Frequent amplification of <i>PTP1B</i> is associated with poor survival of gastric cancer patients

<p>The protein tyrosine phosphatase 1B (<i>PTP1B</i>), a non-transmembrane protein tyrosine phosphatase, has been implicated in gastric pathogenesis. Several lines of recent evidences have shown that <i>PTP1B</i> is highly amplified in breast and prostate cancers. The aim of this study was to investigate <i>PTP1B</i> amplification in gastric cancer and its association with poor prognosis of gastric cancer patients, and further determine the role of <i>PTP1B</i> in gastric tumorigenesis. Our data demonstrated that <i>PTP1B</i> was significantly up-regulated in gastric cancer tissues as compared with matched normal gastric tissues by using quantitative RT-PCR (qRT-PCR) assay. In addition, copy number analysis showed that <i>PTP1B</i> was amplified in 68/131 (51.9%) gastric cancer cases, whereas no amplification was found in the control subjects. Notably, <i>PTP1B</i> amplification was positively associated with its protein expression, and was significantly related to poor survival of gastric cancer patients. Knocking down <i>PTP1B</i> expression in gastric cancer cells significantly inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrested and apoptosis. Mechanically, <i>PTP1B</i> promotes gastric cancer cell proliferation, survival and invasiveness through modulating Src-related signaling pathways, such as Src/Ras/MAPK and Src/phosphatidylinositol-3-kinase (PI3K)/Akt pathways. Collectively, our data demonstrated frequent overexpression and amplification <i>PTP1B</i> in gastric cancer, and further determined the oncogenic role of <i>PTP1B</i> in gastric carcinogenesis. Importantly, <i>PTP1B</i> amplification predicts poor survival of gastric cancer patients.</p

Epithelial cell-derived periostin functions as a tumor suppressor in gastric cancer through stabilizing p53 and E-cadherin proteins via the Rb/E2F1/p14ARF/Mdm2 signaling pathway

<div><p>Periostin is usually considered as an oncogene in diverse human cancers, including breast, prostate, colon, esophagus, and pancreas cancers, whereas it acts as a tumor suppressor in bladder cancer. In gastric cancer, it has been demonstrated that periglandular periostin expression is decreased whereas stromal periostin expression is significantly increased as compared with normal gastric tissues. Moreover, periostin produced by stromal myofibroblasts markedly promotes gastric cancer cell growth. These observations suggest that periostin derived from different types of cells may play distinct biological roles in gastric tumorigenesis. The aim of this study was to explore the biological functions and related molecular mechanisms of epithelial cell-derived periostin in gastric cancer. Our data showed that periglandular periostin was significantly down-regulated in gastric cancer tissues as compared with matched normal gastric mucosa. In addition, its expression in metastatic lymph nodes was significantly lower than that in their primary cancer tissues. Our data also demonstrated that periglandular periostin expression was negatively associated with tumor stage. More importantly, restoration of periostin expression in gastric cancer cells dramatically suppressed cell growth and invasiveness. Elucidation of the mechanisms involved revealed that periostin restoration enhanced Rb phosphorylation and sequentially activated the transcription of E2F1 target gene <i>p14^ARF</i>, leading to Mdm2 inactivation and the stabilization of p53 and E-cadherin proteins. Strikingly, these effects of periostin were abolished upon Rb deletion. Collectively, we have for the first time demonstrated that epithelial cell-derived periostin exerts tumor-suppressor activities in gastric cancer through stabilizing p53 and E-cadherin proteins via the Rb/E2F1/p14^ARF/Mdm2 signaling pathway.</p></div

Tolperisone induces UPR-mediated tumor inhibition and synergizes with proteasome inhibitor and immunotherapy by targeting LSD1

Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Tolperisone is an old centrally acting muscle relaxant used for treatment of chronic pain conditions. In this study, we investigated the therapeutic effect and mechanism of tolperisone in human cancers and explored the combination strategy with proteasome inhibitor and immunotherapy. The antitumor effect of tolperisone was evaluated by measuring half maximal inhibitory concentration, cell death, and cell growth. RNA sequencing, western blotting, molecular docking, enzyme activity assay, and ChIP-qPCR were performed to reveal the underlying mechanism. Xenograft models were used to evaluate the efficacy of tolperisone alone or in combination with proteasome inhibitor or immunotherapy. Tolperisone inhibited cell growth and induced cell death in human cancer cell lines. Unfolded protein responses (UPR) pathway was hyperactivated in tolperisone-treated cells. We further identified histone lysine-specific demethylase 1 (LSD1) as a potential target of tolperisone, which directly demethylates UPR-related genes in H3K4me2. Tolperisone synergistically improved the efficacy of MG132 by enhancing UPR and sensitized tumors to immunotherapy by reprogramming M2 macrophages into M1 phenotype. Tolperisone inhibits human cancer by targeting LSD1. Repurposing tolperisone in cancer therapy by a combination strategy implies clinical potential.</p