elafin and Adenocarcinoma

Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment.. Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression.. P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice.. These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.

Topics: Adenocarcinoma; Adenosine Triphosphate; Animals; Carcinoma, Pancreatic Ductal; Cell Proliferation; Cell Survival; Clonal Evolution; Deoxycytidine; Elafin; Gemcitabine; Glycolysis; Heterografts; Humans; Mice; Oncogene Protein v-akt; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y2; RNA, Small Interfering; Sequence Analysis, RNA; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Microenvironment

G-protein coupled receptor 34 (GPR34), which belongs to the G-protein coupled receptors superfamily, is reportedly expressed highly in the spread of several solid tumors. However, its expression in gastric primary tumor and potential role in gastric cancer development and progression have not been determined.. Immunohistochemistry, real-time RT-PCR and western blot methods were used to determine GPR34 expression in human gastric cancer tissues/cell lines and matched adjacent tissues/ normal mucosal cell line. A statistical analysis was performed to establish the potential correlation between GPR34 expression and the patients' clinicopathological characteristics, tumor progression, and prognosis. Stably transfected NCI-N87 cell lines with either GPR34 over-expression or knock-down were constructed to determine the effect of GPR34 on gastric cancer cell invasion and migration, and to explain the preliminary molecular mechanism of GPR34 in gastric cancer metastasis.. GPR34 is up-regulated in primary gastric cancer tissues/cell lines compared with matched adjacent tissues/normal mucosal cell line, and when the relationship between GPR34 expression and the the clinicopathological characteristics was analyzed, it was shown that GPR34 expression is significantly correlated with tumor differentiation, infiltration depth, and lymph node status and had a significant influence on prognosis. Furthermore, GPR34-overexpression increased while GPR34-knockdown inhibited NCI-N87 cell invasion in vitro by PI3K/PDK1/AKT pathway.. Taken together, up-regulation of GPR34 expression in human gastric carcinoma may play a critical role in tumor progression and in determining patient prognosis. GPR34 may be a useful diagnostic or prognostic molecular biomarker, and a potential target for therapeutic intervention.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Blotting, Western; Disease Progression; Elafin; Female; Humans; Immunohistochemistry; Male; Middle Aged; Prognosis; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Real-Time Polymerase Chain Reaction; Receptors, Lysophospholipid; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stomach Neoplasms; Up-Regulation; Young Adult

We previously showed that carbon ion irradiation can inhibit the expression of the anillin (ANLN) gene, which is regulated by the activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway associated with metastasis. The purpose of this study is to compare the effects of carbon ion irradiation on the PI3K/Akt signaling pathway to those of photon irradiation. Our study showed that carbon ion irradiation of human lung adenocarcinoma cells A549 decreased their invasion more effectively than photon irradiation did. We found that carbon ion irradiation reduced the nuclear localization of ANLN at lower dose, but did not affect its expression. Low-dose carbon ion irradiation also reduced the level of phosphorylated Akt compared to untreated controls, whereas photon irradiation did not. These results suggest that carbon ion irradiation effectively suppresses the metastatic potential of A549 cells by suppressing the PI3K/Akt signaling pathway.

Topics: Adenocarcinoma; Carbon Radioisotopes; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Elafin; Heavy Ions; Humans; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt; Radiation Dosage; Signal Transduction