PDLIM2: Signaling pathways and functions in cancer suppression and host immunity

PDZ and LIM domains-containing proteins play pivotal functions in cell cytoskeleton organization, cell polarization and differentiation. As a key member of the family, PDLIM2 regulates stability and activity of transcription factors such as NF-κB, STATs and β-catenin, and thus exert it functions in inflammation, immunity, and cancer. PDLIM2 functions as a tumor suppressor in multiple tissues and it is often genetically mutated or epigenetically silenced in human cancers derived from lung, breast, ovarian and other histologies. However, in certain types of cancers, PDLIM2 may promote cancer cell proliferation and metastases. Therefore, PDLIM2 is added to a long list of genes that can function as tumor suppressor or oncogenic protein. During tumorigenesis induced by oncogenic viruses, PDLIM2 is a key target. Through promotion of NF-κB/RelA and STAT3 degradation, PDLIM2 enhances expression of proteins involved in antigen presentation and promotes T-cell activation while repressing multidrug resistance genes, thereby rendering mutated cells susceptible to immune surveillance and cytotoxicity mediated by immune cells and chemotherapeutic drugs. Intriguingly, PDLIM2 in alveolar macrophages (AMs) plays key roles in monitoring lung tumorigenesis, as its selective genetic deletion leads to constitutive activation of STAT3, driving monocyte differentiation to AMs with pro-tumorigenic polarization and activation. PDLIM2 has also been explored as a therapeutic target for cancer therapy. At the end of this review, we provide perspectives on this important molecule and discuss the future directions of both basic and translational studies.