Dysfunctional Activation of Neurotensin/IL-8 Pathway in Hepatocellular Carcinoma Is Associated with Increased Inflammatory Response in Microenvironment, More Epithelial Mesenchymal Transition in Cancer and Worse Prognosis in Patients

Abstract

AimTo investigate the role of neurotensin (NTS) in hepatocellular carcinoma (HCC) sub- grouping and the clinical and pathological significance of activation of NTS/IL-8 pathway in HCC.MethodsThe genome-wide gene expression profiling were conducted in 10 pairs of cancer tissues and corresponding normal adjacent tissues samples using Affymetrix GeneChip® Human Genome U133 Plus 2.0 microarray to screen differentially expressing genes and enrich dysfunctional activated pathways among different HCC subgroups. The levels of NTS protein and multiple inflammation and epithelial mesenchymal transition (EMT) related proteins, including IL-8, VEGF, MMP9, CD68, E-Cadherin, β-Catenin and Vimentin were examined in 64 cases of paraffin-embedded HCC samples using immunohistochemistry (IHC) staining method. The clinical outcome and overall survival (OS) were compared.ResultsA subgroup of HCC characterized by up-regulated NTS expression was accompanied by up-regulated inflammatory responses and EMT. The direct interaction between NTS and IL-8 was identified by pathway enrichment analysis. Significantly increased IL-8 protein was confirmed in 90.91% of NTS+ HCC samples and significantly positively correlated to the levels of NTS protein in cancer tissues (P = 0.036), which implied activation of NTS/IL-8 pathway in HCC. The levels of VEGF and MMP9 correlated with co-expression of NTS and IL-8. Increased infiltration of CD68+ macrophages and more cancer cells displaying EMT features were found in NTS+IL-8+ samples. The co-expression of NTS and IL-8 in cancer significantly correlated with the clinical outcomes, as the mortality rate of NTS+IL-8+ HCC patients is 2.5-fold higher than the others after the surgery (P = 0.022). Accordingly, the OS of NTS+IL-8+ HCC patients significantly decreased who are under a higher hazard of death at an expected hazard ratio (HR) of 3.457.ConclusionDysfunctional activation of the NTS/IL-8 pathway was detected in HCC which is associated with increased inflammatory response in microenvironment, enhanced EMT in cancer, and worse prognosis in HCC patients.

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…The fact that neutrophils are frequent residents of solid tumors is not surprising as many of these tumors express and secrete high levels of neutrophil mobilizing factors and neutrophil chemoattractants. For example, IL-8/CXCL8, a potent neutrophil chemotactic factor and activator, was found to be expressed in a wide variety of human cancers [253,[269][270][271][272]. In most cases, IL-8 is secreted by the tumor cells themselves [210], while in others, other stromal cells such as fibroblasts [273] and macrophages [274] secrete IL-8.…”

Autocrine IL-8 promotes F-actin polymerization and mediate mesenchymal transition via ELMO1-NF-κB-Snail signaling in glioma

“…It has recently been suggested that IL-8 could promote cancer cell metastasis via autocrine and paracrine means which is associated with enhanced epithelial-mesenchymal transition (EMT). [21][22][23] However, the effect of IL-8 on the MT of glioma remains unclear.…”

Interleukin-8 promotes cell migration through integrin αvβ6 upregulation in colorectal cancer

“…Numerous studies have suggested that IL-8 plays a critical role during tumor angiogenesis, growth and metastasis in colon, gastric and pancreatic carcinoma [10][11][12]. Moreover, IL-8 has been found to have prognostic value in a variety of malignancies, including hepatocellular and nasopharyngeal carcinoma, gastric, lung and prostate cancer [13][14][15][16][17].…”