CCL25-CCR9 相互作用调节卵巢癌细胞迁移、金属蛋白酶表达和侵袭。
CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion.
机构信息
Department of Microbiology, Biochemistry, & Immunology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310-1495, USA.
出版信息
World J Surg Oncol. 2010 Jul 22;8:62. doi: 10.1186/1477-7819-8-62.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
These results demonstrate both biological significance and clinical relevance of CCL25 and CCR9 interactions in OvCa cell metastasis.
背景
卵巢癌（OvCa）是女性中最致命的妇科恶性肿瘤，其预后不良主要是由于转移。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 主要在胸腺中表达，随着年龄的增长而退化。除了胸腺外，CCL25 还由小肠表达。CCL25 与 CCR9 的相互作用已被牵连到白细胞向小肠的迁移，这是 OvCa 细胞经常转移的部位。本研究表明 OvCa 组织和细胞显著表达 CCR9，其与 CCL25 相互作用以支持癌细胞的迁移和侵袭。
方法
使用 RT-PCR 和流式细胞术技术来量化 OvCa 细胞中 CCR9 的表达。使用卵巢癌组织微阵列（TMA）来确认临床样本中 CCR9 的表达。使用 Aperio ScanScope 扫描系统来量化免疫组织化学染色。使用细胞迁移和基质胶侵袭室进行细胞侵袭和迁移测定。通过 RT-PCR 量化基质金属蛋白酶（MMP）mRNA，通过 ELISA 量化活性 MMPs。
结果
我们的结果表明，与非肿瘤性卵巢组织相比，黏液性腺癌、乳头状浆液性癌和子宫内膜样卵巢癌病例中 CCR9 的表达显著升高（p<0.001）。此外，与正常成人卵巢上皮细胞 mRNA 相比，OvCa 细胞系（OVCAR-3 和 CAOV-3）中 CCR9 的表达显著升高。OvCa 细胞对 CCL25 趋化梯度表现出更高的迁移和侵袭潜力，这可以通过抗 CCR9 抗体抑制。OvCa 细胞中胶原蛋白酶（MMP-1、-8 和 -13）、明胶酶（MMP-2 和 -9）和基质金属蛋白酶（MMP-3、-10 和 -11）的表达通过 CCR9 依赖的方式被 CCL25 调节。
结论
这些结果证明了 CCL25 和 CCR9 相互作用在 OvCa 细胞转移中的生物学意义和临床相关性。
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