Tumor Suppressor DAB2IP as a target for post-transcriptional inactivation in cancer

The intricate network established among cancer cells and their microenvironment, strongly affect cancer progression. The tumor suppressor DAB2IP (Disable homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), is an essential factor in this context, since it modulates signal transduction by several growth factors and inflammatory cytokines, affecting cancer cells’ behavior. Importantly, DAB2IP modulates TNF alpha signaling in endothelial and cancer cells sustaining the activation of the pro-apoptotic JNK/ASK1 pathway, while counteracting the activation of the NF-kB. Moreover, acting as a scaffold protein, this tumor suppressor counteracts the activation of other oncogenic pathways, exerting an important control on epithelial-to mesenchymal transition (EMT), migration, and survival of tumor cells. In summary, behaving as a guardian of signal transduction in tumor cells, DAB2IP can be considered a cytoplasmic tumor suppressor. Despite significant knowledge on its molecular function, little is known about its regulation. DAB2IP is rarely mutated, but it is epigenetically silenced in different types of tumors. In addition, other molecular mechanism might exist in cancer to counteract the tumor suppressive activity of this protein. Therefore, their identification could provide novel therapeutic and diagnostic strategies against tumors. Point mutations of the TP53 gene represent a significant factor in cancer progression. In this Thesis, I report data demonstrating that mutp53 binds DAB2IP in the cytoplasm of tumor cells, counteracting its inhibitory role on NF-kB and blocking the activation of JNK pathway. I demonstrate that mutp53, through the interaction with DAB2IP, reprograms tumor cell response to TNF, sustaining a pro-invasive behavior and counteracting apoptosis. Notably, this action is coupled to an increased expression of chemokines that can expose tumor cells to host immunity, potentially affecting response to therapy and patient outcome. We hypothesize that other conditions that would impair DAB2IP protein levels - or function - could promote tumor progression. Its potentially represents a good target for microRNAs (miRNA)-mediated regulation. Up to known, 2 miRNAs regulating DAB2IP (miR-338-5p and miR-889) have been reported, in a model of neuronal differentiation and in esophageal squamous cells carcinoma. To discover additional DAB2IP-targeting miRNAs, we functionally screened a large collection of human miRNA mimics. Among several hits, we identified one miRNA showing strongly ability to down-regulate DAB2IP protein levels in multiple transformed cell lines. In this Thesis I report how this miRNA can affects DAB2IP protein levels in tumor cells, the activation of pathways downstream DAB2IP and increasing invasiveness of cancer cells. The DAB2IP inhibitory activity exerted by miRNA can be blocked using specific inhibitors, or target protectors, thus reducing aggressive phenotypes of cancer cells. These results suggest that the inhibition of miRNA oncogenic activity, and the consequent rescue of DAB2IP protein levels in cancer cells could potentially represent a mechanism to affect tumor progression and outcome.