I-II and stage III-IV endometriosis groups in terms of caspase-3 levels (both, p < 0.001), ANXA2 levels (p = 0.007 and p = 0.002), and sFasL levels (p = 0.022 and p = 0.044). After receiver operating characteristic analysis, the area under curve was 93% (95% CI 57-82) at 10.7 ng/mL cut-off level for caspase-3 with 90% sensitivity and 87% specificity. CONCLUSION: Serum caspase-3 level may be a reliable predictor of endometriosis severity.

Anxa2 attenuates osteoblast growth and is associated with hip BMD and osteoporotic fracture in Chinese elderly.

Low bone mineral density (BMD) is a risk factor of osteoporotic fracture (OF). Peripheral blood monocytes (PBM) can differentiate into osteoclasts to resorb bone. It was known that PBM-expressed Anxa2 protein is associated with BMD, and extracellular Anxa2 protein promotes osteoclastogenesis. This study aimed to test 1) whether Anxa2 protein level in PBM differs significantly between subjects with OF and without fracture history (NF); 2) whether Anxa2 level in plasma is associated with BMD; 3) how Anxa2 protein at various concentrations would affect osteoblastic activity in vitro. All the study subjects were Chinese Han elderly. Firstly, Anxa2 protein in PBM was identified and quantitated by LC-MS/MS and compared between 45 OF cases and 42 healthy controls. Secondly, plasma Anxa2 protein level was quantitated by ELISA and compared between unrelated subjects with extremely low vs. high hip BMD (0.63±0.10 vs. 1.05±0.10 g/cm2, n = 75). Furthermore, in vitro functional assay was utilized to test the effects of extracellular Anxa2 protein on osteoblastic growth. We found that Anxa2 protein expression in PBM was significantly up-regulated in OF vs. NF subjects (fold change [FC)] = 1.16, P<0.05). Plasma Anxa2 protein concentration (range: 31.69-227.35ng/ml) was significantly elevated in low vs. high BMD subjects (84.85 vs. 66.15ng/ml, FC = 1.28, P<0.05). Cellular dynamical monitoring demonstrated that the general shape of dose-response relationship is the inverse U-shaped curve. Specifically, lower dose of Anxa2 protein may promote osteoblast growth and the optimal concentration for osteoblastic growth was around 50ng/ml, but even higher concentration could attenuate hFOB1.19 osteoprogenitor cell growth. We concluded that Anxa2 protein could attenuate osteoblast growth and be associated with hip BMD and OF in Chinese elderly.

Expression correlates between Annexin A1 and A2 autoantibodies in patients with Behçet's disease.

The autoantibodies profile of Behçet's disease (BD) is yet incompletely understood. Annexins are a family of highly conserved proteins which are involved in some human autoimmune diseases. Autoantibodies directed toward Annexin A1 and A2 are involved in BD pathology, but correlation in their clinical role is controversial. The aim of our study is to estimate and evaluate the expression correlation between Annexin A1 and A2 autoantibodies in BD patients. We have designed and implemented different technical approaches to prove the hypothesis. First, bioinformatics tools such as amino acid sequence alignment, epitope prediction analysis, and 3D structural comparison were performed to find out the correlation between Annexin A1 and A2. Second, amplification of the corresponding gene by RT-PCR, then cloning, and purification techniques were applied to acquire the recombinant Annexin A1. Third, the target protein band was excised from gel electrophoresis, digested with trypsin, and analyzed by MALDI-TOF/TOF. Finally, in-house ELISA was developed to determine the induced anti-Annexin A1 autoantibodies in BD patients. Obtained results demonstrated that the BD serum reactivity against recombinant Annexin A1 was significantly higher as compared with healthy control (HC) (P<0.001). Moreover, bioassay results of Annexin A1 and A2 also showed the presence, absence, and independent coexistence of autoantibodies, when reacted with BD sera. In conclusion, Annexin A1 has a similar immunogenic expression and correlation with its analog Annexin A2 and their association may be a novel immune target of BD in Han Chinese population.

Assessment of annexin A5 and annexin A2 levels as biomarkers for pre-eclampsia: A pilot study.

Deficient anticoagulant activity of annexin A5 and deficient profibrinolytic activity of annexin A2 have been linked to increased risk of thrombotic events. Placental dysfunction due to fibrin deposition/microthrombi has been implicated in the pathogenesis of pre-eclampsia (PE). In this study, we aimed to assess serum levels of annexin A5 and annexin A2 in a cohort of PE patients and investigate their role as biomarkers for the development of the disease. We examined 80 women in total; 40 healthy pregnant women and 40 pregnant women with PE after 20weeks of pregnancy. Women were subjected to full clinical assessment, ultrasonography, and laboratory testing including complete blood picture, liver and kidney function tests and assessment of serum and urine proteins. Annexin A5 and annexin A2 were analyzed using enzyme-linked immunosorbent assay. The study showed serum annexin A2 but not annexin A5 was significantly reduced (P=0.029) in women with PE (total and severe cases) compared to those with normal pregnancy. The ROC analysis of annexin A2 level for the prediction of development of PE showed an area under the curve of 0.64 (P=0.029), and the best cut-off value was 0.89ng/ml with a sensitivity of 70.0% and a specificity of 70.0%. Univariate analysis showed annexin A2 of <0.89ng/ml, proteinuria, lower platelet count and higher BP were associated with significantly higher risk to develop PE. Based on this pilot study, serum annexin A2 levels may be a useful biomarker for pre-eclampsia. However, a larger study is required before a final conclusion is made.

Annexin II-binding immunoglobulins in patients with lupus nephritis and their correlation with disease manifestations.

Annexin II on mesangial cell surface mediates the binding of anti-dsDNA antibodies and consequent downstream inflammatory and fibrotic processes. We investigated the clinical relevance of circulating annexin II-binding immunoglobulins (Igs) in patients with severe proliferative lupus nephritis, and renal annexin II expression in relation to progression of nephritis in New Zealand Black and White F1 mice (NZBWF1/J) mice. Annexin II-binding Igs in serum were measured by ELISA. Ultrastructural localization of annexin II was determined by electron microscopy. Seropositivity rates for annexin II-binding IgG and IgM in patients with active lupus nephritis were significantly higher compared with controls (8.9%, 1.3% and 0.9% for annexin II-binding IgG and 11.1%, 4.0% and 1.9% for annexin II-binding IgM for patients with active lupus nephritis, patients with non-lupus renal disease and healthy subjects respectively). In lupus patients, annexin II-binding IgM level was higher at disease flare compared with remission. Annexin II-binding IgG and IgM levels were associated with that of anti-dsDNA and disease activity. Annexin II-binding IgG and IgM levels correlated with histological activity index in lupus nephritis biopsy samples. In NZBWF1/J mice, serum annexin II-binding IgG and IgM levels and glomerular annexin II and p11 expression increased with progression of active nephritis. Annexin II expression was present on mesangial cell surface and in the mesangial matrix, and co-localized with electron-dense deposits along the glomerular basement membrane. Our results show that circulating annexin II-binding IgG and IgM levels are associated with clinical and histological disease activity in proliferative lupus nephritis. The co-localization of annexin II and p11 expression with immune deposition in the kidney suggests pathogenic relevance.

Alterations of p11 in brain tissue and peripheral blood leukocytes in Parkinson's disease.

Individuals with Parkinson's disease (PD) often suffer from comorbid depression. P11 (S100A10), a member of the S100 family of proteins, is expressed widely throughout the body and is involved in major depressive disorder and antidepressant response. Central p11 levels are reduced in postmortem tissue from depressed individuals; however, p11 has not yet been investigated in PD patients with depression or those without depression. We investigated p11 levels in postmortem PD brains and assessed whether peripheral p11 levels correlate with disease severity. Substantia nigra, putamen, and cortical p11 protein levels were assessed in postmortem brain samples from PD patients and matched controls. In a different set of postmortem brains, p11 mRNA expression was measured in dopaminergic cells from the substantia nigra. Both p11 protein and mRNA levels were decreased in PD patients. Peripheral p11 protein levels were investigated in distinct leukocyte populations from PD patients with depression and those without depression. Monocyte, natural killer (NK) cell, and cytotoxic T-cell p11 levels were positively associated with the severity of PD, and NK cell p11 levels were positively associated with depression scores. Given that inflammation plays a role in both PD and depression, it is intriguing that peripheral p11 levels are altered in immune cells in both conditions. Our data provide insight into the pathological alterations occurring centrally and peripherally in PD. Moreover, if replicated in other cohorts, p11 could be an easily accessible biomarker for monitoring the severity of PD, especially in the context of comorbid depression.

Decreased S100B serum levels after treatment in bipolar patients in a manic phase.

BACKGROUND: Previous studies have suggested that patients with bipolar disorder might have brain damage. The aim of this study was to investigate the serum levels of brain injury biomarkers and S100A10 in bipolar patients in a manic phase, and evaluate the changes in S100B, neuron specific enolase (NSE), heat shock protein 70 (HSP70) and S100A10 after treatment. METHOD: We consecutively enrolled 17 bipolar inpatients in a manic phase and 30 healthy subjects. Serum brain injury biomarkers and S100A10 were measured with assay kits. All patients were evaluated by examining the correlation between brain injury biomarkers and Young Mania Rating Scale (YMRS) scores. RESULT: We found significantly decreased S100B levels only in bipolar manic patients after treatment (p=0.002), but S100B levels were not significantly different from those in healthy controls (p>0.05). CONCLUSION: Our results indicate there were decreased S100B serum levels in bipolar patients in a manic phase after treatment and that increased serum S100B levels might be a possible indicator of transient disruption of the blood-brain barrier in bipolar patients in a manic phase.

Serum Annexin A2 Level Is Associated With Diagnosis and Prognosis in Patients With Oral Squamous Cell Carcinoma.

PURPOSE: In several human cancer types, serum annexin A2 levels are increased, but little is known regarding oral squamous cell carcinoma (OSCC). This study aimed to measure serum annexin A2 levels in OSCC patients and assess the association with diagnosis and prognosis. MATERIALS AND METHODS: This case-control study compared serum annexin A2 concentrations in a group of OSCC patients and a control group. The predictor variable was the presence or absence of OSCC, and the outcome variable was the level of serum annexin A2. Annexin A2 concentrations were measured with an enzyme-linked immunosorbent assay, and correlations with clinicopathologic characteristics of OSCC were further evaluated. Receiver operating characteristic (ROC) curves, Kaplan-Meier curves, log-rank analyses, and a Cox proportional hazards model were used to evaluate the diagnostic and prognostic value of annexin A2. RESULTS: Serum samples were taken from 399 individuals: 126 patients with OSCC (aged 62.7 ± 10.6 years, 79 men and 47 women); 115 patients with benign oral disease (aged 63.9 ± 10.8 years, 73 men and 42 women); and 158 healthy controls (aged 65.4 ± 12.8 years, 92 men and 66 women). The annexin A2 level was significantly higher in OSCC patients than in patients with benign disease and controls (27.1 ± 9.81 ng/mL vs 15.9 ± 6.97 ng/mL and 15.0 ± 6.69 ng/mL, respectively). To distinguish OSCC patients from the other 2 groups, ROC curve-area under the ROC curve (AUC) analysis for serum annexin A2 levels provided an AUC of 0.80 (sensitivity, 0.62; specificity, 0.87) and an AUC of 0.77 (sensitivity, 0.57; specificity, 0.89). Furthermore, OSCC patients with high annexin A2 levels had poorer overall survival. CONCLUSIONS: This study suggested that an elevated serum annexin A2 level might be a novel diagnostic and prognostic biomarker for OSCC patients.

Annexin A2 and its downstream IL-6 and HB-EGF as secretory biomarkers in the differential diagnosis of Her-2 negative breast cancer.

Background AnnexinA2 (AnxA2) membrane deposition has a critical role in HB-EGF shedding as well as IL-6 secretion in breast cancer cells. This autocrine cycle has a major role in cancer cell proliferation, migration and metastasis. The objective of the study is to demonstrate annexinA2-mediated autocrine regulation via HB-EGF and IL-6 in Her-2 negative breast cancer progression. Methods Secretory annexinA2, HB-EGF and IL-6 were analysed in the peripheral blood sample of Her-2 negative ( n = 20) and positive breast cancer patients ( n = 16). Simultaneously, tissue expression was analysed by immunohistochemistry. The membrane deposition of these secretory ligands and their autocrine regulation was demonstrated using triple-negative breast cancer cell line model. Results Annexina2 and HB-EGF expression are inversely correlated with Her-2, whereas IL-6 expression is seen in both Her-2 negative and positive breast cancer cells. RNA interference studies and upregulation of annexinA2 proved that annexinA2 is the upstream of this autocrine pathway. Abundant soluble serum annexinA2 is secreted in Her-2 negative breast cancer (359.28 ± 63.73 ng/mL) compared with normal (286.10 ± 70.04 ng/mL, P < 0.01) and Her-2 positive cases (217.75 ± 60.59 ng/mL, P < 0.0001). In Her-2 negative cases, the HB-EGF concentrations (179.16 ± 118.81 pg/mL) were highly significant compared with normal (14.92 ± 17.33 pg/mL, P < 0.001). IL-6 concentrations were increased significantly in both the breast cancer phenotypes as compared with normal ( P < 0.001). Conclusion The specific expression pattern of annexinA2 and HB-EGF in triple-negative breast cancer tissues, increased secretion compared with normal cells, and their major role in the regulation of EGFR downstream signalling makes these molecules as a potential tissue and serum biomarker and an excellent therapeutic target in Her-2 negative breast cancer.

Evaluation of annexin A2 and as potential biomarkers for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) ranks as the fifth most common malignancy worldwide. Early detection of HCC is difficult due to the lack of reliable markers. We aimed to assess the diagnostic role of annexin A2 (ANXA2) and follistatin as serum markers for HCC patients. This study included 50 patients with confirmed diagnosis of HCC, 30 patients with chronic liver disease, and 20 normal persons. Subjects performed thorough assessment and laboratory investigations. Serum levels of alpha fetoprotein (AFP), annexin A2, and follistatin were measured using ELISA technique. Annexin A2 significantly increased in the sera of HCC patients (median, 69.6 ng/ml) compared to chronic liver disease patients (median, 16.8 ng/ml) and control group (median, 9.5 ng/ml) (p < 0.001). Follistatin was higher in sera of HCC patients (median, 24.4 ng/ml) compared to the control group (median, 4.2 ng/ml) (p = 0.002) while no such significant difference was achieved between HCC and chronic liver disease patients. At a cutoff level 29.3 ng/ml, area under the receiver-operating characteristic curve for ANXA2 was 0.910 (95 % confidence interval (CI) 0.84-0.97). For follistatin, it was 0.631 (95 % confidence interval 0.52-0.74) at cutoff level 15.7 ng/ml. Combining both annexin A2 and AFP increased the diagnostic efficiency (98 % specificity, LR + 41 and 97.6 % PPV). Follistatin combined with AFP provided 92 % specificity while lower sensitivity (50 %) was observed. Serum ANXA2 is a promising biomarker for HCC, certainly when measured with AFP. Follistatin could not differentiate between HCC and chronic liver disease, but its combination with AFP improved the specificity for HCC diagnosis.

Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma.

Hepatic annexin A2 (ANXA2) orchestrates multiple biologic processes and clinical symptoms and plays a key role in development, metastasis, and drug resistance of lethal hepatocellular carcinoma (HCC). However, the prognostic significance of ANXA2 for HCC has not been elucidated up to now. In this study, ANXA2 was frequently found to be up-regulated in HCC tissues compared with benign liver disease (BLD) tissues, which was consistent with the results in serum samples and tissue specimens of patients with HCC. Furthermore, ANXA2 expression was significantly correlated with differentiated degree, intrahepatic metastasis, portal vein thrombus, and tumor node metastasis (TNM) staging. More importantly, increased ANXA2 level was first confirmed to be closely associated with shortened overall survival of HCC (χ (2) = 12.872, P = 0.005) and identified as an independent prognostic factor (hazard ratio 1.338, 95 % confidence interval (CI) 1.013 ~ 1.766, P = 0.040), suggesting that ANXA2 up-regulation might represent an acquired metastasis phenotype of HCC, help to screen out high-risk population for HCC, or more effectively treat a subset of postsurgical HCC patients positive for ANXA2.

Circulating annexin A2 as a biomarker in gastric cancer patients: correlation with clinical variables.

Annexin A2 (ANXA2) plays an important role in the pathogenesis of multiple malignancies and its expression strongly also affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of ANXA2 in patients with gastric cancer. A total of 63 patients with a pathologically confirmed diagnosis of gastric cancer were enrolled into this study. Serum ANXA2 concentrations were determined by the solid-phase sandwich ELISA method. Age- and sex-matched 30 healthy controls were included in the analysis. The median age at diagnosis was 62years, range 28 to 82years. The baseline serum ANXA2 levels of the gastric cancer patients were a significantly higher than those in the control group (P<0.001). The known clinical variables including age of patient, gender, site of lesion, histology, histological grade, stage of disease, and serum levels of LDH, carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19.9 were not found to be correlated with serum ANXA2 concentrations (P>0.05). However, the chemotherapy-unresponsive patients had higher serum ANXA2 levels compared with chemotherapy-responsive ones (P=0.04). Conversely, serum ANXA2 concentration was found no prognostic role on survival (P=0.53). In conclusion, serum levels of ANXA2 may have a good diagnostic and predictive marker for response to chemotherapy in patients with gastric cancer and have not associated with prognosis.

Annexin-A2 as predictor biomarker of recurrent disease in endometrial cancer.

Endometrial carcinomas, the most common malignant tumour of the female genital tract, are usually diagnosed at an early stage with uterine-confined disease and an overall favourable prognosis. However, up to 20% of endometrial carcinomas will end up in recurrent disease, associated with a drop in survival and representing the major clinical challenge. Management of this group of risk patients relies on robust biomarkers that may predict which endometrial carcinomas will relapse. For this, we performed a proteomic analysis comparing primary lesions with recurrences and identified ANXA2 as a potential biomarker associated with recurrent disease that we further validated in an independent series of samples by immunohistochemistry. We demonstrated in vitro a role for ANXA2 in the promotion of metastasis rather than interfering with sensitivity to radio/chemotherapy. In addition, ANXA2 silencing resulted in a reduced metastatic pattern in a mice model of endometrial cancer dissemination, with a limited presence of circulating tumor cells. Finally, a retrospective study in a cohort of 93 patients showed that ANXA2 effectively predicted those endometrioid endometrial carcinomas that finally recurred. Importantly, ANXA2 demonstrated a predictive value also among low risk Stage I endometrioid endometrial carcinomas, highlighting the clinical utility of ANXA2 biomarker as predictor of recurrent disease in endometrial cancer. Retrospective and prospective studies are ongoing to validate ANXA2 as a potential tool for optimal stratification of patients susceptible to receive radical surgery and radio/chemotherapy.