Neve Polimeno Maria, Ierano Caterina, D'Alterio Crescenzo, Simona Losito Nunzia, Napolitano Maria, Portella Luigi, Scognamiglio Giosuè, Tatangelo Fabiana, Maria Trotta Anna, Curley Steven, Costantini Susan, Liuzzi Raffaele, Izzo Francesco, Scala Stefania
Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.
Cell Mol Immunol. 2015 Jul;12(4):474-82. doi: 10.1038/cmi.2014.102. Epub 2014 Nov 3.
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.
肝细胞癌（HCC）是一种异质性疾病，预后较差，预测患者生存的标志物有限。由于趋化因子和趋化因子受体在HCC疾病进展中发挥着众多且不可或缺的作用，因此对HCC患者的CXCR4 - CXCL12 - CXCR7轴进行了研究。通过免疫组织化学分析了86例HCC患者（训练队列）的CXCR4和CXCR7表达情况，并在42例不相关的HCC患者（验证队列）中进行了验证。在训练队列中，22.1%的患者CXCR4水平低，30.2%的患者为中等水平，47.7%的患者为高水平；而CXCR7水平低的患者占9.3%，中等水平的患者占44.2%，高水平的患者占46.5%。当与患者预后相关联时，只有CXCR4影响总生存期（P = 0.03）。对86例患者中的33例检测了CXCR4 - CXCL12 - CXCR7 mRNA水平。有趣的是，与相邻正常肝脏相比，肿瘤组织中常见的CXCR4 - CXCR7配体CXCL12的表达水平显著降低（P = 0.032）。还在几种人HCC细胞系中分析了CXCR4和CXCR7的表达及功能。CXCR4在Huh7、Hep3B、SNU398、SNU449和SNU475细胞中表达，而CXCR7在HepG2、Huh7、SNU449和SNU475细胞中表达。Huh7、SNU449和SNU475细胞向CXCL12迁移，这种迁移受到AMD3100/抗CXCR4和CCX771/抗CXCR7的抑制。此外，SNU449和Huh7细胞在CXCL12和CXCL11（CXCR7特有的一种配体）存在的情况下表现出基质侵袭。总之，CXCR4影响HCC患者的预后，但CXCR7不影响。因此，CXCR4 - CXCL12 - CXCR7轴在HCC与周围正常组织的相互作用中发挥作用，是一个合适的治疗靶点。
