ABSTRACT
Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Despite the advanced surgical resection techniques and anticancer drugs currently available to treat early stage gastric cancer, the prognosis of patients with gastric cancer remains poor. The epithelial to mesenchymal transition (EMT) is an important process for the initiation of tumorigenesis. Recent studies suggested that reactive oxygen species (ROS) can promote cell migration and invasion. Thus, an imbalance of redox homeostasis can result in cancer cells exhibiting EMT properties. PRXs are upregulated in various tumors in the breast, bladder, lung, cervical, ovarian, prostate, esophageal, and hepatocellular. However, PRX expression and its impact on disease prognosis, patient survival rate, and EMT are rarely studied in the context of human gastric cancer. The expression of PRX5 was significantly correlated with tumor size, depth of tumor, lymphatic invasion in patients of gastric cancer. In addition, overexpression of PRX5 enhanced carcinogenicity by increasing the proliferation and invasiveness of gastric cancer cells via upregulation of Snail. Taken together, we suggest that PRX5 may be a potential factor that may contribute to poor prognosis of gastric cancer through enhancing the mesenchymal phenotype. Finally, PRX5 is a putative therapeutic target and clinical strategy for various cancers overexpressing PRX5.
Subject(s)
Adenocarcinoma/secondary , Biomarkers, Tumor/metabolism , Peroxiredoxins/metabolism , Stomach Neoplasms/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/surgery , Animals , Apoptosis , Biomarkers, Tumor/genetics , Cell Proliferation , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Humans , Lymphatic Metastasis , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Neoplasm Invasiveness , Peroxiredoxins/genetics , Prognosis , Stomach Neoplasms/metabolism , Stomach Neoplasms/surgery , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
XBP1 (X-box-binding protein 1) is activated in cancer and has a pivotal role in tumorigenesis and progression of human cancer. In particular, the XBP1 transcriptional regulatory network is well known to drive cancer development, but little is known about whether the stability of XBP1 is regulated and, if so, what controls the stability of XBP1. In the present study we show that PIN1 prolyl isomerase interacts with the active form of XBP1 (XBP1s) in a phosphorylation-dependent manner and promotes XBP1s-induced cell proliferation and transformation through the regulation of XBP1 stability. By contrast, depletion of Pin1 in cancer cells reduced XBP1s expression, which subsequently inhibits cell proliferation and transformation. Interestingly, XBP1s activates multiple oncogenic pathways including NF-κB (nuclear factor κB), AP1 (activator protein 1) and Myc, and down-regulates PIN1 transcription via a negative-feedback mechanism through p53 induction. Ultimately, reciprocal regulation of Pin1 and XBP1s is associated with the activation of oncogenic pathways, and the relationship of PIN1 and XBP1 may be an attractive target for novel therapy in cancers.
