Abstract
ABSTRACTWe 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 in vitro and in vivo, was produced by NTS-induced HCC cells and was effectively attenuated by blocking IL-8 receptors in vitro. 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.
Highlights
Hepatocellular carcinoma (HCC) represents one of the most common causes of cancer-related death, with the third highest mortality rate worldwide.[1]
There was no difference in hepatitis B virus (HBV) infection status, inflammation or immunological response-related pathways found to be enriched in patients showing a relatively poor outcome, which implied that the non-pathogenic inflammatory microenvironment might play a vital role in promoting HCC progression
A significant correlation between IL-8 and NTS was detected in HCC tissues, which was associated with a poor clinical outcome
Summary
Hepatocellular carcinoma (HCC) represents one of the most common causes of cancer-related death, with the third highest mortality rate worldwide.[1] With the development of surgical resection and interventional therapy, the prognosis of early HCC has improved. Gaining a further understanding of the regulatory mechanisms underlying tumor invasion and progression will help to improve the poor clinical outcome of HCC patients. Especially pathogen-induced inflammation, has been identified as a factor that promotes tumor invasion and progression in HCC.[2,3] the pro-carcinogenic effects of the non-pathogenic inflammatory microenvironment in HCC have not been elucidated yet. There was no difference in hepatitis B virus (HBV) infection status, inflammation or immunological response-related pathways found to be enriched in patients showing a relatively poor outcome, which implied that the non-pathogenic inflammatory microenvironment might play a vital role in promoting HCC progression
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