IGF-1R糖基化修饰通过调控内质网应激影响卵巢癌细胞生物学行为的机制研究

Insulin-like growth factor plays an important role in promoting cell differentiation, proliferation, growth of the individual. The increasing activity of IGF-1R tyrosine could promote cell proliferation, invasion, anti-apoptotic through the downstream signal transduction pathways. Endoplasmic reticulum stress is an aggregating process of variety of stimulations which lead to proteins misfolding or unfolding in the endoplasmic reticulum. Persistent ERS induced cell death. Both the IGF-1R and ERS can regulate the biological behavior of ovarian cancer. The endoplasmic reticulum homeostasis is influenced by IGF-1R pathway. While the correlation of them in the occurrence and development of carcinoma is still unclear. Our preliminary work has proved that IGF-1R with glycosylation could strengthen the tyrosine receptor activation of its downstream pathways. This study demonstrates to prove that IGF-1R glycosylation regulates ERS by promoting p38/MAPK and NFκB signaling pathway in ovarian cancer cells, which could affect the biological behavior of ovarian cancer cells.

胰岛素样生长因子受体1(Insulin like growth factor receptor 1，IGF-1R)在细胞的分化、增殖、个体的生长发育中具有重要的促进作用。IGF-1R酪氨酸活性增强激活下游信号转导通路促进细胞增殖、侵袭，抑制凋亡。内质网应激(Endoplasmic reticulum stress, ERS)是由各种刺激引起的内质网腔内错误折叠、未折叠的蛋白质聚集。持续的ERS将诱导细胞死亡。IGF-1R与ERS均能调控卵巢癌细胞的生物学行为，前者可调控其下游通路的活性影响内质网稳态，但二者是否直接相关，其在肿瘤发生、发展中的作用及机制仍未明确。申请者前期工作证明IGF-1R的糖基化修饰能够增强其受体酪氨酸活性激活其下游通路，本研究旨在证明IGF-1R糖基化修饰促进其下游的p38/MAPK信号通路和NFκB信号通路调控卵巢癌细胞内质网应激，影响卵巢癌细胞的生物学行为。

岩藻糖基化抗原是一种肿瘤相关抗原，在肿瘤早期的检测及生物学治疗方面具有广泛的前景。申请者前期工作证明：IGF-1R上存在岩藻糖基化抗原，岩藻糖基化抗原含量增加时能够升高IGF-1R的磷酸化水平，促进细胞增殖。有研究显示IGF-1R能调节细胞的内质网应激。内质网应激是细胞抵抗外来不良刺激的一种重要保护机制，也是决定细胞命运的关键。适度的内质网应激能够促进肿瘤细胞生存和转移，过度的内质网应激则促进肿瘤细胞发生自噬和凋亡。因此我们推测岩藻糖基化抗原能够调控肿瘤细胞的内质网应激。本研究首次发现与α1,2-fucosyl转移酶基因（FUT1）相关的全序列差异表达基因DEGs 参与到MAPK、类固醇生物合成、细胞周期、p53乏氧途径和内质网应激以及自噬等途径。其中，高表达差异BCL6蛋白在不同恶性程度卵巢肿瘤及正常卵巢组织中的表达率之间均有明显的差异，并与卵巢癌临床期别、淋巴结转移、分化等相关。首次研究证明ANXA4与NF-kB p50为相互作用蛋白，ANXA4能够使细胞增殖能力增强，凋亡减少。Lewis y抗原作为IGF-1R、ANXA4结构上的一部分，通过调控p38MAPK、NF-kB、ERK/MAPK等多种信号通路网络调控内质网应激、自噬等相关蛋白的表达及活性，影响卵巢癌细胞的生物学行为，最终促进卵巢癌的发生发展。为寻找卵巢癌治疗靶点提供实验依据。