Cancer is one of the major fatal diseases of the 21st century that has caused 19.3 million cases and about 10 million deaths in 2020. According to GLOBOCAN 2020 estimates, Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, accounting for approximately 459.773 new cases and 466.003 deaths (Sung et al.2021). PC is frequently diagnosed at an advanced stage due to the lack of symptoms in the early stages, a lack of early detection strategies, limited therapeutic options, and the development of resistance during therapy, resulting in a low survival rate (Tonini and Zanni 2021). Most pancreatic cancers are characterized as ductal adenocarcinoma which arises from precursor lesions, termed pancreatic intraepithelial neoplasia. These lesions can cause localized cancer and eventually develop the capacity for invasion and metastasis (Kenner et al.2020). It is well known from previous studies that cancer evolution is driven by successive accumulation of genetic and epigenetic alterations (Berkel and Cacan 2020; Cacan 2016). Whereas, the genomic analysis of PC tissues showed multiple genetic alterations, and mutations including those in the CDKN2A, SMAD4 and TP53 tumor suppressor genes, and in the KRAS oncogene. These genes play a pivotal role in the cell, and their alteration causes a massive disruption in regulating DNA repair, cell proliferation, cell survival, and death, promoting the progression of PC, migration, and metastasis (Takai and Yachida 2015; Wu and al. 2021). In addition to the genomic alterations, the disruption of epigenetic mechanisms such as DNA methylation may conduct in the deregulation of gene expression and is also part of the oncogenic process (Wang et al.2015; Caldiran and Cacan 2022). Given the poor prognosis of PC, it is critical to identify specific biomarkers for the early diagnosis.
Annexin A2 (ANXA2) is a calcium-dependent phospholipid binding protein encoded by the ANXA2 gene located in chromosome 15 (Wang and Lin 2014). In cells, ANXA2 can form as monomeric or heterotetrameric (attached with S100A10). The monomer is located in the cytoplasm, nucleus, and early endosomes, whereas the heterotetramer is found on cell membranes. Moreover, ANXA2 has three functional domains that support its binding and aggregating action: The N-terminal domain contains the binding sites for S100A10 and tissue-type plasminogen activator (tPA), the core domain has phosphorylation binding sites including Tyr23 and Ser25, the C-terminal involve binding sites for calcium, and the actin cytoskeleton (Wang et al. 2012; Li and al. 2021). ANXA2 participates in many important pathways within the cells such as cell proliferation, endocytosis, angiogenesis, adhesion, and apoptosis (Christensen et al. 2018). However, ANXA2 is overexpressed in several human tumors, particularly in PC, making it an emerging biomarker and potential cancer therapeutic target (Christensen et al. 2018; Takahashi et al. 2019). Several studies have revealed that ANXA2 is implicated in tumor development, invasion, metastasis, and drug resistance. In Non-Small Cell Lung Cancer (NSCLC) ANXA2 overexpression promotes cancer proliferation through activation of JNK/c-Jun signaling which in turn results in suppression of P53 expression (Feng et al. 2017). In vitro studies on breast cancer indicated that ANXA2 promotes epithelial-mesenchymal transformation (EMT) by interacting with STAT3, which in turn upregulates the expression of the EMT-associated transcription factor Slug, resulting in EMT (Wang et al.2019). Moreover, it has been noted that ANXA2 interacts with HAb18G/CD147 to promote the invasion of hepatocellular carcinoma (Zhao et al.2010). It was also demonstrated that ANXA2 enhances cancer neoangiogenesis, invasion, and metastasis by converting plasminogen to plasmin which causes in activation of metalloproteinases and breakdown of extracellular matrix (Sharma et al.2010). Collectively, ANXA2 overexpression corresponds to the aggressiveness of many cancers. Therefore, it is crucial to know the mechanism underlying the regulation of ANXA2 expression. Previously, it was noted that genetic and epigenetic alteration may contribute to the suppression or overexpression of some genes (Ding et al.2016; Ali et al. 2013). Therefore, in this study, we focused on exploring the regulatory mechanism of ANXA2 by investigating the transcriptional profile, methylation pattern, somatic mutation and prognostic value of ANXA2 in pancreatic cancer using integrated bioinformatics tolls.