TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis.
TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis.
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DOI：
10.1126/sciadv.adg7125
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发表时间：
2023-09
期刊：
影响因子：
13.6
通讯作者：
Wang, Yu-Long
中科院分区：
文献类型：
--
作者：
Yu, Pengcheng;Qu, Ning;Zhu, Rui;Hu, Jiaqian;Han, Peizhen;Wu, Jiahao;Tan, Licheng;Gan, Hualei;He, Cong;Fang, Chuantao;Lei, Yubin;Li, Jian;He, Chenxi;Lan, Fei;Shi, Xiao;Wei, Wenjun;Wang, Yu;Ji, Qinghai;Yu, Fa-Xing;Wang, Yu-Long
TERT再激活在人类恶性肿瘤，尤其是晚期癌症中频繁发生。然而，在体内，TERT重新激活在肿瘤进展中的作用和潜在的机制还不完全清楚。在本研究中，我们特异性地在小鼠甲状腺上皮细胞表达了TERT和/或活性BRAF(BRAF V600E)。BRAF V600E单独诱导甲状腺乳头状癌(PTC)，BRAF V600E和TERT共同表达导致低分化甲状腺癌(PDTC)。空间转录组分析表明，共表达BRAF V600E和TERT的小鼠肿瘤具有高度的异质性，细胞去分化与核糖体的生物发生呈正相关。机制上，TERT通过与参与核糖体生物发生的多种蛋白质相互作用，促进核糖体RNA(RRNA)的表达和蛋白质合成。此外，我们还发现rRNA转录抑制剂CX-5461能有效地抑制甲状腺癌细胞的增殖并诱导其再分化。因此，TERT通过诱导癌细胞去分化来促进甲状腺癌的进展，而核糖体抑制是治疗TERT再激活癌症的潜在策略。有证据表明，TERT通过促进核糖体生物发生而诱导甲状腺癌进展，具有良好的治疗意义。
TERT reactivation occurs frequently in human malignancies, especially advanced cancers. However, in vivo functions of TERT reactivation in cancer progression and the underlying mechanism are not fully understood. In this study, we expressed TERT and/or active BRAF (BRAF V600E) specifically in mouse thyroid epithelium. While BRAF V600E alone induced papillary thyroid cancer (PTC), coexpression of BRAF V600E and TERT resulted in poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome analysis revealed that tumors from mice coexpressing BRAF V600E and TERT were highly heterogeneous, and cell dedifferentiation was positively correlated with ribosomal biogenesis. Mechanistically, TERT boosted ribosomal RNA (rRNA) expression and protein synthesis by interacting with multiple proteins involved in ribosomal biogenesis. Furthermore, we found that CX-5461, an rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation of thyroid cancer. Thus, TERT promotes thyroid cancer progression by inducing cancer cell dedifferentiation, and ribosome inhibition represents a potential strategy to treat TERT-reactivated cancers. Evidence shows TERT induces thyroid cancer progression by promoting ribosomal biogenesis, with promising therapeutic implications.
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发表时间：
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影响因子：
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