TNF-α augments CXCL10/CXCR3 axis activity to induce Epithelial-Mesenchymal Transition in colon cancer cell

Abstract

Chronic inflammation-induced metastases have long been regarded as one of the significant obstacles in treating cancer. Tumor necrosis factor-α (TNF-α), a main inflammation mediator within tumor microenvironment, affects tumor development by inducing multiple chemokines to establish a complex network. Recent reports have revealed that CXCL10/CXCR3 axis affects cancer cells invasiveness and metastases, and Epithelial-mesenchymal transition (EMT) is the main reason for frequent proliferation and distant organ metastases of colon cancer (CC) cells, However, it is unclear whether TNF-α-mediated chronic inflammation can synergically enhance EMT-mediated CC metastasis through promoting chemokine expression. According to this study, TNF-α activated the PI3K/Akt and p38 MAPK parallel signal transduction pathways, then stimulate downstream NF-κB pathway p65 into the nucleus to activate CXCL10 transcription. CXCL10 enhanced the metastases of CC-cells by triggering small GTPases such as RhoA and cdc42. Furthermore, overexpression of CXCL10 significantly enhanced tumorigenicity and mobility of CC cells in vivo. We further clarified that CXCL10 activated the PI3K/Akt pathway through CXCR3, resulting in suppression of GSK-3β phosphorylation and leading to upregulation of Snail expression, thereby regulating EMT in CC cells. These outcomes lay the foundation for finding new targets to inhibit CC metastases.

Tumor metastasis: Mechanistic insights and therapeutic interventions

“… 158 , 159 These cytokines/chemokines are involved in ECM remodeling, tumor invasion, EMT, angiogenesis, pre‐metastatic niche reprogramming, extravasation, and modulating stromal cells and immune cells. 115 , 154 , 160 , 161 , 162 The cytokines/chemokines including TNF‐α, IL‐8, CCL20, CXCL5, CXCL12. 163 , 164 , 165 , 166 CXCR2, CXCR3, and CXCR4, up‐regulate EMT‐TFs (snail and ZEB1), promote MMP‐2 expression, and accelerate EMT of cancer cells, thereby promoting tumor metastasis.…”

“… 163 , 164 , 165 , 166 CXCR2, CXCR3, and CXCR4, up‐regulate EMT‐TFs (snail and ZEB1), promote MMP‐2 expression, and accelerate EMT of cancer cells, thereby promoting tumor metastasis. 160 , 165 , 166 Cytokine IL‐8 mainly down‐regulates E‐cadherin through activating the Wnt/β‐catenin pathway in ovarian cancer, thereby promoting tumor invasion. 163 Some cytokines can promote the expression of chemokines and mesenchymal transformation.…”

“…For example, TNF‐α has been reported to promote the up‐regulation of CXCL10 and activate the phosphoinositide3‐kinase/protein kinase B (PI3K/AKT) pathway to inhibit the phosphorylation of GSK‐3β, leading to the up‐regulation of snail and promoting tumor metastasis. 160 …”

Enterobacterial LPS-inducible LINC00152 is regulated by histone lactylation and promotes cancer cells invasion and migration

“…The previous studies reported that Salmonella infection will induce activation of NF-kB pathway (Itoh et al, 2005;Ning et al, 2011;Kobelt et al, 2020;Wang et al, 2021). Based on the previous studies on Wnt protein (Liu et al, 2012), we The graphic summary of this study.…”

Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade

“…Mechanistically, p38MAPK may activate MAPK-activated protein kinase 2, which in turn phosphorylates HSP27 and then promotes cytoskeletal remodelling, leading to increased cell motility and invasiveness 38 , 39 . In addition, p38MAPK may promote cancer metastasis by activating NF- k B and stabilizing FOXC1 40 , 41 . Moreover, MMPs have important roles in cell invasion and cancer metastasis 42 .…”