Alterations of the secretory pathway induced by a mutant p53/miR-30d axis

Abstract

Cancer is, nowadays, among the most prevalent and deadly diseases worldwide. This term describes a group of pathologies characterized by an abnormal growth of a mass of cells harboring mutations in their DNA, resulting in uncontrolled growth, evasion from the cell control checkpoint mechanisms and spreading throughout the body. In recent years, the investigation of the interplay between cancer cells and the tumor micro-environment has gained a central spot in the comprehension of the neoplastic development and outgrowth. At a cellular level, the main hub regulating the communication with the surrounding tissues is the secretory pathway, which is deputed to the movement of proteins and lipids between the ER, the Golgi apparatus, and, through the secretory vesicles, to the extracellular space. Alterations in the functions of the secretory pathway could have an important role in helping the development and progression of the malignancies, fostering metastasis, invasion, altered secretion patterns and cytoskeletal remodeling.These phenotypes, among the others, have been linked by a vast amount of data to the mutated forms of p53, derived by missense point mutations in the TP53 gene which lose the oncosuppressive function of the wild-type form, and acquire, in many cases, novel pro-oncogenic features. mutp53s exert their pro-neoplastic functions through a plethora of interactors, both coding and non-coding. In our laboratory, we identified miR-30d as a new target gene of mutp53, which appears to be regulated through the interaction of this protein with the hypoxia-inducible factor HIF1\u3b1. Preliminary evidence show that miR-30d-regulated genes are enriched for factors involved in the unfolded protein response activation and protein secretion, suggesting an effect on the structure and functions of the secretory pathway. Our results show that miR-30d expression is able to blunt the activation of the UPR following drug-induced ER stress and concomitantly to induce major alterations in the secretory pathway organelles, mainly represented by a strong vesiculo-tubulation of the Golgi apparatus. Moreover, miR-30d, through the modulation of its direct and indirect targets, as its upstream regulators mutant p53 and HIF1\u3b1, is able to strongly promote the secretion of proteins by cancer and normal cells. Taken all together, the findings reported in this thesis suggest a role for this newly described mutant p53/HIF1\u3b1/miR-30d axis in the regulation of the structures and functions of the secretory pathway, and particularly on the Golgi apparatus