Toll-like receptor 2 stimulation promotes colorectal cancer cell growth via PI3K/Akt and NF-κB signaling pathways

Liu, You Dong; Ji, Chenfeng; Li, Shan Bao; Yan, Feng; Gu, Qi; Balic, Jesse J.; Yu, Liang; Li, Ji Kun

doi:10.1016/j.intimp.2018.04.033

Cited by 35 publications

(32 citation statements)

References 30 publications

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“…In mantle cell lymphoma, TLR2 promotes the proliferation of tumor cells, and it can also inhibit the cell cycle progression of mantle cell lymphoma, leading to G1 phase arrest [19]. Colorectal cancer tissues usually have higher TLR2 gene expression levels than normal colorectal mucosa from the same patient, and activation of TLR2 and TLR4 in previous studies of colorectal cancer has also been shown to promote tumor cell proliferation [9,10,14,20]. Our study demonstrates that knocking out the TLR2 gene inhibits CAC growth, reduces tumor Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Toll-like receptors (TLRs) are innate immune sensors that recognize a variety of pathogenic components, called pathogen-associated molecular patterns, and can initiate proinflammatory responses to maintain intestinal homeostasis [9]. TLRs not only are an important part of the innate immune system but also activate the adaptive immune system and are widely involved in infectious diseases, inflammatory and allergic diseases, and carcinogenesis [10,11].…”

Section: Introductionmentioning

confidence: 99%

“…TLRs not only are an important part of the innate immune system but also activate the adaptive immune system and are widely involved in infectious diseases, inflammatory and allergic diseases, and carcinogenesis [10,11]. Currently, 10 human TLRs and 13 mouse TLRs have been identified [9]. In the past, most studies have focused on intracellular TLRs such as TLR3, TLR7, and TLR9, but recent studies have shown that cell-surface TLRs, particularly TLR2, also play an important role in the development of autoimmune diseases, and TLR2 expression is not limited to cells related to inflammation and immune function [12].…”

Section: Introductionmentioning

confidence: 99%

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Effect of TLR2 on the proliferation of inflammation-related colorectal cancer and sporadic colorectal cancer

Meng

Li²,

Zang³

et al. 2020

Cancer Cell Int

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Background: Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD) with a poor prognosis because it is often diagnosed in advanced stages with local progression or metastasis. Compared with the more common polyp-induced sporadic colorectal cancer (sCRC), CAC has different molecular mechanisms. Toll-like receptor 2 (TLR2) expression is not limited to cells related to inflammation and immune function. High levels of TLR2 expression in tumor tissues of colorectal cancer (CRC) patients have been reported. This report is to investigate the effects of knockout and knockdown of the TLR2 gene on the proliferation of CAC and sCRC. Methods: Twelve C57BL/6 J wild-type mice (WT) and 12 TLR2 knockout mice (TLR2-/-) were used to rapidly establish a colitis-associated cancer (CAC) model via the 1,2-dimethylhydrazine-dextran sodium sulfate (DMH-DSS) method and were divided into the normal WT control group (NC), TLR2 knockout control group (KC), normal wild-type tumor modeling group (NT), and TLR2 knockout tumor modeling group (KT), with 6 mice in each group. The general performance of the mice during modeling, the gross changes of the colon and the rectum, and the pathological score of HE staining were used to observe tumor growth. The expression of TLR2 was detected by immunohistochemistry, and tumor proliferation was detected by Ki67 labeling. Lentivirus carrying TLR2-RNAi was used to stably infect colorectal cancer cells (HCT116 and HT29) to knock down TLR2 gene expression. The experimental groups included the uninfected control group, negative control group, and gene knockdown group. After infection, the expression of TLR2 protein was detected by Western blot, and cell proliferation and the cell cycle were detected by the CCK-8 method and fluorescence-activated cell sorting. Western blot was used to detect the expression levels of p-NF-κβ, cyclin D1 and cyclin D3 protein in each group of cells. Results: TLR2 knockout in the CAC model resulted in greater changes in body weight and more severe diarrhea and colorectal hemorrhage. However, knocking out the TLR2 gene reduced the shortening of colorectal length, the number of tumors, and the total tumor volume and inhibited the growth of CAC. Knocking out the TLR2 gene also reduced the pathological score and tumor severity. TLR2 was localized in the cell membrane of the colorectal epithelium of the NC group and of the colorectal tumors of the NT group and was highly expressed in the NT group, while antigen Ki67 was localized in the nucleus of the colorectal tumor cells of the NT group and the KT group, and its expression was reduced in the KT group. In an in vitro sporadic colorectal cancer cell experiment, TLR2 protein in the TLR2 knockdown group was significantly downregulated, and TLR2 knockdown significantly inhibited the

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of TLR2 on the proliferation of inflammation-related colorectal cancer and sporadic colorectal cancer

Meng

Li²,

Zang³

et al. 2020

Cancer Cell Int

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“…WISP1 activates AKT signaling pathway to promote a variety of cellular functions, such as proliferation, survival, migration, and invasion in normal tissue and cancer cells (25,27,29,32,36,47,48). It also stimulates the MEK/ERK pathway to enhance tumor migration and invasion (30,34,45,46), possibly through the induction of MEK/ERK signaling-induced EMT (44).…”

Section: Wisp1 Activated Akt/mapk Signaling To Promote Emt In Mouse Mmentioning

confidence: 99%

“…In human glioblastoma, the WISP1-activated MEK/ ERK pathway might be responsible for the EMT of the tumor cells (44). The activation of various signaling, including PI3K/ AKT, MEK/ERK, NF-B, or JNK/p38 pathways, has been shown to be essential for WISP1-induced cell migration and/or invasion in vascular smooth muscle cells, cholangiocarcinoma, chondrosarcoma, oral squamous cell carcinoma, osteosarcoma, and colorectal cancer cells (30,33,34,(45)(46)(47)(48).…”

mentioning

confidence: 99%

WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial–mesenchymal transition

Deng

Fernández

McLaughlin

et al. 2019

Journal of Biological Chemistry

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Besides intrinsic changes, malignant cells also release soluble signals that reshape their microenvironment. Among these signals is WNT1-inducible signaling pathway protein 1 (WISP1), a secreted matricellular protein whose expression is elevated in several cancers, including melanoma, and is associated with reduced survival of patients diagnosed with primary melanoma. Here, we found that WISP1 knockout increases cell proliferation and represses wound healing, migration, and invasion of mouse and human melanoma cells in multiple in vitro assays. Metastasis assays revealed that WISP1 knockout represses tumor metastasis of B16F10 and YUMM1.7 melanoma cells in both C57BL/ 6Ncrl and NOD-scid IL2R␥ null (NSG) mice. WT B16F10 cells having an invasion phenotype in a transwell assay possessed a gene expression signature similar to that observed in the epithelial-mesenchymal transition (EMT), including E-cadherin repression and fibronectin and N-cadherin induction. Upon WISP1 knockout, expression of these EMT signature genes went in the opposite direction in both mouse and human cell lines, and EMT-associated gene expression was restored upon exposure to media containing WISP1 or to recombinant WISP1 protein. In vivo, Wisp1 knockout-associated metastasis repression was reversed by the reintroduction of either WISP1 or snail family transcriptional repressor 1 (SNAI1). Experiments testing EMT gene activation and inhibition with recombinant WISP1 or kinase inhibitors in B16F10 and YUMM1.7 cells suggested that WISP1 activates AKT Ser/Thr kinase and that MEK/ ERK signaling pathways shift melanoma cells from proliferation to invasion. Our results indicate that WISP1 present within the tumor microenvironment stimulates melanoma invasion and metastasis by promoting an EMT-like process.

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Toll‐like receptors: A pathway alluding to cancer control

Ayala-Cuellar

Cho

Choi

2019

Journal Cellular Physiology

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Toll-like receptors (TLRs) are usually expressed on immune cells such as macrophages, dendritic cells, mast cells, as well as on eosinophils and some epithelial cells. They play a central role in the recognition of harmful molecules that belong to invading microorganisms or internal damaged tissues, which lead to inflammation.Among the hallmarks of cancer, there is immune evasion and inflammation. Summing this with the discovery that a majority of cancers also seem to express TLRs, made researchers realize these receptors might also be linked with cancer progression. This review will cover some of the effects of TLR engagement in cancer cells that might induce the promotion or inhibition of cancer with mechanisms involved. The differences of TLR expression in cancer progression and its possible relation with patient prognosis, TLR genetic disorders found in cancer, and new strategies to cancer therapy will be discussed to target TLRs in cancer cells.

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Toll-like receptor 2 stimulation promotes colorectal cancer cell growth via PI3K/Akt and NF-κB signaling pathways

Cited by 35 publications

References 30 publications

Effect of TLR2 on the proliferation of inflammation-related colorectal cancer and sporadic colorectal cancer

Effect of TLR2 on the proliferation of inflammation-related colorectal cancer and sporadic colorectal cancer

WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial–mesenchymal transition

Toll‐like receptors: A pathway alluding to cancer control

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