Roles of HMGA proteins in cancer: Expression, pathways, and redundancies

The expression of the High Mobility Group A (HMGA) proteins, their participation in cancer signalling pathways, and their redundant functions have been reviewed in seven types of cancer: breast, colorectal, prostate, lung, ovarian, thyroid, and brain.The analysis of cell lines and tumours revealed an elevated level of their expression in all fully transformed cancer systems, which represents a step of the main cancer signalling pathways.In breast, colorectal, prostate, and lung cancers Wnt/-catenin pathway is a master inducer of cell transformation in which are deeply involved HMG A1 and A2 proteins.On the other hand, IL-6/Stat3 pathway is responsible for cancer transformation in breast, lung, and prostate.The expression of HMGA1 in lung and ovarian cancers is due to an active PI3K/Akt pathway.The let-7 family of microRNA represses the expression of HMGA showing specificity by its different forms: the let-7b form is able to inhibit both proteins A1 and A2, the last also inhibited by a, c, d, and g forms.Moreover, both proteins are down-regulated by the repressor couple p53/microRNA-34a.The protein A1 and A2 participate to the Epithelial-Mesenchymal Transition cooperating with the three couples of factors Twist1/2, Snai1/2, and Zeb1/2.Through a combination of pathways, there is the simultaneous presence of high levels of both A1 and A2 together with the expression of other factors: a high co-operating efficiency is reached that supplies the tumour cells with properties of self-renewal, resistance, and invasiveness.