Revealing the Molecular Mechanism of Gastric Cancer Marker Annexin A4 in Cancer Cell Proliferation Using Exon Arrays

Abstract

Gastric cancer is a malignant disease that arises from the gastric epithelium. A potential biomarker for gastric cancer is the protein annexin A4 (ANXA4), an intracellular Ca2+ sensor. ANXA4 is primarily found in epithelial cells, and is known to be involved in various biological processes, including apoptosis, cell cycling and anticoagulation. In respect to cancer, ANXA4-overexpression has been observed in cancers of various origins, including gastric tumors associated with Helicobacter pylori infection. H. pylori induces ANXA4 expression and intracellular [Ca2+]i elevation, and is an important risk factor for carcinogenesis that results in gastric cancer. Despite this correlation, the role of ANXA4 in the progression of gastric tumors remains unclear. In this study, we have investigated whether ANXA4 can mediate the rate of cell growth and whether ANXA4 downstream signals are involved in tumorigenesis. After observing the rate of cell growth in real-time, we determined that ANXA4 promotes cell proliferation. The transcription gene profile of ANXA4-overexpressing cells was measured and analyzed by human exon arrays. From this transcriptional gene data, we show that overexpression of ANXA4 regulates genes that are known to be related to cancer, for example the activation of hyaluronan mediated motility receptor (RHAMM), AKT, and cyclin-dependent kinase 1 (CDK1) as well as the suppression of p21. The regulation of these genes further induces cancer cell proliferation. We also found Ca2+ could regulate the transmission of downstream signals by ANXA4. We suggest that ANXA4 triggers a signaling cascade, leading to increased epithelial cell proliferation, ultimately promoting carcinogenesis. These results might therefore provide a new insight for gastric cancer therapy, specifically through the modification of ANXA4 activity.

Annexin A4 and cancer

“…1). Anxa4 promotes vesicle aggregation in vitro, plays an important role in synaptic exocytosis and membrane repair [13,14]; it also regulates Ca 2+ -activated Cl − conductance, alters the physical properties of membranes to regulate passive membrane permeability [15][16][17], and induces calcium signaling, anticoagulation, and resistance to apoptosis [18]. Anxa4 has been reported to be associated with the progression, invasion, migration, adhesion, and drug resistance of a variety of cancers [19][20][21][22].…”

Association Between Functional PSMD10 Rs111638916 Variant Regulated by MiR-505 and Gastric Cancer Risk in a Chinese Population

“…Recent surgical, chemotherapeutic, immunologic, and radiation approaches have resulted in significant improvements in survival of patients with localized disease [4]; However, the successful management of patients with GC is still hampered by a lack of highly sensitive and specific biomarkers capable of predicting prognosis and the likelihood of metastasis [5]. Etiological studies have suggested that environmental factors, including diets high in salted and nitrated foods, tobacco use, alcohol consumption, and Helicobacter pylori infection are all highly associated with GC [6][7][8]. However, only some people exposed to the same environmental risk factors eventually develop GC, suggesting that genetic factors may also be involved in the etiology of this disease.…”

Annexin Proteins: Novel Promising Targets for Anticancer Drug Development

“…It also takes part in calcium signaling, anticoagulation, and resistance to apoptosis [49]. Accumulated data show that annexin A4 also involves in tumor progression, invasion, metastasis, and drug resistance in various cancer types [50].…”