CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion.
CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion.
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DOI：
10.1186/1477-7819-8-62
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发表时间：
2010-07-22
影响因子：
3.2
通讯作者：
Lillard JW Jr
中科院分区：
文献类型：
--
作者：
Johnson EL;Singh R;Singh S;Johnson-Holiday CM;Grizzle WE;Partridge EE;Lillard JW Jr
卵巢癌(OvCa)是女性最致命的妇科恶性肿瘤，其预后不良的主要原因是转移。趋化因子受体CCR9主要由一小部分免疫细胞表达，其唯一的天然配体CCL25主要在胸腺表达，胸腺随着年龄的增长而退化。除胸腺外，CCL25还通过小肠表达。CCL25和CCR9之间的相互作用与白细胞向小肠的转移有关，小肠是OvCa细胞的常见转移部位。目前的研究表明，卵巢组织和细胞显著表达CCR9，CCR9与CCL25相互作用，支持癌细胞的迁移和侵袭。用RT-PCR和流式细胞仪技术检测卵巢癌细胞CCR9的表达。用OvCa组织芯片(TMA)证实CCR9在临床标本中的表达。用Aperio ScanScope扫描系统对免疫组织化学染色进行定量。采用细胞迁移和基质侵袭小室进行细胞侵袭和迁移分析。采用逆转录聚合酶链式反应(RT-PCR)和酶联免疫吸附试验(ELISA)分别检测基质金属蛋白酶(MMPs)和活性MMPs。我们的结果显示，与非肿瘤性卵巢组织相比，粘液性腺癌、乳头状浆液性癌和子宫内膜样癌组织中CCR9的表达显著升高(p<；0.001)。此外，CCR9在OvCa细胞系(OVCAR-3和CAOV-3)中的表达显著高于正常成人卵巢上皮细胞。OvCa细胞对CCL25的趋化梯度表现出较高的迁移和侵袭能力，而CCR9抗体对CCL25的趋化梯度有抑制作用。CCL25以CCR9依赖的方式调节OvCa细胞胶原酶(MMP1、-8和-13)、明胶酶(MMP2和-9)和基质蛋白(MMP3、-10和-11)的表达。这些结果表明CCL25和CCR9相互作用在OvCa细胞转移中具有生物学意义和临床相关性。
Ovarian carcinoma (OvCa) is the most lethal gynecological malignancy among women and its poor prognosis is mainly due to metastasis. Chemokine receptor CCR9 is primarily expressed by a small subset of immune cells and its only natural ligand, CCL25, is largely expressed in the thymus, which involutes with age. Other than the thymus, CCL25 is expressed by the small bowel. Interactions between CCL25 and CCR9 have been implicated in leukocyte trafficking to the small bowel, a frequent metastatic site for OvCa cells. The current study shows OvCa tissue and cells significantly express CCR9, which interacts with CCL25 to support carcinoma cell migration and invasion. RT-PCR and flow cytometry techniques were used to quantify the expression CCR9 by OvCa cells. OvCa tissue microarrays (TMA) was used to confirm CCR9 expression in clinical samples. The Aperio ScanScope scanning system was used to quantify immunohistochemical staining. Cell invasion and migration assays were performed using cell migration and matrigel invasion chambers. Matrix metalloproteinase (MMP) mRNAs were quantified by RT-PCR and active MMPs were quantified by ELISA. Our results show significantly (p < 0.001) higher expression of CCR9 by mucinous adenocarcinoma, papillary serous carcinoma, and endometriod ovarian carcinoma cases, than compared to non-neoplastic ovarian tissue. Furthermore, CCR9 expression was significantly elevated in OvCa cell lines (OVCAR-3 and CAOV-3) in comparison to normal adult ovarian epithelial cell mRNA. OvCa cells showed higher migratory and invasive potential towards chemotactic gradients of CCL25, which was inhibited by anti-CCR9 antibodies. Expression of collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), and stromelysins (MMP-3, -10, and -11) by OvCa cells were modulated by CCL25 in a CCR9-dependent fashion. These results demonstrate both biological significance and clinical relevance of CCL25 and CCR9 interactions in OvCa cell metastasis.
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