title: 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: OBJECTIVE
  To 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  A 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.
  
  
  CONCLUSIONS
  Dysfunctional 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.
authors: Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors: Jinpu
authors: J
authors: Yu
authors: Xiubao
authors: X
authors: Ren
authors: Yongzi
authors: Y
authors: Chen
authors: Pengpeng
authors: P
authors: Liu
authors: Xiyin
authors: X
authors: Wei
authors: Hui
authors: H
authors: Li
authors: Guoguang
authors: G
authors: Ying
authors: Kexin
authors: K
authors: Chen
authors: Hans
authors: H
authors: Winkler
authors: Xishan
authors: X
authors: Hao
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D016000:Cluster Analysis; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009496:Neurotensin / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D016209:Interleukin-8; D009496:Neurotensin