CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression.
CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression.
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CXCR7 刺激 MAPK 信号传导调节肝细胞癌进展
DOI：
10.1038/cddis.2014.392
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发表时间：
2014-10-23
影响因子：
9
通讯作者：
Yang PY
中科院分区：
文献类型：
--
作者：
Lin L;Han MM;Wang F;Xu LL;Yu HX;Yang PY
CXCL12/CXCR4轴已被广泛认为在许多原发性肿瘤和转移性肿瘤中发挥重要作用。众所周知，CXCR7也可以被CXCL12参与，但CXCR7的确切功能尚存争议。这促使我们研究CXCR7在肝细胞癌（HCC）中的表达、特异性功能和信号转导。在本研究中，CXCR7和CXCR4在9种HCC细胞系中存在差异表达，CXCR7和CXCL4的表达升高与HCC细胞的高转移能力相关。此外，通过对48例人类HCC标本构建的高密度组织微阵列进行染色，发现与非转移性HCC相比，转移性HCC样本中CXCR7的表达显著上调。在体外，过表达CXCR7增强细胞生长和侵袭性，在体内增强致瘤性和肺转移。相比之下，CXCR7稳定敲低可显著减少这些恶性行为。此外，我们观察到CXCR7表达的改变与丝裂原活化蛋白激酶（MAPK）途径蛋白的磷酸化水平呈正相关。使用U0126抑制剂或选择性CXCR7拮抗剂CCX771靶向细胞外调节激酶通路，可显著降低CXCR7介导的细胞增殖。重要的是，通过使用基于人类生物素的抗体阵列，在cxcr7过表达组和缺失组中鉴定了几种差异表达蛋白。对比分析表明，上游调控因子TP53和IL-6参与了CXCR7的信号转导。进一步证实CXCR7的表达调节血管内皮生长因子A和半凝集素-3的表达，可能参与肿瘤的血管生成和侵袭性。因此，CXCR7的表达升高通过激活MAPK和血管生成信号通路促进HCC的生长和侵袭性。靶向CXCR7可能会预防转移，并为HCC提供潜在的治疗策略。
The CXCL12/CXCR4 axis has been posited widely to have significant roles in many primary tumors and metastases. It is known that CXCR7 can also be engaged by CXCL12, but the exact function of CXCR7 is controversial. This prompted us to investigate the expression, specific function and signal transduction of CXCR7 in hepatocellular carcinoma (HCC). In this study, CXCR7 and CXCR4 were differentially expressed in nine cell lines of HCC, and that elevated expression of both CXCR7 and CXCL4 were correlated with highly metastatic ability of HCC cells. Moreover, CXCR7 expression was significantly upregulated in metastatic HCC samples compared with the non-metastatic ones by staining of high-density tissue microarrays constructed from a cohort of 48 human HCC specimens. CXCR7 overexpression enhanced cell growth and invasiveness in vitro, and tumorigenicity and lung metastasis in vivo. By contrast, CXCR7 stable knockdown markedly reduced these malignant behaviors. In addition, it was observed that alterations in CXCR7 expression were positively correlated with the phosphorylation levels of mitogen-activated protein kinase (MAPK) pathway proteins. Targeting extracellular regulated kinase pathway by using U0126 inhibitor or using CCX771, a selective CXCR7 antagonist, drastically reduced CXCR7-mediated cell proliferation. Importantly, by using human biotin-based antibody arrays, several differentially expressed proteins were identified in CXCR7-overexpression and depletion groups. Comparative analysis indicated that upstream regulators including TP53 and IL-6 were involved in CXCR7 signal transduction. CXCR7 expression was further proved to regulate expression of vascular endothelial growth factor A and galectin-3, which may contribute to tumor angiogenesis and invasiveness. Consequently, elevated expression of CXCR7 contributes to HCC growth and invasiveness via activation of MAPK and angiogenesis signaling pathways. Targeting CXCR7 may prevent metastasis and provide a potential therapeutic strategy for HCC.