Impact of stroma LOXL2 overexpression on the prognosis of intrahepatic cholangiocarcinoma

J Surg Res. 2016 Jun 15;203(2):441-50. doi: 10.1016/j.jss.2016.03.044. Epub 2016 Mar 26.


Background: Intrahepatic cholangiocarcinoma (ICC) is associated with a poor prognosis related to early recurrence especially in the remnant liver after surgery. ICC exhibits a dense desmoplastic stroma which plays a pivotal role in ICC aggressiveness. Thus, analyzing gene deregulation in the stroma of ICC may help to identify new prognosis biomarkers and promising therapeutic targets. The aim of this study was to evaluate the clinical relevance of the matrix-remodeling enzyme lysyl oxidase-like 2 (LOXL2) expression in ICC.

Material and methods: LOXL2 messenger RNA levels were evaluated in microdissected tumoral stroma (TS) and in nontumoral fibrous tissue by gene expression profiling (testing set, n = 10) obtained from gene expression omnibus database and by quantitative real time polymerase chain reaction (validating set, n = 6). LOXL2 protein levels were evaluated by immunohistochemistry on a tissue microarray containing 80 independent patients. The relationship between LOXL2 expression and survival was assessed by univariate and multivariate analyses.

Results: LOXL2 messenger RNA levels were increased in TS, both in the testing and the validating sets (P < 0.01). These results were confirmed at a protein level, with a significantly higher LOXL2 immunostaining in TS (P < 0.01). Univariate analysis revealed that LOXL2 expression was correlated with a poor overall survival and disease-free survival (P < 0.01). Importantly, high expression of LOXL2 was an independent prognostic factor of worst overall survival (hazard ratio = 5.29, confidence interval [CI] 95% = 1.71-16.3, P < 0.01) and disease-free survival (hazard ratio = 5.55, CI 95% = 2.14-14.37, P < 0.01).

Conclusions: Our study provides additional arguments for a role of extracellular matrix remodeling in ICC aggressiveness and identifies LOXL2 as a new prognostic marker and a promising therapeutic target in ICC.

Keywords: Extracellular matrix; Intrahepatic cholangiocarcinoma; LOXL2; Microenvironment; Prognosis biomarker.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Oxidoreductases / genetics
  • Amino Acid Oxidoreductases / metabolism*
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / mortality
  • Bile Duct Neoplasms / surgery*
  • Bile Ducts, Intrahepatic* / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Case-Control Studies
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / mortality
  • Cholangiocarcinoma / surgery*
  • Female
  • Follow-Up Studies
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Hepatectomy*
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Prognosis
  • Real-Time Polymerase Chain Reaction
  • Retrospective Studies
  • Survival Analysis
  • Tissue Array Analysis


  • Biomarkers, Tumor
  • Amino Acid Oxidoreductases
  • LOXL2 protein, human