RESUMO
Progress in the identification of core multi-protein modules within JAK/STAT pathway has enabled researchers to develop a better understanding of the linchpin role of deregulated signaling cascade in carcinogenesis and metastasis. More excitingly, complex interplay between JAK/STAT pathway and non-coding RNAs has been shown to reprogramme the outcome of signaling cascade and modulate immunological responses within tumor microenvironment. Wealth of information has comprehensively illustrated that most of this complexity regulates the re-shaping of the immunological responses. Increasingly sophisticated mechanistic insights have illuminated fundamental role of STAT-signaling in polarization of macrophages to M2 phenotype that promotes disease aggressiveness. Overall, JAK/STAT signaling drives different stages of cancer ranging from cancer metastasis to the reshaping of the tumor microenvironment. JAK/STAT signaling has also been found to play role in the regulation of infiltration and activity of natural killer cells and CD4/CD8 cells by PD-L1/PD-1 signaling. In this review, we have attempted to set spotlight on regulation of JAK/STAT pathway by microRNAs, long non-coding RNAs and circular RNAs in primary tumors and metastasizing tumors. Therefore, existing knowledge gaps need to be addressed to propel this fledgling field of research to the forefront and bring lncRNAs and circRNAs to the frontline of clinical practice. Leveraging the growing momentum will enable interdisciplinary researchers to gain transition from segmented view to a fairly detailed conceptual continuum.
RESUMO
Discoveries related to an intriguing feature of ubiquitination have prompted a detailed analysis of the ubiquitination patterns in malignant cells. How the "ubiquitinome" is reshaped during multistage carcinogenesis has garnered significant attention. Seminal studies related to the structural and functional characterization of NEDD4 (Neuronal precursor cell-expressed developmentally downregulated-4) have consolidated our understanding at a new level of maturity. Additionally, regulatory roles of non-coding RNAs have further complicated the complex interplay between non-coding RNAs and the members of NEDD4 family. These mechanisms range from the miRNA-mediated targeting of NEDD4 family members to the regulation of transcriptional factors for a broader range of non-coding RNAs. Additionally, the NEDD4-mediated degradation of different proteins is modulated by lncRNAs and circRNAs. The miRNA-mediated targeting of NEDD4 family members is also regulated by circRNAs. Tremendous advancements have been made in the identification of different substrates of NEDD4 family and in the comprehensive analysis of the molecular mechanisms by which various members of NEDD4 family catalyze the ubiquitination of substrates. In this review, we have attempted to summarize the multifunctional roles of the NEDD4 family in cancer biology, and how different non-coding RNAs modulate these NEDD4 family members in the regulation of cancer. Future molecular studies should focus on the investigation of a broader drug design space and expand the scope of accessible targets for the inhibition/prevention of metastasis.
