Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Bioinformatics Unit, George Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1045-1050. doi: 10.1073/pnas.1715930115. Epub 2018 Jan 16.
Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is the best-characterized entity among the congenital insulin-like growth factor 1 (IGF1) deficiencies. Life-long exposure to minute endogenous IGF1 levels is linked to low stature as well as a number of endocrine and metabolic abnormalities. While elevated IGF1 is correlated with increased cancer incidence, epidemiological studies revealed that patients with LS do not develop tumors. The mechanisms associated with cancer protection in LS are yet to be discovered. Recent genomic analyses identified a series of metabolic genes that are overrepresented in patients with LS. Given the augmented expression of these genes in a low IGF1 milieu, we hypothesized that they may constitute targets for IGF1 action. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular redox control by thioredoxin. TXNIP serves as a glucose and oxidative stress sensor, being commonly silenced by genetic or epigenetic events in cancer cells. Consistent with its enhanced expression in LS, we provide evidence that gene expression is negatively regulated by IGF1. These results were corroborated in animal studies. In addition, we show that oxidative and glucose stresses led to marked increases in expression. Supplementation of IGF1 attenuated TXNIP levels, suggesting that IGF1 exerts its antiapoptotic effect via inhibition of Augmented expression in LS may account for cancer protection in this condition. Finally, TXNIP levels could be potentially useful in the clinic as a predictive or diagnostic biomarker for IGF1R-targeted therapies.
拉隆综合征（LS），或称为原发性生长激素（GH）不敏感，是先天性胰岛素样生长因子 1（IGF1）缺乏症中研究最透彻的疾病。终生接触微量内源性 IGF1 水平与身材矮小以及许多内分泌和代谢异常有关。虽然 IGF1 升高与癌症发病率增加相关，但流行病学研究表明 LS 患者不会发生肿瘤。与 LS 中癌症保护相关的机制尚待发现。最近的基因组分析确定了一系列在 LS 患者中过度表达的代谢基因。鉴于这些基因在 IGF1 低水平环境下的表达增强，我们假设它们可能构成 IGF1 作用的靶点。硫氧还蛋白相互作用蛋白（TXNIP）通过硫氧还蛋白在细胞氧化还原控制中发挥关键作用。TXNIP 作为葡萄糖和氧化应激传感器，在癌细胞中通常因遗传或表观遗传事件而沉默。与 LS 中增强的表达一致，我们提供了证据表明基因表达受 IGF1 负调控。这些结果在动物研究中得到了证实。此外，我们表明氧化和葡萄糖应激导致表达显著增加。IGF1 的补充降低了 TXNIP 水平，表明 IGF1 通过抑制 TXNIP 的表达发挥其抗凋亡作用。LS 中增强的表达可能是该疾病中癌症保护的原因。最后，TXNIP 水平可能在临床上作为 IGF1R 靶向治疗的预测或诊断生物标志物。
