HSCs-derived COMP drives hepatocellular carcinoma progression by activating MEK/ERK and PI3K/AKT signaling pathways.
HSCs-derived COMP drives hepatocellular carcinoma progression by activating MEK/ERK and PI3K/AKT signaling pathways.
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HSC 衍生的 COMP 通过激活 MEK/ERK 和 PI3K/AKT 信号通路驱动肝细胞癌进展。
DOI：
10.1186/s13046-018-0908-y
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发表时间：
2018-09-19
期刊：
影响因子：
--
通讯作者：
Tu K
中科院分区：
文献类型：
--
作者：
Li Q;Wang C;Wang Y;Sun L;Liu Z;Wang L;Song T;Yao Y;Liu Q;Tu K
已知胡萝卜素寡聚基质蛋白（COMP）促进皮肤、肺和肝中的纤维化。新的证据表明COMP在肿瘤的发展中起着关键作用，包括乳腺癌、结肠癌和肝细胞癌（HCC）。然而，COMP在HCC增殖和转移中的作用及其潜在机制仍不清楚。ELISA法测定血清COMP。进行细胞计数试剂盒-8和平板集落形成以评价细胞增殖。伤口愈合和transwell试验用于确定HCC细胞的迁移和侵袭。采用免疫印迹法和免疫荧光法检测肝癌细胞中上皮间质转化（EMT）标志物和基质金属蛋白酶（MMPs）的表达。使用小鼠模型评价COMP的体内作用。我们还利用transwell共培养系统检测了肝星状细胞（HSC）条件培养基（CM）对HCC进展的影响。在这里，我们发现，血清COMP水平在肝癌患者显着高于健康对照组。因此，HCC患者中高血清COMP水平与恶性临床特征和不良临床结局显著相关。接下来，我们研究了重组人COMP蛋白（rCOMP）处理导致HCC细胞增殖、侵袭和迁移能力的增加。此外，rCOMP处理增强了体内HCC细胞的增殖和转移定植。从机制上讲，CD 36受体在COMP介导的HCC细胞增殖和转移中起着重要作用。在功能上，COMP/CD 36信号传导引起ERK和AKT的磷酸化，导致HCC细胞中肿瘤进展基因如EMT标记物、MMP-2/9、Slug和Twist的上调。有趣的是，我们发现COMP由HSC分泌。与对照CM相比，COMP敲低的LX 2细胞的CM对HCC细胞中MEK/ERK和PI 3 K/AKT信号通路的激活的影响较弱。我们的研究结果表明，HSCs来源的COMP与CD 36合作，随后在MEK/ERK和PI 3 K/AKT介导的HCC进展中发挥重要作用。COMP有望成为侵袭性肝癌诊断和治疗的新靶点。本文的在线版本（10.1186/s13046-018-0908-y）包含补充材料，可供授权用户使用。
Cartilage oligomeric matrix protein (COMP) is known to promote fibrosis in skin, lung and liver. Emerging evidence shows that COMP plays critical roles in tumor development, including breast cancer, colon cancer and hepatocellular carcinoma (HCC). Nevertheless, the role of COMP in HCC proliferation and metastasis and its underlying mechanisms remain fully unclear. Serum COMP was determined by ELISA. Cell Counting Kit-8 and plate colony formation were performed to evaluate cell proliferation. Wound healing and transwell assays were used to determine migration and invasion of HCC cells. Western blotting and immunofluorescence were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers and MMPs in HCC cells. The in vivo role of COMP was evaluated using mouse models. We also measured effects of hepatic stellate cells (HSCs)-conditioned medium (CM) on HCC progression using transwell coculture system. Here, we found that serum COMP levels in HCC patients were significantly higher than those in healthy controls. Accordingly, high serum COMP levels in HCC patients significantly correlated with malignant clinical characteristics and poor clinical outcomes. Next, we investigated that recombinant human COMP protein (rCOMP) treatment resulted in increased abilities of proliferation, invasion and migration of HCC cells. Furthermore, rCOMP treatment enhanced proliferative and metastatic colonization of HCC cells in vivo. Mechanistically, CD36 receptor played an essential role in COMP-mediated HCC cell proliferation and metastasis. Functionally, COMP/CD36 signaling caused phosphorylation of ERK and AKT, resulting in the upregulation of tumor-progressive genes such as EMT markers, MMP-2/9, Slug and Twist in HCC cells. Interestingly, we revealed that COMP was secreted by HSCs. CM of LX2 cells with COMP knockdown showed weaker effects on the activation of MEK/ERK and PI3K/AKT signaling pathways in HCC cells compared to control CM. Our findings indicated that HSCs-derived COMP collaborated with CD36 and subsequently played an essential role in MEK/ERK and PI3K/AKT-mediated HCC progression. COMP might act as a promising target for the diagnosis and treatment of aggressive HCC. The online version of this article (10.1186/s13046-018-0908-y) contains supplementary material, which is available to authorized users.
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影响因子：
11.2
作者：
Ulrich TA;de Juan Pardo EM;Kumar S
通讯作者：
Kumar S
影响因子：
13.5
作者：
Reichl, Patrick;Dengler, Mirko;van Zijl, Franziska;Huber, Heidemarie;Fuehrlinger, Gerhard;Reichel, Christian;Sieghart, Wolfgang;Peck-Radosavljevic, Markus;Grubinger, Markus;Mikulits, Wolfgang
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影响因子：
9.7
作者：
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作者：
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