title: CXCR4 expression affects overall survival of HCC patients whereas CXCR7 expression does not.
abstract: Hepatocellular carcinoma (HCC) is a heterogeneous disease with a poor prognosis and limited markers for predicting patient survival. Because chemokines and chemokine receptors play numerous and integral roles in HCC disease progression, the CXCR4-CXCL12-CXCR7 axis was studied in HCC patients. CXCR4 and CXCR7 expression was analyzed by immunohistochemistry in 86 HCC patients (training cohort) and validated in 42 unrelated HCC patients (validation cohort). CXCR4 levels were low in 22.1% of patients, intermediate in 30.2%, and high in 47.7%, whereas CXCR7 levels were low in 9.3% of patients, intermediate in 44.2% and high in 46.5% of the patients in the training cohort. When correlated to patient outcome, only CXCR4 affected overall survival (P=0.03). CXCR4-CXCL12-CXCR7 mRNA levels were examined in 33/86 patients. Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032). The expression and function of CXCR4 and CXCR7 was also analyzed in several human HCC cell lines. CXCR4 was expressed in Huh7, Hep3B, SNU398, SNU449 and SNU475 cells, whereas CXCR7 was expressed in HepG2, Huh7, SNU449 and SNU475 cells. Huh7, SNU449 and SNU475 cells migrated toward CXCL12, and this migration was inhibited by AMD3100/anti-CXCR4 and by CCX771/anti-CXCR7. Moreover, SNU449 and Huh7 cells exhibited matrix invasion in the presence of CXCL12 and CXCL11, a ligand exclusive to CXCR7. In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not. Therefore, the CXCR4-CXCL12-CXCR7 axis plays a role in the interaction of HCC with the surrounding normal tissue and represents a suitable therapeutic target.
authors.affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Neve Polimeno
authors.affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Ierano
authors.affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Crescenzo
authors.initials: C
authors.lastname: D'Alterio
authors.affiliation: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Simona Losito
authors.affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Napolitano
authors.affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Portella
authors.affiliation: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Giosuè
authors.initials: G
authors.lastname: Scognamiglio
authors.affiliation: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Tatangelo
authors.affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Maria Trotta
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Curley
authors.affiliation: CROM-Centro Ricerche Oncologiche Mercogliano, Mercogliano (AV), Italy.
authors.forename: Susan
authors.initials: S
authors.lastname: Costantini
authors.affiliation: Institute of Biostructure and Bioimaging (IBB) of the Italian National Research Council, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Liuzzi
authors.affiliation: Hepato-Biliary Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Izzo
authors.affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism / Q000401:mortality*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology*; D054387:Receptors, CXCR / Q000096:biosynthesis / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000276:immunology*; D015996:Survival Rate
chemical_list: C501896:ACKR3 protein, human; C527276:CXCR4 protein, human; D009363:Neoplasm Proteins; D054387:Receptors, CXCR; D019718:Receptors, CXCR4