Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Endocrine and Diabetes Research Unit, Schneider Children's Medical Center, Petah Tikva 49292, Israel.
Eur J Cancer. 2020 Dec;141:115-127. doi: 10.1016/j.ejca.2020.09.034. Epub 2020 Oct 30.
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis has a key role in normal growth and development. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor, leading to congenital IGF1 deficiency. Epidemiological studies have shown that LS patients are protected from cancer. Genome-wide profiling led to the identification of a series of metabolic genes whose differential expression in LS might be linked to cancer protection. Nephronectin (NPNT) is an intracellular and secreted extracellular matrix protein with important roles in kidney development. NPNT was identified as the top-downregulated gene in LS-derived cells in comparison with ethnic-, age- and gender-matched controls (p-value = 0.0148; fold-change = -3.12 versus controls). NPNT has not been previously linked to the IGF1 signaling pathway. The present study was aimed at evaluating the hypothesis that NPNT is a new target for IGF1 action and that decreased expression of NPNT in LS is correlated with cancer protection.
Basal and IGF1-stimulated NPNT expression were assessed in LS lymphoblastoid cells as well as in human breast and prostate cancer cells. NPNT silencing experiments were conducted using siRNA methodology.
We provide evidence that IGF1 stimulates NPNT expression in LS-derived lymphoblastoids and various cancer cell lines. In addition, we demonstrate that NPNT silencing results in diminished activation of the AKT and ERK1/2 pathways, with ensuing decreases in cellular proliferation.
Our data identified the NPNT gene as a target for IGF1 action. The clinical implications of the functional and physical interactions between NPNT and the IGF1 pathway merit further investigation.
生长激素（GH）-胰岛素样生长因子 1（IGF1）内分泌轴在正常生长和发育中起着关键作用。拉隆综合征（LS）是一种由 GH 受体突变引起的侏儒症，导致先天性 IGF1 缺乏。流行病学研究表明，LS 患者可预防癌症。全基因组分析导致了一系列代谢基因的鉴定，这些基因在 LS 中的差异表达可能与癌症保护有关。纤连蛋白（NPNT）是一种细胞内和分泌的细胞外基质蛋白，在肾脏发育中具有重要作用。与种族、年龄和性别匹配的对照组相比，NPNT 被确定为 LS 衍生细胞中下调最多的基因（p 值=0.0148；倍数变化=-3.12 与对照组相比）。NPNT 以前与 IGF1 信号通路无关。本研究旨在评估 NPNT 是 IGF1 作用的新靶点，并且 LS 中 NPNT 的表达降低与癌症保护相关的假设。
评估 IGF1 刺激 LS 淋巴母细胞系以及人乳腺癌和前列腺癌细胞中 NPNT 表达的基础和 IGF1 刺激作用。使用 siRNA 方法进行 NPNT 沉默实验。
我们提供的证据表明，IGF1 刺激 LS 衍生的淋巴母细胞和各种癌细胞系中的 NPNT 表达。此外，我们证明 NPNT 沉默导致 AKT 和 ERK1/2 途径的激活减少，从而导致细胞增殖减少。
我们的数据将 NPNT 基因鉴定为 IGF1 作用的靶点。NPNT 与 IGF1 途径之间的功能和物理相互作用的临床意义值得进一步研究。
