LOXL2 is a prognosis biomarker and a potential therapeutic target in intrahepatic cholangiocarcinoma

Abstract

Aims: Intrahepatic cholangiocarcinoma (ICC) is associated with a poor prognosis related to early recurrence especially in the remnant liver following surgery. ICC exhibit 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 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. Methods: LOXL2 expression was evaluated at mRNA level in microdissected tumoral stroma (TS) and in non tumoral fibrous tissue (NFT): by gene expression profiling, n=10 (testing set), and by qPCR, n=6 (validating set). Secondly, LOXL2 expression was confirmed by immunohistochemistry (IHC) on a tissue micro array (TMA) containing an independent cohort, n=80. The relationship between LOXL2 expression and survival was assessed by univariate and multivariate analyses. Results: LOXL2 was up regulated at mRNA level in TS, both in the testing set as in the validating set (P<0.01). These results were confirmed at protein level, showing a significantly higher immunostaining in TS (P<0.01). Univariate analysis revealed that LOXL2 staining was correlated with poor overall survival (OS) and disease free survival (DFS) (P<0.01). Moreover, high expression of LOXL2 was an independent prognostic marker of OS (HR=5.29, IC95%(1.71–16.3), P<0.01) as well as DFS (HR=5.55, IC95%(2.14–14.37), P<0.01). Conclusions: Our study provides new arguments for the pivotal role of the stroma in ICC progression and reveals a new prognostic marker. LOXL2 over expression was directly correlated with the aggressiveness of ICC and should be now routinely performed by IHC. Moreover, targeting LOXL2 by neutralizing antibodies might represent an appealing strategy, which should be explorer in the context of personalized therapy.