The Olfactory Receptor Gene Product, OR5H2, Modulates Endometrial Cancer Cells Proliferation via Interaction with the IGF1 Signaling Pathway.
The Olfactory Receptor Gene Product, OR5H2, Modulates Endometrial Cancer Cells Proliferation via Interaction with the IGF1 Signaling Pathway.
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嗅觉受体基因产物OR5H2通过与IGF1信号通路相互作用调节子宫内膜癌细胞增殖
DOI：
10.3390/cells10061483
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发表时间：
2021-06-12
期刊：
影响因子：
6
通讯作者：
Werner H
中科院分区：
文献类型：
--
作者：
Shibel R;Sarfstein R;Nagaraj K;Lapkina-Gendler L;Laron Z;Dixit M;Yakar S;Werner H
子宫内膜癌是西方国家最常见的妇科恶性肿瘤。胰岛素样生长因子-1 (IGF1) 轴在子宫内膜癌生物学中发挥着重要作用，并成为肿瘤学中有前途的治疗靶点。然而，迫切需要确定可能有助于患者分层和预后的生物标志物。拉伦综合征 (LS) 是一种侏儒症，由生长激素受体 (GHR) 基因突变引起，导致先天性 IGF1 缺乏。虽然高循环 IGF1 被认为是癌症的危险因素，但流行病学研究表明 LS 患者可以免受癌症的发展。最近对 LS 衍生的淋巴母细胞进行的全基因组分析发现了一系列基因，这些基因在这种情况下的过度或不足可能与癌症保护机制相关。嗅觉受体5亚家族H成员2（OR5H2）是LS中下调最多的基因，其表达水平比对照细胞低5.8倍。除了在嗅觉上皮中的典型作用外，嗅觉受体（OR）还在多种组织中表达，并在包括癌症在内的各种病理中发挥非经典作用。我们研究的目的是研究子宫内膜癌中 IGF1 对 OR5H2 基因表达的调节。数据显示，IGF1 和胰岛素刺激表达野生型或突变型 p53 的子宫癌细胞系中 OR5H2 mRNA 和蛋白质水平。 OR5H2 沉默导致 IGF1R 下调，随后下游细胞质介质减少。此外，OR5H2 敲低降低了增殖率和细胞周期进程。对 GHR 缺乏或 GH 过度表达的动物模型中 olfr196（OR5H2 的小鼠直系同源物）mRNA 表达的分析证实了人类数据。总之，OR5H2 成为 IGF1 正向调节的新靶点，与子宫内膜癌具有潜在相关性。
Endometrial cancer is the most common gynecologic malignancy in Western countries. The insulin-like growth factor-1 (IGF1) axis has an important role in endometrial cancer biology and emerged as a promising therapeutic target in oncology. However, there is an urgent need to identify biomarkers that may help in patient stratification and prognosis. Laron syndrome (LS) is a type of dwarfism that results from the mutation of the growth hormone receptor (GHR) gene, leading to congenital IGF1 deficiency. While high circulating IGF1 is regarded as a risk factor in cancer, epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide profilings conducted on LS-derived lymphoblastoid cells led to the identification of a series of genes whose over- or under-representation in this condition might be mechanistically linked to cancer protection. The olfactory receptor 5 subfamily H member 2 (OR5H2) was the top downregulated gene in LS, its expression level being 5.8-fold lower than in the control cells. In addition to their typical role in the olfactory epithelium, olfactory receptors (ORs) are expressed in multiple tissues and play non-classical roles in various pathologies, including cancer. The aim of our study was to investigate the regulation of OR5H2 gene expression by IGF1 in endometrial cancer. Data showed that IGF1 and insulin stimulate OR5H2 mRNA and the protein levels in uterine cancer cell lines expressing either a wild-type or a mutant p53. OR5H2 silencing led to IGF1R downregulation, with ensuing reductions in the downstream cytoplasmic mediators. In addition, OR5H2 knockdown reduced the proliferation rate and cell cycle progression. Analyses of olfr196 (the mouse orthologue of OR5H2) mRNA expression in animal models of GHR deficiency or GH overexpression corroborated the human data. In summary, OR5H2 emerged as a novel target for positive regulation by IGF1, with potential relevance in endometrial cancer.
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