The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis
The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis
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DOI：
10.1093/carcin/bgt248
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发表时间：
2013-12-01
期刊：
影响因子：
4.7
通讯作者：
Fernandez-Salguero, Pedro M.
中科院分区：
文献类型：
--
作者：
Contador-Troca, Maria;Alvarez-Barrientos, Alberto;Fernandez-Salguero, Pedro M.
黑色素瘤是一种高度转移的恶性皮肤癌，患者存活率很低。由于黑色素瘤的发病率在人群中稳步增加，寻找预后和治疗靶点是癌症治疗的关键任务。二恶英受体 (AhR) 是异生素诱导的毒性和致癌作用以及细胞生理学和器官稳态所必需的。然而，AhR 影响肿瘤生长和扩散的机制在很大程度上尚不清楚。我们在这里报告，AhR 有助于肿瘤-基质相互作用，当在肿瘤细胞中表达时阻止黑色素瘤的生长和转移，但当在基质中表达时支持黑色素瘤。被设计为缺乏AhR（AhR的小发夹RNA）的B16F10细胞在注射到AhR（+/+）受体小鼠中时会加剧黑色素瘤原发性肿瘤发生和肺转移，但注射到AhR（-/-）小鼠中或与AhR（-/-）基质中的AhR（-/-）成纤维细胞共同注射时不会加剧。相反，表达组成型活性 AhR 的 B16F10 细胞在任一 AhR 遗传背景下均降低了致瘤性和侵袭性。 AhR 在黑色素瘤细胞中的抑癌作用与迁移和侵袭减少、癌症干细胞样细胞数量减少以及 β1-整合素和 Caveolin1 水平改变相关。 AHR 表达最高的人黑色素瘤细胞系的迁移和侵袭也最低。此外，在人类黑色素瘤中，与痣病变相关的 AHR 表达降低。我们得出的结论是，黑色素瘤细胞中的 AhR 敲低需要基质 AhR 才能实现最大的肿瘤进展和转移。因此，AhR 可以作为黑色素瘤的分子标记，并且应考虑其在肿瘤和基质区室中的活性。
Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR(+/+) recipient mice but not when injected in AhR(-/-) mice or when co-injected with AhR(-/-) fibroblasts in an AhR(+/+) stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of beta 1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.