Inflammation Promotes Progression of Pancreatic Cancer Through WNT/β-Catenin Pathway-Dependent Manner

Abstract

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, β-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/β-catenin pathway. Results Differentially expressed genes of macrophage-conditioned medium-treated pancreatic cancer cells were related with WNT/β-catenin pathway. Inflammatory stimuli could activate WNT/β-catenin signaling pathway. In 106 pancreatic cancer patients, nuclear β-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/β-catenin pathway and inhibited the chemotaxis of CD103+ dendritic cells. Six pancreatic cancer prognosis associating genes were upregulated by inflammatory stimuli via WNT/β-catenin pathway. Transforming growth factor-β promoted malignant biological behavior of pancreatic cancer cells through WNT/β-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/β-catenin pathway-dependent manner.

Characterization of the prognostic and oncologic values of ITGB superfamily members in pancreatic cancer

“…Both TGF‐β and WNT signalling were previously reported to be implicated in pancreatic carcinogenesis by promoting the EMT process 46,47 . Ren et al reported that TGF‐β could promote the migration of PC cells by inducing EMT during the activation of WNT signalling pathway 48 . The activation of TGF‐β signalling pathway promotes Treg cells recruitment and TAMs polarization and induces immunosuppression in the TME 49,50 .…”

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…CCL3 may be expressed in a cancer cell [ 127 ]. The immune response reduces the expression of CCL3 in cancer cells via the activation of β-catenin [ 129 ]. Both CCL3 and CCL4 are also expressed in chronic myeloid leukemia and multiple myeloma [ 130 , 131 , 132 , 133 ].…”

“…Increased expression of CCL19 and CCL21 in a tumor results in anti-cancer TIL infiltration and an improved prognosis for many tumor patients [ 195 , 196 , 197 , 198 ]. Cancer immune evasion mechanisms reduce the expression of these chemokines in a cancer cell [ 129 ]. Nevertheless, if the tumor microenvironment has favorable conditions for tumor development, then CCL19 and CCL21 may participate in T reg recruitment to the tumor niche [ 226 , 227 ].…”

Isoalantolactone inhibits pancreatic cancer proliferation by regulation of PI3K and Wnt signal pathway

“…Phase contrast images were taken at beginning and after 24 hours and 48 hours. The cell migration effects were measured by the closure area of scratch [17]. Invasion assays were performed on an 8μm pore size transwell (BD Falcon cell culture insert, BD Bioscience) with modifications.…”