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Ligand-activated PPAR? modulates the migration and invasion of melanoma cells by regulating Snail expression.

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR) ? is implicated in the carcinogenesis of several types of cancer. However, the therapeutic efficacy of PPAR? ligands against cancer progression is unclear. Here, we showed that PPAR? modulates the migration and invasion of melanoma cells by up-regulating Snail expression. Activation of PPAR? by GW501516, a specific ligand for PPAR?, significantly increased the migration and invasion of highly metastatic A375SM cells, but not that of low metastatic A375P cells. The migration- and invasion-promoting effects of PPAR? on A375SM cells was associated with increased Snail expression, which was accompanied by a decrease in E-cadherin expression. Furthermore, a significant concentration- and time-dependent increase in the levels of Snail mRNA and protein was observed in A375SM cells (but not A375P cells) treated with GW501516. The effects of GW501516 were almost completely abrogated by a small interfering RNA against PPAR?, suggesting that PPAR? mediates the effects of GW501516. Activation of PPAR? in SK-MEL-2 and SK-MEL-5 (but not SK-MEL-3) melanoma cell lines also led to significant increases in the expression of Snail mRNA and protein, which mirrored the invasive and migratory potential of these cell lines. These results suggest that PPAR? promotes the aggressive phenotype observed in highly metastatic melanoma cells by up-regulating Snail.

SUBMITTER: Ham SA

PROVIDER: S-EPMC4266703 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Ligand-activated PPARδ modulates the migration and invasion of melanoma cells by regulating Snail expression.

Ham Sun Ah SA Yoo Taesik T Hwang Jung Seok JS Kang Eun Sil ES Lee Won Jin WJ Paek Kyung Shin KS Park Chankyu C Kim Jin-Hoi JH Do Jeong Tae JT Lim Dae-Seog DS Seo Han Geuk HG

American journal of cancer research 20141119 6

Peroxisome proliferator-activated receptor (PPAR) δ is implicated in the carcinogenesis of several types of cancer. However, the therapeutic efficacy of PPARδ ligands against cancer progression is unclear. Here, we showed that PPARδ modulates the migration and invasion of melanoma cells by up-regulating Snail expression. Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly increased the migration and invasion of highly metastatic A375SM cells, but not that of low metastati ...[more]

PMID: 25520859

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Project description:BackgroundOvarian 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.MethodsRT-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.ResultsOur 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.ConclusionsThese results demonstrate both biological significance and clinical relevance of CCL25 and CCR9 interactions in OvCa cell metastasis.

Dataset Information

Ligand-activated PPAR? modulates the migration and invasion of melanoma cells by regulating Snail expression.

Publications

Ligand-activated PPARδ modulates the migration and invasion of melanoma cells by regulating Snail expression.

Similar Datasets

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