TBX2 Drives Neuroendocrine Prostate Cancer through Exosome-Mediated Repression of miR-200c-3p.

Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype.

Functional aspects of T cell diversity in visceral leishmaniasis.

Co-ordination between innate and adaptive immunity is a foremost crucial immunological interactions. The interaction is beneficial for the survival of the host against infectious agent and also detrimental for the pathogen during their future encounter. Major cellular components to bridge the gap of innate and adaptive immune system include B cells, varieties of T cell subsets and their interaction with antigen presenting cells. T cells are the components of immune system which recognise antigen that are specifically presented with the different class of MHC molecules like MHCI and MHCII marking the diversity of exogenous and endogenous nature of antigen. T cells further differentiate in varieties of morphological and immunological forms like CD4+, CD8+ T cells, Th-17, Treg and γδ-T cells based on the nature of antigen, interaction and polarizing factors. Therefore the evolutionary selections of these diversities have a different functional aspect which is not only dependent upon their percentage presence but more promisingly dependent upon their physiological state and local environment. Thus this review is highlighting the major contributions of T cells subsets using an infectious disease model of visceral leishmaniasis and also helpful in explaining the reason for the non-responsiveness of the T cells subsets during the onset and progression of infection.