Toll-like receptor 6 inhibits colorectal cancer progression by suppressing NF-κB signaling
Lina Ma,
Yancun Yin,
Zhenhai Yu,
Ning Xu,
Lianhuan Ma,
Weiwei Qiao,
Xiaowen Zhen,
Fan Yang,
Naili Zhang,
Yue Yu
Affiliations
Lina Ma
Cheeloo College of Medicine, Shandong University, 44 Wenhua West Road, Jinan, Shandong, 250012, China; Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Department of Diagnostics, The Second School of Medicine, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong, 264003, China
Yancun Yin
Department of Human Anatomy, School of Basic Medical Science, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong, 264003, China
Zhenhai Yu
Department of Human Anatomy, School of Basic Medical Science, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong, 264003, China
Ning Xu
Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, Shandong, 264100, China
Lianhuan Ma
Department of Diagnostics, The Second School of Medicine, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong, 264003, China
Weiwei Qiao
Department of Diagnostics, The Second School of Medicine, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong, 264003, China
Xiaowen Zhen
Department of Diagnostics, The Second School of Medicine, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong, 264003, China
Fan Yang
Department of Diagnostics, The Second School of Medicine, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong, 264003, China
Naili Zhang
Department of Human Anatomy, School of Basic Medical Science, Binzhou Medical University, 346 Guanhai Road, Laishan, Yantai, Shandong, 264003, China
Yue Yu
Cheeloo College of Medicine, Shandong University, 44 Wenhua West Road, Jinan, Shandong, 250012, China; Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Corresponding author. Cheeloo College of Medicine, Shandong University, 44 Wenhua West Road, Jinan, Shandong, 250012, China.
Background: Toll-like receptors (TLRs) are implicated in the pathogenesis and progression of inflammation-associated cancers, except their role in regulating innate immunity. Specifically, a berrant expression of TLR6 has been observed in colorectal cancers (CRC). However, the effect of abnormal TLR6 expression on CRC remians unclear. Therefore, the present study evaluated TLR6 expression in CRC, its effect on CRC proliferation, and its underlying mechanism. Methods: The expression of TLR6 in CRC was assessed using data from TCGA, GTEx, and HPA datasets and immunohistochemical assays of tumor tissues from patients with CRC. In human CRC cell lines, TLR6 signaling was activated using the TLR6 agonist Pam2CSK4 and was blocked using antiTLR6-IgG; subsequently, cell growth, migration, invasion, cell cycle, and apoptosis were compared in CRC cells. The levels of the anti-apoptotic protein Bcl-2 and the apoptotic protein Bax were identified using western blotting. In addition, the effect of TLR6 knockdown by shRNAs in CRC cells was observed both in vitro and in vivo. Nuclear factor κB (NF-κB) level was evaluated using immunofluorescence and western bolt. Results: TLR6 expression was significantly downregulated in CRC tissues. The activation of TLR6 by Pam2CSK4 (100 pg/mL to 10 ng/mL) inhibited the proliferation of CRC cells. Compared with blocking TLR6 signaling using antiTLR6-IgG, activating TLR6 signaling significantly inhibited CRC cell growth, migration, and invasion as well as decreased the proportion of cells in the S and G2/M phases and promoted apoptosis. Furthermore, the knockdown of TLR6 by shRNA promoted the biological activity of CRC cells both in vitro and in vivo. Moreover, the activation of TLR6 signaling by Pam2CSK4 significantly downregulated NF-κB and Bcl-2 levels but upregulated Bax levels. Conclusion: The findings of this study demonstrate that TLR6 may play a inhibitive role in CRC tumorigenesis by suppressing the activity of NF-κB signaling.
