Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells

Abstract

We previously demonstrated that neurotensin (NTS) induces local inflammation and promotes tumor invasion in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms are not clear. In this study, positive correlations between NTS and interleukin (IL)-8 were identified at both the mRNA and protein levels in 71 fresh HCC tissues and 100 paraffin-embedded HCC tissues. Furthermore, significant correlations were determined among the co-expression of NTS and IL-8, infiltration of inflammatory cells and enhanced epithelial-mesenchymal transition (EMT) of HCC cells. NTS-induced IL-8 production was associated with activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways rather than the protein kinase C (PKC) and phosphoinositide-3 kinase (PI3K) pathways, whose specific antagonists significantly inhibited activation of the NTS/IL-8 pathway. IL-8, which promoted EMT and HCC invasion both and, was produced by NTS-induced HCC cells and was effectively attenuated by blocking IL-8 receptors . Moreover, HCC-derived IL-8 attracted more CD68 tumor-associated macrophages (TAMs) and CD66b polymorphonuclear neutrophils (PMNs) to the local microenvironment, displaying enhanced cytokine secretion and phagocytosis. IL-8 stimulated the M2 polarization of TAMs, which promoted the EMT and invasive potential of HCC cells. Blockage of the IL-8 receptor, NTR1 receptor or both significantly reduced HCC metastases in tumor-bearing mouse models via inhibiting EMT. In summary, aberrant activation of the NTS/IL-8 pathway in HCC dramatically stimulated the invasive potential of HCC cells. HCC-derived IL-8 promoted a pro-oncogenic inflammatory microenvironment by inducing M2-type TAMs and indirectly promoting EMT, which might be a valuable therapeutic target to prevent tumor progression.

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

“…NTS has been identified as a local hormone and plays a critical role in the regulation of fat storage, obesity and metabolic disorders. Previous studies also revealed an association of NTS with progression and invasiveness of various cancers, thus is considered to be a potential pharmacological target in cancer therapy [21][22][23][24]. NTS increases cell proliferation by a protein kinase C (PKC)-dependent ligand-induced transactivation of EGFR, which in turn activates the Raf-mitogen-activated protein kinase (MEK)-ERK signaling transduction [25][26][27].…”

The role of Neurotensin and its receptors in non-gastrointestinal cancers: a review

“…Chronic inflammation is thought to be a driving factor for tumour invasion and progression, regardless of the cause [67,68]. NT has been reported to promote cytokine release, particularly IL-8 via the MAPK and NF-kB pathways, enhancing the migration and invasion capacity of HCC cells [69]. Overexpression of both interleukin-8 and NT in HCC has been associated with portal vein invasion and worse prognosis [69,70].…”

IRGM promotes glioma M2 macrophage polarization through p62/TRAF6/NF‐κB pathway mediated IL‐8 production

“…Some cytokines and chemokines play an important role during glioma development and M2 cell polarization. IL‐8 promotes a pro‐oncogenic inflammatory microenvironment by inducing M2‐type tumor‐associated macrophages (TAMs) (Xiao et al, ; Li et al, ). The chemokine MIP‐3α (also called CCL20) could influence tumor growth through mediating macrophage recruitment (Jayaraman et al, ).…”