Journal
PANCREAS
Volume 48, Issue 8, Pages 1003-1014Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MPA.0000000000001386
Keywords
pancreatic cancer; inflammation; WNT; beta-catenin pathway; CD103(+) DCs
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Funding
- National Natural Science Foundation of China [81602091, 81873587, 81874454, 81472296, 81572992, 81772645]
- Six Major Talent Peak Project of Jiangsu Province [2015-WSN-022]
- Project of Invigorating Health Care through Science, Technology and Education, Jiangsu Provincial Medical Youth Talent [QNRC2016709]
- Project of Jiangsu Provincial Commission of Health and Family Planning [H201518]
- Science and Education for Health Foundation of Suzhou for Youth [kjxw2015003]
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Objective Identify the molecular mechanism of inflammatory stimuli induced pancreatic cancer progression. Methods RNA-seq, microarray assay and bioinformatics analyses were used to identify differentially expressed genes. Immunohistochemical staining was performed to evaluate CD68, CD163, beta-catenin, CD103, CCL3 markers. Quantitative real-time polymerase chain reaction (qRT-PCR), luciferase reporter assay, apoptosis assay, wound healing assay and immunofluorescence were performed to study the relationship of inflammatory stimuli and WNT/beta-catenin pathway. Results Differentially expressed genes of macrophage-conditioned medium-treated pancreatic cancer cells were related with WNT/beta-catenin pathway. Inflammatory stimuli could activate WNT/beta-catenin signaling pathway. In 106 pancreatic cancer patients, nuclear beta-catenin expression of CD68-high group was much higher than CD68-low group (P < 0.05), as same as CD163 (P < 0.05). Inflammatory stimuli downregulated the expression of CCL3 via WNT/beta-catenin pathway and inhibited the chemotaxis of CD103(+) dendritic cells. Six pancreatic cancer prognosis associating genes were upregulated by inflammatory stimuli via WNT/beta-catenin pathway. Transforming growth factor-beta promoted malignant biological behavior of pancreatic cancer cells through WNT/beta-catenin pathway-dependent mechanism. Conclusions Our present study provided a novel mechanism involved in the inflammation-driven cancer progression through tumor immune escape and downstream gene regulation of WNT/beta-catenin pathway-dependent manner.
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