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Pancreatic Cancer HPAF/CD18 cells: Ecd knockdown vs Scrambled

ABSTRACT: Purpose: To study the expression and function of a novel cell cycle regulatory protein, human ecdysoneless (Ecd), during pancreatic cancer (PC) pathogenesis. Experimental Design: Immunohistochemical expression profiling of Ecd was done in non-neoplastic normal pancreatic tissues and pancreatic ductal adenocarcinoma lesions (from tissue microarray and Rapid Autopsy program) as well as precancerous PanIN lesions and metastatic organs. To analyze the biological significance of Ecd in PC progression, Ecd was stably knocked down in PC cell line followed by in vitro and in vivo functional assays. Results: Normal pancreatic ducts show very weak to no Ecd expression compared to significant positive expression in PC tissues (mean±SE composite score: 0.3±0.2 and 3.8±0.2 respectively, p<0.0001) as well as in PanIN precursor lesions with a progressive increase in Ecd expression with increasing dysplasia (PanIN-1 to PanIN-3). Analysis of matched primary tumors and metastases from PC patients revealed that Ecd is highly expressed in both primary pancreatic tumor and in distant metastatic sites. Further, knockdown of Ecd suppressed cell proliferation in vitro and tumorigenicity of PC cells in mice orthotopic tumors. Microarray study revealed that Ecd regulates expression of glucose transporter GLUT4 in PC cells and was subsequently shown to modulate glucose uptake, lactate production and ATP generation by PC cells. Finally, knockdown of Ecd also reduced level of pAkt, key signaling molecule known to regulate aerobic glycolysis in cancer cells. Conclusion: Ecd is a novel tumor promoting factor that is differentially expressed in pancreatic cancer and potentially regulates glucose metabolism within cancer cells. Two-condition experiment, Ecd knockdown vs Scrambled cells. Biological replicates: 3 Ecd knockdownl, 3 Scrambled, independently grown and harvested. One replicate per array

ORGANISM(S): Homo sapiens

SUBMITTER: Dey Parama

PROVIDER: S-ECPF-GEOD-39988 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Purpose: Core 3 derived glycans, a major type of O-glycan expressed by normal epithelial cells of the gastrointestinal tract, are downregulated during malignancy, because of loss of expression of functional β3-N-acetylglucosaminyltransferase-6 (core 3 synthase). We investigated the expression of core 3 synthase in normal pancreas and pancreatic cancer and evaluated the biological effects of re-expressing core 3 synthase in pancreatic cancer cells that had lost expression. Experimental Design: We determined that pancreatic tumors and tumor cell lines have lost expression of core 3 synthase. We therefore re-expressed in human pancreatic cancer cells (Capan-2 and FG) to investigate the contribution of core 3 glycans to malignant progression. Results: Pancreatic cancer cells expressing core 3 synthase showed reduced in vitro cell proliferation, migration and invasion compared with vector control cells. Expression of core 3 O-glycans induced altered expression of β1 integrin, decreased activation of focal adhesion kinase, led to the down regulation of expression of several genes including REG1α and FGFR3, and altered lamellipodia formation. The addition of a GlcNAc residue by core 3 synthase leads to the extension of the tumor associated Tn structure on MUC1. Orthotopic injection of FG cells expressing core 3 synthase into the pancreas of nude mice produced significantly smaller tumors and decreased metastasis to the surrounding tissues compared to vector control FG cells. Conclusions: These findings indicate that expression of core 3 derived O-glycans in pancreatic cancer cells suppresses tumor growth and metastasis through modulation of glycosylation of mucins and other cell surface and extracellular matrix proteins. Two-condition experiment, Core 3 synthase stable expression (C3) vs. vector control (PLVX) cells. Biological replicates: 3 Core 3 synthase stable expression, 3 vector control, independently grown and harvested. One replicate per array.

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Pancreatic Cancer HPAF/CD18 cells: Ecd knockdown vs Scrambled

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