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Abstract：
Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of IGF2 upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined the IGF2R, the primary receptor of IGF2, WNT, and autophagy/lysosomal pathways in BWS patient-derived lymphoblastoid cell lines, showing different genetic and epigenetic defects. The findings reveal a decreased expression and mislocalization of IGF2R protein, suggesting receptor dysfunction. Additionally, our results point to a dysregulation in the AKT/GSK-3/mTOR pathway, along with imbalances in autophagy and the WNT pathway. In conclusion, BWS cells, regardless of the genetic/epigenetic profiles, are characterized by alteration of the IGF2R pathway that is associated with the perturbation of the autophagy and lysosome processes. These alterations seem to be a key point of the molecular pathogenesis of BWS and potentially contribute to BWS\'s characteristic overgrowth and cancer susceptibility. Our study also uncovers alterations in the WNT pathway across all BWS cell lines, consistent with its role in growth regulation and cancer development.
摘要：
Beckwith-Wiedemann综合征（BWS）是一种以过度生长为特征的印记障碍，源于各种遗传和表观遗传变化。本研究探讨了IGF2上调在BWS中的作用，专注于胰岛素样生长因子途径，在这种综合症中鲜为人知。我们检查了IGF2R,IGF2的主要受体，WNT，和BWS患者来源的淋巴母细胞细胞系中的自噬/溶酶体途径，表现出不同的遗传和表观遗传缺陷。这些发现揭示了IGF2R蛋白的表达减少和错误定位,提示受体功能障碍。此外,我们的结果表明AKT/GSK-3/mTOR通路失调，以及自噬和WNT通路的失衡。总之,BWS细胞,无论遗传/表观遗传特征如何，其特征在于与自噬和溶酶体过程的扰动相关的IGF2R途径的改变。这些改变似乎是BWS分子发病机制的关键点，并可能导致BWS的特征性过度生长和癌症易感性。我们的研究还揭示了所有BWS细胞系中WNT途径的变化，与其在生长调节和癌症发展中的作用一致。
