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CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion.

ABSTRACT: 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.

SUBMITTER: Johnson EL

PROVIDER: S-EPMC2927595 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion.

Johnson Erica L EL Singh Rajesh R Singh Shailesh S Johnson-Holiday Crystal M CM Grizzle William E WE Partridge Edward E EE Lillard James W JW

World journal of surgical oncology 20100722

<h4>Background</h4>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 fre ...[more]

PMID: 20649989

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Project description:Background: Accumulating evidence indicates that aberrant activation of the Hedgehog (Hh) signalling pathway by Glioma-associated oncogene (Gli) transcription factors is involved in the aggressive progression of cancers, including ovarian cancer. Whereas the molecular mechanism underlying this phenomenon remains unelucidated. Matrix metalloproteinase-7 (MMP-7) facilitates degradation of the extracellular matrix, promoting the invasion of tumour cells, and is associated with cancer progression and metastasis. In previous reports, we identified a set of genes regulated by Hh signalling in ovarian tumour cells among which MMP-7 was identified as a potential Hh target gene candidate. However, establishing an association between Hh signalling activation and MMP-7 expression requires further validation, and the function of this regulation remains unknown. Methods: A cDNA microarray was utilized to identify potential downstream targets of Hh signalling. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate mRNA expression, and immunoblotting (IB) was conducted to evaluate protein expression. The invasive and migratory capabilities of tumour cells were tested with the transwell and wound healing assays, respectively. The mRNA levels of Gli2 and MMP-7 in normal ovarian tissues and cancerous tissues in various stages together with the corresponding clinical information were acquired from the indicated GEO datasets to elucidate associations between MMP-7 expression and cancer progression and prognosis. Additionally, immunohistochemistry (IHC) was performed in multiple ovarian cancers, benign tumours and normal tissues to evaluate Gli2 and MMP-7 protein expression. Results: MMP-7 expression was regulated by the Hh ligand, antagonist and downstream transcript factor Gli2, demonstrating this gene as an Hh target. MMP-7 facilitated the invasion and migration of ovarian tumour cells, indicating its key function in ovarian cancer progression. IHC analysis demonstrated abnormally increased Gli2 and MMP-7 expression levels in benign tumours and ovarian cancer tissues. Moreover, high MMP-7 levels were significantly associated with poor overall survival (OS) and poor progression-free survival (PFS) in ovarian cancer patients. Conclusion: Aberrant activation of the Hh-Gli-MMP-7 signalling axis is essential for acceleration of the progression and metastasis of human ovarian cancer, implicating its use as a novel therapeutic target of ovarian cancer. In addition, MMP-7 can potentially serve as a prognostic marker of ovarian cancer.

Project description:BackgroundCC chemokine receptor 9 (CCR9), an organ-specific chemokine receptor, interacts with its exclusive ligand CCL25 to promote tumor proliferation and metastasis. However, the effect of CCR9 on salivary adenoid cystic carcinoma (SACC) malignant behavior remains unknown. This study aimed to investigate the specific molecular mechanism by which CCR9/CCL25 modulates malignant progression in SACC.MethodsImmunohistochemistry staining and RT-qPCR analyses were performed to detect the correlation of CCR9 expression and tumor progression-associated markers in SACC. In vitro, SACC cell proliferation and apoptosis were evaluated using Cell Counting Kit-8 and colon formation, and cell migration and invasion were detected by wound healing and transwell assays. Vercirnon was used as an inhibitor of CCR9, and LY294002 was used as an inhibitor of the PI3K/AKT pathway in this study. Western blot and RT-qPCR assays were carried out to measure the downstream factors of the interaction of CCL25 and CCR9. The effect of CCL25 on the development of SACC in vivo was examined by a xenograft tumor model in nude mice following CCL25, Vercirnon and LY294002 treatment.ResultsCCR9 was highly expressed in SACC compared with adjacent salivary gland tissues, and its level was associated with tumor proliferation and metastases. CCL25 enhanced cell proliferation, migration, and invasion through its interaction with CCR9 and exerted an antiapoptotic effect on SACC cells. Targeting CCR9 via Vercirnon significantly reduced the phosphorylation level of AKT induced by CCL25. CCL25/CCR9 could activate its downstream factors through the PI3K/AKT signaling pathway, such as cyclin D1, BCL2 and SLUG, thus promoting SACC cell proliferation, antiapoptosis, invasion and metastasis. The in vivo data from the xenograft mouse models further proved that CCL25 administration promoted malignant tumor progression by activating the PI3K/AKT pathway.ConclusionThe interaction of CCL25 and CCR9 promotes tumor growth and metastasis in SACC by activating the PI3K/AKT signaling pathway, offering a promising strategy for SACC treatment.

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CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion.

Publications

CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion.

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