Ham Sun Ah, Yoo Taesik, Hwang Jung Seok, Kang Eun Sil, Lee Won Jin, Paek Kyung Shin, Park Chankyu, Kim Jin-Hoi, Do Jeong Tae, Lim Dae-Seog, Seo Han Geuk
Department of Animal Biotechnology, Konkuk University 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea.
Department of Nursing, Semyung University 65 Semyung-ro, Jecheon 390-711, Republic of Korea.
Am J Cancer Res. 2014 Nov 19;4(6):674-82. eCollection 2014.
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 metastatic A375P cells. The migration- and invasion-promoting effects of PPARδ 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 PPARδ, suggesting that PPARδ mediates the effects of GW501516. Activation of PPARδ 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 PPARδ promotes the aggressive phenotype observed in highly metastatic melanoma cells by up-regulating Snail.
过氧化物酶体增殖物激活受体（PPAR）δ与多种癌症的发生有关。然而，PPARδ配体对癌症进展的治疗效果尚不清楚。在此，我们表明PPARδ通过上调Snail表达来调节黑色素瘤细胞的迁移和侵袭。PPARδ的特异性配体GW501516激活PPARδ后，显著增加了高转移性A375SM细胞的迁移和侵袭能力，但对低转移性A375P细胞没有这种作用。PPARδ对A375SM细胞迁移和侵袭的促进作用与Snail表达增加有关，同时伴有E-钙黏蛋白表达降低。此外，在用GW501516处理的A375SM细胞（而非A375P细胞）中，观察到Snail mRNA和蛋白水平有显著的浓度和时间依赖性增加。针对PPARδ的小干扰RNA几乎完全消除了GW501516的作用，表明PPARδ介导了GW501516的作用。在SK-MEL-2和SK-MEL-5（而非SK-MEL-3）黑色素瘤细胞系中激活PPARδ也导致Snail mRNA和蛋白表达显著增加，这反映了这些细胞系的侵袭和迁移潜能。这些结果表明，PPARδ通过上调Snail促进高转移性黑色素瘤细胞中观察到的侵袭性表型。
