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. Author manuscript; available in PMC: 2020 Aug 1.
Published in final edited form as: Surgery. 2019 Jun 3;166(2):150–156. doi: 10.1016/j.surg.2019.04.011

High expression of Annexin A2 is associated with DNA repair, metabolic alteration, and worse survival in pancreatic ductal adenocarcinoma

Hideo Takahashi 1,*, Eriko Katsuta 1,*, Li Yan 2, Subhamoy Dasgupta 3, Kazuaki Takabe 1,4,5,6,7
PMCID: PMC6661011  NIHMSID: NIHMS1528668  PMID: 31171367

Abstract

Introduction:

Annexin A2 (ANXA2) is a known driver of cancer progression. We investigated what mechanism associate with ANXA2 high expression and its survival impact utilizing bio-informatic approach in pancreatic ductal adenocarcinoma (PDAC).

Methods:

Primary pancreatic tumor (n=185) cohort in The Cancer Genome Atlas (TCGA), and Gene set enrichment analysis (GSEA) were utilized.

Results:

There were no significant associations between ANXA2 expression and clinicopathological features of the patients investigated. The ANXA2 high tumors enriched some of the known downstream signaling, such as NF-κB (p=0.028) and TNF (p=0.044) pathways, whereas others such as angiogenesis or epithelial-mesenchymal transition were not associated. ANXA2 high expression tumors enriched DNA repair related (DNA repair; p=0.011, p53 pathway; p=0.036), and cell proliferation related gene set (MYC targets; p=0.041). Additionally, new association with metabolism related gene sets, such as glycolysis (p=0.016), nucleic acid metabolism (p<0.001), and pyrimidine metabolism (p=0.004) were identified in the ANXA2 high group. Patients with high ANXA2 expression demonstrated significantly worse disease-free survival (p=0.001) as well as overall survival (p=0.014), with high ANXA2 being an independent risk factor.

Conclusion:

High ANXA2 expression was associated with NF-κB and TNF signaling, DNA repair, cell proliferation, and metabolic alteration and worse prognosis in PDAC.

Keywords: Annexin A2, NF-κB, pancreatic ductal adenocarcinoma, TCGA, metabolism, DNA repair, pancreatic cancer

Backgrounds:

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States (1). The overall 5-year survival is approximately 8% despite the advancement in multidisciplinary cancer treatment in the last decade (2). This poor prognosis is not only due to advanced disease stage at the time of clinical presentation, but also because of resistance to current chemotherapy and radiation therapy (2, 3). One of very unique features of PDAC is a dense fibrotic and hypovascular stroma, resulting in severe tissue hypoxia and limited nutrient availability in tumor micro-environment (2, 4). Given the harsh environment, PDAC acquires metabolic alterations for cancer cell survival, including enhanced glucose uptake, increased glycolysis, diversion of glucose to biosynthetic pathways, and increased macropinocytosis, scavenging of serum lipids and proteins by endocytic process (2, 5).

Annexin A2 (ANXA2) is a member of the annexin family, which is a calcium-dependent phospholipid binding protein, playing major roles in regulation of cellular growth as well as signaling pathways (6). While small amount of ANXA2 monomer exists, ANXA2 mainly presents as a heterotetramer with S100A10 on the cell membrane and in the cytoplasm, which takes a major part in fibrinolysis by facilitating plasmin production, exocytosis, endocytosis, membrane trafficking, and cellular cytoskeleton upon phosphorylation (7, 8). Previous studies revealed that ANXA2 plays a crucial role in cancer cell proliferation, migration, invasion, and adhesion, as well as angiogenesis (7–9). With plasmin generation from plasminogen, ANXA2 facilitates extracellular matrix (ECM) degradation, promoting cell migration and tumor invasion (8, 10, 11). Further, intracellular ANXA2 is suggested to take part in chemotherapy resistance through NF-κB signaling (12). Several studies demonstrated that cell-surface localization of ANXA2 was associated with cancer invasion and metastasis through enhanced epithelial-mesenchymal transition (EMT) (13–15). Furthermore, its elevated expression is associated with worse prognosis in various malignancies, including non-small cell lung cancer, cervical cancer, breast cancer, colorectal cancer, prostate cancer, and renal cell cancer (7, 16–18). Chaudhary and colleagues published that ANXA2 activated epidermal growth factor receptor (EGFR), resulting in worse prognosis in triple-negative breast cancer (19).

In PDAC, ANXA2 has been demonstrated to play a role in cancer cell invasion and migration, in enhancement of metastatic activity through EMT activation, and in chemotherapy resistance (20–23). High expression of ANXA2 has been shown to associate with worse survival, but only in small sample sizes (20, 22). Given this background, we hypothesized that high ANXA2 expression associates with DNA repair, EMT activation, and worse survival in PDAC utilizing full genomic and clinical information from The Cancer Genome Atlas (TCGA).

Material and Methods:

Data acquisition from The Cancer Genome Atlas (TCGA)

Genomic and clinicopathological data were obtained from TCGA pancreatic cancer cohort (PAAD) (https://cancergenome.nih.gov/) through cBioportal (24, 25), as described previously (26–29). Among 185 primary tumors, 154 patients were registered as “Pancreas-Adenocarcinoma Ductal Type” in histological diagnosis section. Of those, 147 patients were identified to have both gene expression from RNA-sequence and overall survival (OS) data. The median observation period was 15 months (Inter-quartile range (IQR): 8-21 months). Since TCGA is a de-identified, publicly accessible database, institutional Review Board (IRB) was waived. The pathological assessments of the PDAC cohort of TCGA, such as perineural invasion (PNI) and lymphovascular invasion (LVI) were manually obtained from TIES system that include pathological reports of part of TCGA cohort (http://ties.dbmi.pitt.edu/#) through Roswell Park Comprehensive Cancer Center. A validation cohort (GSE85916) that contained genomic information and survival information of 79 patients was identified through Gene Expression Omnibus (GEO) datasets. No validation cohorts were available for disease-free survival (DFS).

Gene Set Enrichment Analysis (GSEA)

GSEA was performed comparing the ANXA2 low and high expression tumors, utilizing the Hallmark gene sets (30) and GO Biological Process gene sets (31, 32) with the software provided by the Broad Institute (https://software.broadinstitute.org/gsea/index.jsp), as described before (33, 34). Significantly enriched GO Biological Process gene sets were categorized using GO classification system (http://geneontology.org/) (31, 32).

Survival analysis

OS was defined as the time from date of diagnosis to the date of death by any cause, and DFS was defined as the time from date of diagnosis to the date of recurrence. Univariate and multivariate analyses for OS and DFS were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with several valuables, using age, gender, tumor size, American Joint Committee on Cancer (AJCC) Staging system factors, such as T, N, M classifications, histological grade, pathological AJCC stage, residual tumor status, ANXA2 status, PNI, and LVI. Some of the parameters were dichotomized as followings; age below 65 and age 65 and above, tumor size below 3.5cm and greater than or equal to 3.5cm, AJCC T classification T1+T2 and T3+T4, histologic grade G3 (poorly differentiated) and G1+G2 (well-differentiated + moderately-differentiated), pathological AJCC stage I+II and III+IV, and residual tumor status R1+R2 and R0. Parameters with p-value <0.20 on univariate analyses were included in the subsequent multivariate analyses.

Statistical analysis

Statistical comparisons of the clinicopathological parameters were performed by Fisher’s exact test. Continues values were compared by ANOVA or Student t-test. All statistical analyses were performed using R software (http://www.r-project.org/) together with Bioconductor (http://bioconductor.org/) and JMP 14.0 (SAS, Cary, NC). A p-value <0.05 was considered as statistically significant. In GSEA, False Discovery Rate (FDR), cut of 25%, is commonly considered a reasonable testing adjustment in the setting of exploratory discovery study, such as ours, where the interest is in finding candidate hypothesis to be further validated (35).

Results:

Patient demographics were not significantly different between high and low expression of ANXA2 in TCGA PDAC cohort

The patients were divided into two groups based on ANXA2 mRNA expression level using higher tertile. This is based on the previous reports that defined the cutoffs of ANXA2 expression between 50 to 80 percentile of their cohorts (16, 36, 37). First, we investigated whether there is any association between the patient clinicopathological features and ANXA2 expression levels to rule out the possibility of confounding factors. There was no statistically significant difference between these two groups in any of the features analyzed, which are age, sex, diabetes, chronic pancreatitis, race, tumor location, AJCC categories (T, N, M), tumor size and residual tumor, shown in Table 1.

Table 1.

Patient demographics in TCGA cohort

ANXA2 High (49) ANXA2 Low (98) p value
Age (Median (IQR)) 65 (56- 75) 66 (58- 72) 0.856
Sex (M/F) 28/21 51/47 0.558
Diabetes (Yes/No) 10/34 23/55 0.420
Chronic pancreatitis (Yes/No) 6/37 5/69 0.198
Race (Asian/Black/White) 3/0/46 6/6/82 0.193
Tumor location (Head/Body& Tail) 41/8 83/13 0.652
AJCC T (T1/T2/T3/T4) 2/5/41/1 2/11/82/2 0.919
AJCC N (N0/N1) 10/39 27/70 0.324
AJCC M (M0/M1) 22/0 48/3 0.137
Tumor size (cm) (Median (IQR)) 4 (3- 4.5) 3.2 (2.8- 4.5) 0.982
Residual tumor (R0/R1/R2) 29/17/1 55/30/4 0.753
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ANXA2, Annexin A2; IQR, interquartile range; AJCC, American Joint Committee on Cancer; TCGA, The Cancer Genome Atlas

ANXA2 level is not associated with known pathological characteristics in PDAC

Several pathological characteristics have been reported to associate with the prognosis of PDAC. In order to rule out the possible confounding factors, association between known prognostic pathological features of PDAC and ANXA2 expression level was analyzed. Neither perineural (PNI) nor lymphovascular invasion (LVI) was associated with ANXA2 expression levels (Fig.1A, 1B). Also, histological grades that indicate aggressiveness of the PDAC and AJCC pathological stages that predict patient survival did not associate with high ANXA2 levels (Fig.1C, 1D).

Figure 1.

Figure 1

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ANXA2 mRNA expression levels of pathological features known to be related with PDAC aggressiveness; A: Perineural invasion (PNI); PNI (−) (n=14) vs. PNI (+) (n=110) (p=0.856), B: Lymphovascular invasion (LVI); LVI (−) (n=45) vs. LVI (+) (n=78) (p=0.293), C: Histological grade; G1 (n=21) vs. G2 (n=84) vs. G3 (n=42) (p=0.397), D: Pathological AJCC stage; Stage I (n=12) vs. Stage II (n=128) vs. Stage III (n= 3) vs. Stage IV (n=3) (p=0.531).

High ANXA2 expression is associated with reported roles, NF-κB and TNF signaling, in PDAC

ANXA2 is known to be involved in the number of malignant processes in cancer cells including cell cycle regulation, cell proliferation, endocytosis, exocytosis, and downstream signaling pathways. A GSEA using 50 Hallmark gene sets (30) and GO Biological Process gene sets (31, 32) were conducted to identify the possible roles of ANXA2 in PDAC. All Hallmark gene sets enriched in the ANXA2 high tumors were shown in Supplementary Table 1. Gene sets that correspond to the previously characterized mechanisms of ANXA2, such as NF-κB ((Normalized Enrichment Score (NES)=1.83, p=0.028, FDR=24.3%) and tumor necrosis factor (TNF) (NES=1.68, p=0.044, FDR=34.2%) pathways were significantly enriched in the ANXA2 high PDACs, whereas angiogenesis (NES=−1.21; p=0.267, FDR=53.6%) or EMT (NES=−0.94; p=0.539, FDR=62.9%) were not (Fig. 2A–D).

Figure 2.

Figure 2

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The association of ANXA2 and known its role by Gene sets enrichment analysis (GSEA) comparing ANXA2 high and low PDACs. A: Enrichment plot with NF-κB (Normalized Enrichment Score (NES)=1.83; p=0.028, False Discovery Rate (FDR)=24.3%), B: Enrichment plot with TNF (NES=1.68; p=0.044, FDR=34.2%). C: Enrichment plot with Angiogenesis (NES=−1.21; p=0.267, FDR=53.6%), D: Enrichment plot with Epithelial-mesenchymal transition (EMT) (NES=−0.94; p=0.539, FDR=62.9%)

High ANXA2 expression is associated with DNA repair, cell proliferation and metabolic alteration in PDAC

Interestingly, gene sets of DNA repair (NES=1.78; p=0.011, FDR=18.2%) and p53 pathway (NES=1.47; p=0.036, FDR=22.8%) were also significantly enriched in the ANXA2 high tumors, suggesting ANXA2 may be associated with DNA repair mechanism in PDAC (Fig. 3A, 3B). MYC targets v1 gene set (NES=1.75; p=0.041, FDR=22.8%) was also enriched in the ANXA2 high group, indicating that higher ANXA2 tumors may have enhanced proliferative capability (Fig. 3C). Additionally, glycolysis gene set was enriched (NES=1.80; p=0.016, FDR=31.0%), which may illustrate a potential association of ANXA2 with glucose metabolism in PDAC (Fig. 3D). Among GO Biological Process 886 gene sets, 67 gene sets were significantly enriched in the ANXA2 high tumors. Of those, 40 gene sets were categorized as metabolic process in GO classification, which further implies that ANXA2 may modulate metabolic alterations in PDAC either directly or indirectly (Fig. 4A). Metabolic process gene sets were further sub-categorized, which revealed that more than half of the genes were involved in nucleic acid or pyrimidine metabolism (Fig. 4B, Supplementary Table 2–5). Taken together, these findings indicate that ANXA2 high PDACs may have inherent metabolic propensity to synthesize increased amounts of nucleotides to sustain rapid cellular proliferation as well as DNA repair.

Figure 3.

Figure 3

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The association of ANXA2 and unreported signaling of ANXA2 by Gene sets enrichment analysis (GSEA). A: Enrichment plot with DNA repair (Normalized Enrichment Score (NES)=1.78; p=0.011, False Discovery Rate (FDR)= 18.2%), B: Enrichment plot with p53 pathway (NES=1.47; p=0.036, FDR= 22.8%), C: Enrichment plot with MYC targets v1 (NES=1.75; p=0.041, FDR= 22.8%), D: Enrichment plot with Glycolysis (NES=1.80; p=0.016, FDR= 31.0%).

Figure 4.

Figure 4

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Gene sets enrichment analysis (GSEA) with GO Biological Process gene sets. A: Categories in GO Biological Process enriched in the high ANXA2 expression group. Numbers within the pie indicate percentage of the enriched categories. B: Subcategories of Metabolic Process in the high ANXA2 expression group. Numbers within the pie indicate percentage of the enriched categories.

High ANXA2 expression is associated with worse prognoses in PDAC

We found that the ANXA2 high tumors were associated with aggressive features of cancer, such as DNA repair, higher cell proliferation and metabolic alteration. These findings led us to further hypothesize that patients with high ANXA2 tumors may have worse survival. As we expected, patients with ANXA2 high expression tumor demonstrated significantly worse DFS than the low expression group (median DFS time: 8.5 months vs. 17.3 months, p<0.001) (Fig. 5A), which suggests that those tumors are more likely to recur. Further, the ANXA2 high expression group demonstrated significantly worse OS compared to the low expression group (median OS time: 12.5 months vs. 20.6 months, p=0.004) (Fig. 5B). This association between ANXA2 high expression and poor OS was validated in another cohort (GSE85916; median OS time: 14.6 months vs. 21.1 months, p=0.041) (Fig.5C). In order to investigate if ANXA2 is an independent prognostic factor, univariate and multivariate analyses were performed. High ANXA2 expression (HR=2.85, p=0.001) remained an independent risk factor for DFS in the patients with PDAC (Table 2). Similarly, ANXA2 high expression was the only significant independent risk factor for OS (HR=1.90, p=0.014) (Table 3).

Figure 5.

Figure 5

Figure 5

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Kaplan-Meier curves depicting patient survivals by expression of ANXA2 in the TCGA pancreatic cancer cohort. A: Disease-free survival (DFS). Median survival time: ANXA2 low 17.3 months vs. ANXA2 high 8.5 months. B: Overall survival (OS). Median survival time: ANXA2 low 20.6 months vs. ANXA2 high 12.5 months. C: Overall survival (OS) with a validation cohort (GSE85916). ANXA2 low 21.1 months vs. ANXA2 high 14.6 months.

Table 2.

Univariate/multivariable analysis (COX proportional hazards model) for DFS

Univariate analysis Multivariate analysis
p value Hazard Ratio 95% CI p value Hazard Ratio 95% CI
Age (>65) 0.839 0.953 0.601- 1.515
Sex (M) 0.479 0.845 0.531- 1.351
Tumor size (≥3.5cm) 0.035 1.695 1.038- 2.798 0.114 1.642 0.888- 3.035
AJCC T (T3+T4/T1+T2) 0.960 0.983 0.523- 2.048
AJCC N (N1) 0.142 1.476 0.881- 2.592 0.753 1.131 0.525- 2.436
AJCC M (M1) 0.873 0.853 0.048- 3.989
Histologic grade (G3/G1+G2) 0.039 1.712 1.028- 2.780 0.263 1.500 0.737- 3.050
Pathological stage (III+IV/I+II) 0.833 0.863 0.141- 2.758
Residual tumor status (R1+R2/R0) 0.017 1.879 1.123- 3.109 0.076 1.856 0.937- 3.679
Perineural invasion (PNI +) 0.458 1.339 0.644- 3.266
Lymphovascular invasion (LVI +) 0.063 1.679 0.973- 3.031 0.736 1.128 0.559- 2.279
ANXA2 expression (High) 0.002 2.246 1.360- 3.649 0.001 2.847 1.504- 5.388
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DFS, Disease-free survival; CI, Confidence interval; AJCC, American Joint Committee on Cancer; ANXA2, Annexin A2

Table 3.

Univariate/multivariable analysis (COX proportional hazards model) for OS

Univariate analysis Multivariable analysis
p value Hazard Ratio 95% CI p value Hazard Ratio 95% CI
Age (>65) 0.731 1.076 0.710- 1.645
Sex (M) 0.875 0.975 0.709- 1.344
Tumor size (≥3.5cm) 0.529 0.898 0.641- 1.256
AJCC T (T3+T4/T1+T2) 0.717 1.128 0.611- 2.326
AJCC N (N1) 0.080 1.556 0.950- 2.691 0.686 1.139 0.607- 2.138
AJCC M (Ml) 0.605 1.385 0.333- 3.859
Histologic grade (G3/G1+G2) 0.132 1.412 0.898- 2.173 0.192 1.453 0.829- 2.544
Pathological stage (III+IV/I+II) 0.997 1.001 0.351- 2.240
Residual tumor status (R1+R2/R0) 0.024 1.703 1.076- 2.667 0.087 1.616 0.933- 2.799
Perineural invasion (PNI +) 0.282 1.472 0.747- 3.342
Lymphovascular invasion (LVI +) 0.011 1.883 1.150- 3.216 0.376 1.303 0.725- 2.343
ANXA2 expression (High) 0.006 1.872 1.201- 2.887 0.014 1.902 1.114- 3.175
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OS, Overall survival; CI, Confidence interval; AJCC, American Joint Committee on Cancer; ANXA2, Annexin A2

Discussion:

In the present study, we demonstrated that ANXA2 did not associate with the known clinical nor pathological features that indicate cancer aggressiveness, including PNI, LVI, histological grade, and pathological AJCC stage. On the other hand, high ANXA2 expressing PDACs were associated with DNA repair, metabolic alterations, as well as cell proliferation, but not angiogenesis or EMT gene sets. We further found that PDAC patients with high ANXA2 expression tumors had significantly worse prognoses. To our knowledge, this is the first study demonstrating association between ANXA2 and DNA repair, metabolic alteration and survival in PDAC.

ANXA2 expression is elevated in various solid organ malignancies and associated with recurrence, metastasis, and worse survival, which implicates that ANXA2 is a molecular signature for aggressive cancers (7, 8). It has been reported that silencing ANXA2 resulted in cell cycle arrest in non-small cell lung cancer and down-regulated MYC, contributing loss of invasive capacity of breast cancer (17, 38). These reports support our results that ANXA2 was associated with MYC targets genes, suggesting the potential ANXA2 function in tumor proliferation. Our finding that ANXA2 was associated with TNF and NF-κB signaling pathway is in agreement with previous reports demonstrating that ANXA2 mediates upregulation of NF-κB signaling and subsequent chemotherapy resistance in PDAC (12, 39). Also, TNF is one of the major stimulation of NF-κB and there were several reports demonstrating correlation between ANXA2 and TNF in inflammatory disease (40, 41). It was also reported that ANXA2 is accumulated in the nucleus to reduce DNA damage in response to genotoxic agents in normal tissues (42, 43). Enhanced DNA repair is known to be one of the mechanisms of chemotherapy resistance in cancer cells (12, 14). Our finding that DNA repair was associated with ANXA2 expression may explain that ANXA2 high group has enhanced chemo-resistance that resulted in poor prognosis.

While some of the known ANXA2 functions were comparable in our results as above, we did not find any association of ANXA2 with some of other known roles, such as angiogenesis or EMT. In contrast, we identified the association of ANXA2 and metabolic alteration, which is one of the hallmarks of cancer (44). Accelerated glycolysis has been well documented in cancer as Warburg effect, although it is relatively less efficient to generate ATP compared to mitochondrial oxidative phosphorylation. Increased glycolysis was found to divert glycolytic intermediates into various biosynthetic pathways such as generating nucleosides and amino acids for assembling new cells (2, 3, 45). Increased metabolism, such as enhanced nucleic acid metabolism, and increased carbohydrate and protein metabolism, are well known phenomena in PDAC as well to compensate the increased cellular demand (46). Glycolysis and subsequent pentose phosphate pathway are being utilized to generate the pentose sugars, which serve as primary intermediates in the nucleotides and nucleic acid synthesis in PDAC (46). Although there are limited reports demonstrating the involvement of ANXA2 in tumor metabolic alterations, our results suggest that in PDAC ANXA2 is associated with glucose metabolism and pyrimidine metabolism, resulting in poor prognosis of PDAC.

There are limitations with this study. What we found in this study is only the association of high ANXA2 expression with worse OS as well as possible aggressive tumor biology features using TCGA. TCGA has a few disadvantages. Although it does offer significant benefits with myriad of gene expression data associated with clinical information, the median follow-up of PDAC was 15 months (IQR 8- 21 months), which is rather short. TCGA provides only gene expression of the surgically resected primary tumor that account for less than 20% of pancreatic cancer population; hence, ANXA2 role in metastatic tumor is unclear. Lastly, this study does not include any in vitro or in vivo experiments, thus all our findings are mere associations and causality is unknown. In order to prove the role of ANXA2 in PDAC, the experimental results will be required.

Conclusion:

In conclusion, ANXA2 high expression is significantly associated with NF-κB and TNF signaling, cell proliferation, DNA repair, metabolic process gene signatures and worse prognosis in patients with PDAC. Given its association with survival, ANXA2 expression can be a potential candidate as a prognostic biomarker in PDAC. Further investigation is required to elucidate the mechanism of ANXA2 role in DNA repair and altered metabolism.

Supplementary Material

1

Acknowledgement:

This work was supported by NIH grant R01CA160688 to K.T., K22CA207578 to S.D., and National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Center’s Bioinformatics and Biostatistics Shared Resources. Additionally, this research used the TIES system, which is supported by NCI grant U24 CA180921.

Footnotes

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This manuscript was presented at the 14th Annual Academic Surgical Congress, at Houston, TX.

Disclosure:

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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