Low expression of PTEN is essential for maintenance of a malignant state in human gastric adenocarcinoma via upregulation of p‑AURKA mediated by activation of AURKA

Abstract

Gastric adenocarcinoma remains a life‑threatening disease, emphasizing the importance of gaining an improved understanding of signaling pathways involved in this disease, which can lead to the development of novel therapeutic methods targeting common molecular pathways shared across different types of gastric adenocarcinoma. The present study revealed phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and aurora kinase A (AURKA) gene alterations, which were involved in changes in the phenotypes of gastric cancer cells, including increased proliferation by cell counting kit‑8 assay and invasion capacity by Transwell invasion assay, and predicted survival rates by KM Plotter database in gastric cancer. The present study investigated the association between PTEN and AURKA. Western blotting revealed that phosphorylated (p)-AURKA correlated with two target genes, PTEN and AURKA. The downregulation of PTEN by small interfering (si)RNA not only increased the expression of AURKA at the mRNA and protein levels by western blotting and by reverse transcription‑quantitative PCR, but also increased the expression of p‑AURKA by western blotting and immunofluorescence analysis. In addition, western blotting and reverse transcription‑quantitative PCR revealed that the downregulation of AURKA affected the expression level of PTEN. Furthermore, PTEN suppressed the malignant phenotypic changes of gastric adenocarcinoma cells by regulating the expression of AURKA inhibited by p‑AURKA, suggesting that p‑AURKA may be the key mediator of the PTEN‑associated activation of AURKA and may be key in maintaining the PTEN‑induced malignant state of gastric adenocarcinoma cells. This hypothesis was confirmed by western blotting, and changes were observed in the protein expression of p‑AURKA and AURKA under conditions in which cells were treated with either MLN8237 or si‑PTEN transfection only, or with si‑PTEN transfection and MLN8237. Knockdown of the expression of PTEN altered the expression of p‑AKT, p‑glycogen synthase kinase 3β and β‑catenin, which are genes that have been reported to be involved in the development of gastric adenocarcinoma. The present study confirmed that p‑AURKA is important in the development of gastric adenocarcinoma and revealed a novel functional link between PTEN, AURKA and p‑AURKA activation. The results also suggest a novel drug design strategy in targeting PTEN and AURKA for more specific gastric cancer cell death that spares normal cells.

Astragalus Polysaccharide Regulates EGFR and ANXA1 Expression to Inhibit Tumor Growth

“…AURKA is involved in regulating many early mitotic events that also plays an important role in tumorigenesis and tumor progression. Extensive studies have demonstrated that AURKA was overexpressed in certain types of malignancies, such as bladder cancer, esophageal squamous cell carcinoma and breast cancer [34,35]. It is evident from previous studies that ECT2 can improve cell growth, invasion and tumorigenicity [36].…”

Quantum microRNA network analysis in gastric and esophageal cancers: Xenotropic plant microRNAs cure from cancerous paradox via Helicobacter pylori infection

“…On the contrary, enforced expression of phosphatase and Tensin homolog (PTEN) resulted in decreasing of IGF1R expression upon gastric adenocarcinoma cells [75]; however, tumor suppressor PTEN was strongly blocked by both upregulation of miR-486-5p with miR-17-5p and miR-214-3p, and upregulation of miR-92a-1-5p plus miR-21-5p with miR-17-5p, miR-214-3p, miR-20a-5p, miR-106b-5p and miR-222-3p (Figure 2B and 3B). PTEN expression is low in gastric cancer [76] and the downregulation of PTEN is implicated in induction [77], maintenance of a malignant state [78], and progression and metastasis of gastric cancer [79]. These data were strongly supported by our in silico simulation that in the stage I-IV, PTEN was strongly repressed by upregulation of miR-106a/b-5p with miR-17-5p, miR-93-5p and miR-298, and upregulation of miR-92a-1-5p with miR-17-5p, miR-106b-5p, miR-214-3p, miR-20a-5p and miR-222-3p in Figure 2C (the total layer) and 3C (the miRNA hub).…”