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Free keywords:
TOTAL PROTEIN; CANCER; CELLS; TUMOR; SIGNATURE; TRAFFICKING; METASTASIS;
EXPRESSION; MICRORNAS; CHAPERONEScience & Technology - Other Topics;
Abstract:
TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1 alpha, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1 alpha /miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization. p53 mutants can promote tumorigenesis by affecting fundamental cellular pathways and functions. In this study, the authors demonstrate a novel mutant-p53/HIF1 alpha /miR-30d axis that impacts Golgi structure, trafficking, and secretion of proteins essential for tumor growth and metastasis.
