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

Ren, Rui MM*,†,‡; Yu, Jie MM§; Zhang, Yan MM*; Wang, Sheng-Fei MM*; Guo, Xia MB§; Shen, Meng MM*; Xu, Meng-Dan MM*; Jiang, Min MD, PhD*; Zhi, Qiaoming MD, PhD; Chen, Kai MD, PhD*; Tao, Min MD, PhD*; Wu, Meng-Yao MM*; Gu, Dong-Mei MD§; Li, Wei MD, PhD*,∥

doi: 10.1097/MPA.0000000000001386
Original Articles
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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, 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.

From the *Department of Oncology, the First Affiliated Hospital of Soochow University

Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, China

Department of General Surgery

§Department of Pathology, the First Affiliated Hospital of Soochow University

Comprehensive Cancer Center, Suzhou Xiangcheng People's Hospital, Suzhou, China.

Received for publication February 15, 2019; accepted July 12, 2019.

Address correspondence to: Wei Li, MD, PhD, Department of Oncology, the First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, China (e-mail: liwei10@suda.edu.cn; dr_weili@163.com); Meng-Yao Wu, MM, Department of Oncology, the First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, China (e-mail: mywu@suda.edu.cn).

R.R., J.Y., Y.Z., and S.F.W. contributed equally to this work.

This work was supported by the National Natural Science Foundation of China (grants 81602091, 81873587, 81874454, 81472296, 81572992, 81772645), the Six Major Talent Peak Project of Jiangsu Province (grant 2015-WSN-022), the Project of Invigorating Health Care through Science, Technology and Education, Jiangsu Provincial Medical Youth Talent (grant number QNRC2016709), the Project of Jiangsu Provincial Commission of Health and Family Planning (grant H201518), and the Science and Education for Health Foundation of Suzhou for Youth (grant kjxw2015003).

The authors declare no conflict of interest.

Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pancreasjournal.com).

Online date: August 12, 2019

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