Adrenomedullin2 stimulates progression of thyroid cancer in mice and humans under nutrient excess conditions.
Adrenomedullin2 stimulates progression of thyroid cancer in mice and humans under nutrient excess conditions.
复制标题
DOI：
10.1002/path.5997
复制
发表时间：
2022-11
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
甲状腺癌与基因改变有关，例如BRAFV600E，可能导致激素分泌上皮细胞发生癌变。流行病学研究表明，营养过剩与癌症的发生和进展有关。在这项研究中，我们试图确定营养过剩条件下导致 BRAFV600E 甲状腺癌进展的细胞非自主因素。我们开发了一种可诱导甲状腺细胞特异性激活 BRAFV600E 的小鼠模型，该模型显示出与人乳头状甲状腺癌相似的特征。 LSL-Braf V600E ；TgCreERT2 显示整个甲状腺出现甲状腺肿瘤，并且在高脂饮食 (HFD) 喂养的小鼠中，肿瘤显示出更多异常细胞特征，其中线粒体异常。转录组学显示，喂食 HFD 的 LSL-Braf V600E ;TgCreERT2 小鼠中，肾上腺髓质素 2 (Adm2) 增加。在癌细胞中添加具有综合应激反应 (ISR) 的线粒体复合物 I 抑制剂或棕榈酸后，ADM2 上调。 ADM2 在体外刺激蛋白激酶 A 和细胞外信号调节激酶。 ADM2 的敲除抑制了甲状腺癌细胞的增殖和迁移。我们检索了癌症基因组图谱和基因型组织表达数据库，发现 ADM2 表达增加与 ISR 和较差的总体生存率相关。一致地，肿瘤细胞和循环 ADM2 分子中 ADM2 表达上调与甲状腺癌患者的侵袭性临床病理参数（包括体重指数）相关。总的来说，我们发现 ADM2 在营养过剩导致的线粒体应激下从癌细胞中释放出来，并作为决定甲状腺癌进展特性的分泌因子。 © 2022 作者。 《病理学杂志》由 John Wiley & Sons Ltd 代表大不列颠及爱尔兰病理学会出版。
Thyroid cancer is associated with genetic alterations, e.g. BRAFV600E, which may cause carcinomatous changes in hormone‐secreting epithelial cells. Epidemiological studies have shown that overnutrition is related to the development and progression of cancer. In this study, we attempted to identify the cell nonautonomous factor responsible for the progression of BRAFV600E thyroid cancer under overnutrition conditions. We developed a mouse model for inducible thyrocyte‐specific activation of BRAFV600E, which showed features similar to those of human papillary thyroid cancer. LSL‐Braf V600E ;TgCreERT2 showed thyroid tumour development in the entire thyroid, and the tumour showed more abnormal cellular features with mitochondrial abnormalities in mice fed a high‐fat diet (HFD). Transcriptomics revealed that adrenomedullin2 (Adm2) was increased in LSL‐Braf V600E ;TgCreERT2 mice fed HFD. ADM2 was upregulated on the addition of a mitochondrial complex I inhibitor or palmitic acid with integrated stress response (ISR) in cancer cells. ADM2 stimulated protein kinase A and extracellular signal‐regulated kinase in vitro. The knockdown of ADM2 suppressed the proliferation and migration of thyroid cancer cells. We searched The Cancer Genome Atlas and Genotype‐Tissue Expression databases and found that increased ADM2 expression was associated with ISR and poor overall survival. Consistently, upregulated ADM2 expression in tumour cells and circulating ADM2 molecules were associated with aggressive clinicopathological parameters, including body mass index, in thyroid cancer patients. Collectively, we identified that ADM2 is released from cancer cells under mitochondrial stress resulting from overnutrition and acts as a secretory factor determining the progressive properties of thyroid cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
登录
查看更多内容
肥胖与分化型甲状腺癌的风险：一项大规模病例对照研究
影响因子：
3.2
作者：
He, Qiao;Sun, Hui;Liang, Nan
通讯作者：
Liang, Nan
影响因子：
5.2
作者：
Bokobza E;Hinault C;Tiroille V;Clavel S;Bost F;Chevalier N
通讯作者：
Chevalier N
影响因子：
16.6
作者：
Jung SB;Choi MJ;Ryu D;Yi HS;Lee SE;Chang JY;Chung HK;Kim YK;Kang SG;Lee JH;Kim KS;Kim HJ;Kim CS;Lee CH;Williams RW;Kim H;Lee HK;Auwerx J;Shong M
通讯作者：
Shong M
影响因子：
5.2
作者：
Kang, Yea Eun;Kim, Jung Tae;Koo, Bon Seok
通讯作者：
Koo, Bon Seok
影响因子：
3.5
作者：
Kovaleva, Irina E.;Garaeva, Alisa A.;Evstafieva, Alexandra G.
通讯作者：
Evstafieva, Alexandra G.