C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma.
C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma.
复制标题
C-C趋化因子受体1型介导骨桥蛋白促进肝细胞癌转移
DOI：
10.1111/cas.13487
复制
发表时间：
2018-03
期刊：
影响因子：
5.7
通讯作者：
Qin LX
中科院分区：
文献类型：
--
作者：
Zhu Y;Gao XM;Yang J;Xu D;Zhang Y;Lu M;Zhang Z;Sheng YY;Li JH;Yu XX;Zheng Y;Dong QZ;Qin LX
在肝细胞癌的微环境中，趋化因子受体在肿瘤的发生和转移中起着关键作用。我们以前的研究发现骨桥蛋白(OPN)是肝细胞癌转移的促进剂。然而，趋化因子受体在OPN诱导的肝细胞癌转移中的作用尚不清楚。在这项研究中，我们证明了OPN在有转移的肝细胞癌组织中显著升高，并且OPN的高表达与较差的总体生存率和较高的复发率相关。OPN上调肝细胞癌中趋化因子受体的表达、迁移、侵袭和肺转移。我们发现C-C趋化因子受体1型(CCR1)和C-X-C趋化因子受体6型(CXCR6)是OPN诱导的最高表达的趋化因子受体。CCR1基因敲除可减少OPN在体外和体内诱导的迁移、侵袭和肺转移，而CXCR6基因敲除不能逆转OPN促进的迁移和侵袭。此外，骨桥蛋白通过激活磷脂酰肌醇3-激酶和低氧诱导因子-1α(HIF-1α)上调肝癌细胞中CCR1的表达。此外，用CCR1拮抗剂阻断OPN-CCR1轴可显著抑制OPN对肝癌进展和转移的促进作用。在人肝细胞癌组织中，OPN的表达与CCR1的表达呈显著正相关，OPN和CCR1同时高表达的患者预后最差。综上所述，我们的研究结果表明，OPN-CCR1轴在促进肿瘤转移中起重要作用，CCR1是控制高OPN肝癌患者转移的潜在治疗靶点。
In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN‐induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C‐C chemokine receptor type 1 (CCR1) and C‐X‐C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN‐promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3‐kinase (PI3K)/AKT and hypoxia‐inducible factor 1α (HIF‐1α) in HCC cells. Furthermore, blockade of OPN‐CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN‐CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.
登录
查看更多内容
影响因子：
24.5
作者：
Chew V;Chen J;Lee D;Loh E;Lee J;Lim KH;Weber A;Slankamenac K;Poon RT;Yang H;Ooi LL;Toh HC;Heikenwalder M;Ng IO;Nardin A;Abastado JP
通讯作者：
Abastado JP
DOI：
10.1073/pnas.1002372107
发表时间：
2010-07-20
影响因子：
11.1
作者：
Kitamura, Takanori;Fujishita, Teruaki;Taketo, Makoto M.
通讯作者：
Taketo, Makoto M.
影响因子：
6
作者：
Lu, PR;Nakamoto, Y;Mukaida, N
通讯作者：
Mukaida, N
影响因子：
3.8
作者：
Kato, Taku;Fujita, Yasunori;Ito, Masafumi
通讯作者：
Ito, Masafumi
影响因子：
11.2
作者：
Lanzen, J;Braun, RD;Dewhirst, MW
通讯作者：
Dewhirst, MW