Department of Medical Oncology, Cancer Center, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China.
Basic Medical Sciences, Hangzhou Medical College, Hangzhou, China.
Clin Transl Med. 2023 Oct;13(10):e1457. doi: 10.1002/ctm2.1457.
Insulin-like growth Factor 2 mRNA-binding protein 3 (IGF2BP3) is a highly conserved RNA-binding protein and plays a critical role in regulating posttranscriptional modifications.
Immunoprecipitation was used to examine the interaction of Parkin and IGF2BP3. Mass spectrometry was performed to identify the ubiquitination sites of IGF2BP3. RNA-immunoprecipitation was conducted to examine the target genes of IGF2BP3. Xenograft mouse model was constructed to determine the tumorigenesis of IGF2BP3.
IGF2BP3 expression is negatively correlated with Parkin expression in human cervical cancer cells and tissues. Parkin directly interacts with IGF2BP3, and overexpression of Parkin causes the proteasomal degradation of IGF2BP3, while knockdown of PARK2 increases the protein levels of IGF2BP3. Mechanistically, in vivo and in vitro ubiquitination assays demonstrated that Parkin is able to ubiquitinate IGF2BP3. Moreover, the ubiquitination site of IGF2BP3 was identified at K213 in the first KH domain of IGF2BP3. IGF2BP3 mutation results in the loss of its oncogenic function as an m6A reader, resulting in the inactivation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling pathways. In addition, IGF2BP3 mutation results in the attenuation of Parkin-mediated mitophagy, indicating its inverse role in regulating Parkin. Consequently, the tumourigenesis of cervical cancer is also inhibited by IGF2BP3 mutation.
IGF2BP3 is ubiquitinated and regulated by the E3 ubiquitin ligase Parkin in human cervical cancer and ubiquitination modification plays an important role in modulating IGF2BP3 function. Thus, understanding the role of IGF2BP3 in tumourigenesis could provide new insights into cervical cancer therapy.
胰岛素样生长因子 2 mRNA 结合蛋白 3（IGF2BP3）是一种高度保守的 RNA 结合蛋白，在调节转录后修饰中发挥着关键作用。
免疫沉淀用于检测 Parkin 和 IGF2BP3 的相互作用。质谱法用于鉴定 IGF2BP3 的泛素化位点。RNA 免疫沉淀用于检测 IGF2BP3 的靶基因。构建异种移植小鼠模型以确定 IGF2BP3 的致瘤性。
IGF2BP3 的表达与人宫颈癌细胞和组织中的 Parkin 表达呈负相关。Parkin 直接与 IGF2BP3 相互作用，过表达 Parkin 导致 IGF2BP3 的蛋白酶体降解，而 PARK2 的敲低则增加 IGF2BP3 的蛋白水平。在体内和体外泛素化测定中，机制表明 Parkin 能够泛素化 IGF2BP3。此外，鉴定出 IGF2BP3 的第一个 KH 结构域中的 K213 是 IGF2BP3 的泛素化位点。IGF2BP3 突变导致其作为 m6A 阅读器的致癌功能丧失，从而导致磷酸肌醇 3-激酶（PI3K）和丝裂原活化蛋白激酶（MAPK）信号通路失活。此外，IGF2BP3 突变导致 Parkin 介导的线粒体自噬减弱，表明其在调节 Parkin 方面的反向作用。因此，IGF2BP3 突变抑制了宫颈癌的致瘤性。
IGF2BP3 在人宫颈癌中被 E3 泛素连接酶 Parkin 泛素化和调节，泛素化修饰在调节 IGF2BP3 功能方面起着重要作用。因此，了解 IGF2BP3 在肿瘤发生中的作用可能为宫颈癌治疗提供新的见解。
