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CYP2S1 is a synthetic lethal target in BRAF V600E -driven thyroid cancers

机译:CYP2S1是BRAF V600E -DRIVEN甲状腺癌的合成致死靶

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BRAFV600E is the most common genetic alteration and has become a major therapeutic target in thyroid cancers; however, intrinsic feedback mechanism limited clinical use of BRAFV600E specific inhibitors. Synthetic lethal is a kind of interaction between two genes, where only simultaneously perturbing both of the genes can lead to lethality. Here, we identified CYP2S1 as a synthetic lethal partner of BRAFV600E in thyroid cancers. First, we found that CYP2S1 was highly expressed in papillary thyroid cancers (PTCs) compared to normal thyroid tissues, particularly in conventional PTCs (CPTCs) and tall-cell PTCs (TCPTCs), and its expression was positively associated with BRAFV600E mutation. CYP2S1 knockdown selectively inhibited cell proliferation, migration, invasion and tumorigenic potential in nude mice, and promoted cell apoptosis in BRAFV600E mutated thyroid cancer cells, but not in BRAF wild-type ones. Mechanistically, BRAFV600E-mediated MAPK/ERK cascade upregulated CYP2S1 expression by an AHR-dependent pathway, while CYP2S1 in turn enhanced transcriptional activity of AHR through its metabolites. This AHR/CYP2S1 feedback loop strongly amplified oncogenic role of BRAFV600E in thyroid cancer cells, thereby causing synthetic lethal interaction between CYP2S1 and BRAFV600E. Finally, we demonstrated CYP2S1 as a potential therapeutic target in both BRAFV600E-drived xenograft and transgenic mouse models by targetedly delivering CYP2S1-specific siRNA. Altogether, our data demonstrate CYP2S1 as a synthetic lethal partner of BRAFV600E in thyroid cancers, and indicate that targeting CYP2S1 will provide a new therapeutic strategy for BRAFV600E mutated thyroid cancers.
机译:BRAFV600E是最常见的遗传改变,已成为甲状腺癌的主要治疗靶标;然而,内在反馈机制有限公司临床应用BRAFV600E特异性抑制剂。合成的致死是两种基因之间的一种相互作用,其中仅同时扰动两种基因会导致致命性。在这里,我们将CYP2S1鉴定为甲状腺癌中BRAFV600E的合成致死伴侣。首先,我们发现与正常的甲状腺组织相比,Cyp2S1在乳头状甲状腺癌(PTCS)中高表达,特别是在常规PTCS(CPTC)和高细胞PTC(TCPTC)中,其表达与BRAFV600E突变正相关。 CYP2S1敲低裸鼠中的细胞增殖,迁移,侵袭和致瘤潜力,并促进BRAFV600E突变甲状腺癌细胞的细胞凋亡,但不在BRAF野生型癌细胞中。机械地,BRAFV600E介导的MAPK / ERK级联通过AHR依赖性途径上调CYP2S1表达,而CYP2S1通过其代谢物转动AHR的转录活性。该AHR / CYP2S1反馈回路强大扩增BRAFV600E在甲状腺癌细胞中的致癌作用,从而导致CYP2S1和BRAFV600E之间的合成致死相互作用。最后,通过靶向CYP2S1特异性siRNA,我们证明了CYP2S1作为BRAFV600E驱动的异种移植物和转基因小鼠模型中的潜在治疗靶标。完全,我们的数据证明了CYP2S1作为BRAFV600E的甲状腺癌的合成致死伴侣,并表明靶向CYP2S1将为BRAFV600E突变的甲状腺癌提供新的治疗策略。

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