Growth hormone is permissive for neoplastic colon growth
Growth hormone is permissive for neoplastic colon growth
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DOI：
10.1073/pnas.1600561113
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发表时间：
2016-06-07
影响因子：
11.1
通讯作者：
Melmed, Shlomo
中科院分区：
文献类型：
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作者：
Chesnokova, Vera;Zonis, Svetlana;Melmed, Shlomo
肢端肥大症患者的生长激素（GH）过量与癌前结肠息肉和软组织腺瘤的增加有关，而身材矮小的人携带灭活的GH受体突变不会患上癌症。我们发现局部表达的结肠生长激素在结肠癌易感性和结肠腺癌相关的间质成纤维细胞中丰富。肢端肥大症患者使用生长激素受体（GHR）阻滞剂可诱导结肠p53和腺瘤性大肠息肉病（APC），逆转生长激素信号。p53也在GHR突变的矮个子人的皮肤成纤维细胞中被诱导。垂体特异性阳性转录因子1 (Prop1)（-/-）基因缺失的小鼠表现出诱导的结肠p53水平，将其与正常发生肠道和结肠肿瘤的Apc（min+/-）小鼠杂交，产生gh缺失的双突变体，肿瘤数量和大小明显减少。我们还证明了生长激素在人结肠细胞系和诱导的人多能干细胞衍生的肠道类器官中抑制p53并减少凋亡，并在体内证实了生长激素抑制结肠粘膜p53/p21。生长激素过量导致结肠细胞磷酸酶和10号染色体上张力蛋白同源物缺失（PTEN）减少，细胞存活率增加，APC下调，核β -连环蛋白积累，上皮-间质过渡因子和结肠细胞运动增加。我们认为生长激素是允许肿瘤结肠生长的“场变化”环境的分子组成部分。
Growth hormone (GH) excess in acromegaly is associated with increased precancerous colon polyps and soft tissue adenomas, whereas short-stature humans harboring an inactivating GH receptor mutation do not develop cancer. We show that locally expressed colon GH is abundant in conditions predisposing to colon cancer and in colon adenocarcinoma-associated stromal fibroblasts. Administration of a GH receptor (GHR) blocker in acromegaly patients induced colon p53 and adenomatous polyposis coli (APC), reversing progrowth GH signals. p53 was also induced in skin fibroblasts derived from short-statured humans with mutant GHR. GH-deficient prophet of pituitary-specific positive transcription factor 1 (Prop1)(-/-) mice exhibited induced colon p53 levels, and cross-breeding them with Apc(min+/-) mice that normally develop intestinal and colon tumors resulted in GH-deficient double mutants with markedly decreased tumor number and size. We also demonstrate that GH suppresses p53 and reduces apoptosis in human colon cell lines as well as in induced human pluripotent stem cell-derived intestinal organoids, and confirm in vivo that GH suppresses colon mucosal p53/p21. GH excess leads to decreased colon cell phosphatase and tensin homolog deleted on chromosome 10 (PTEN), increased cell survival with down-regulated APC, nuclear beta-catenin accumulation, and increased epithelial-mesenchymal transition factors and colon cell motility. We propose that GH is a molecular component of the "field change" milieu permissive for neoplastic colon growth.