Chronic inflammation can drive tumor development. Here, we have identified microRNA-146a (miR-146a) as a major negative regulator of colonic inflammation and associated tumorigenesis by modulating IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic colorectal cancer (CRC), presenting with enhanced tumorigenic IL-17 signaling. Within myeloid cells, miR-146a targets RIPK2, a NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17. Accordingly, myeloid-specific miR-146a deletion promotes CRC. Moreover, within intestinal epithelial cells (IECs), miR-146a targets TRAF6, an IL-17R signaling intermediate, to restrict IEC responsiveness to IL-17. MiR-146a within IECs further suppresses CRC by targeting PTGES2, a PGE2 synthesis enzyme. IEC-specific miR-146a deletion therefore promotes CRC. Importantly, preclinical administration of miR-146a mimic, or small molecule inhibition of the miR-146a targets, TRAF6 and RIPK2, ameliorates colonic inflammation and CRC. MiR-146a overexpression or miR-146a target inhibition represent therapeutic approaches that limit pathways converging on tumorigenic IL-17 signaling in CRC.

Recent population‐based epidemiological studies strongly hint towards a link between obesity and its occurrence as well as progression of several cancers including melanoma. Although effects of obesity on breast, colon and liver cancers have been extensively investigated, the links between obesity and melanoma remain largely unexplored. Present study aimed to understand the effect of high fat diet‐induced weight gain on susceptibility of C57BL/6J mice to melanoma. For this, mice routinely were fed on high fat diet for 6 months (HFD mice). Subsequently, mouse melanoma cells were injected subcutaneously in control as well as HFD mice and followed for tumor initiation and progression. We provide strong evidence that diet‐induced obesity leads to increased melanoma progression in male C57BL/6J mice. We observed that increased melanoma progression is associated with enhanced Cav‐1 and FASN expression in tumors from HFD mice. Cav‐1 and FASN are co‐ordinately regulated and Cav‐1 interacts with FASN in melanoma cells. Enhanced levels of Cav‐1, FASN and pAkt control melanoma cell proliferation. Our study establishes a causative relationship between diet‐induced obesity and melanoma progression as well as demonstrates that obesity affects important tumorigenic pathways in melanoma.

Autophagy is a lysosomal protein degradation system that eliminates cytoplasmic components such as protein aggregates, damaged organelles, and even invading pathogens. Autophagy is an evolutionarily conserved homoeostatic strategy for cell survival in stressful conditions and has been linked to a variety of biological processes and disorders. It is vital for the homeostasis and survival of renal cells such as podocytes and tubular epithelial cells, as well as immune cells in the healthy kidney. Autophagy activation protects renal cells under stressed conditions, whereas autophagy deficiency increases the vulnerability of the kidney to injury, resulting in several aberrant processes that ultimately lead to renal failure. Renal fibrosis is a condition that, if chronic, will progress to end-stage kidney disease, which at this point is incurable. Chronic Kidney Disease (CKD) is linked to significant alterations in cell signaling such as the activation of the pleiotropic cytokine transforming growth factor-β1 (TGF-β1). While the expression of TGF-β1 can promote fibrogenesis, it can also activate autophagy, which suppresses renal tubulointerstitial fibrosis. Autophagy has a complex variety of impacts depending on the context, cell types, and pathological circumstances, and can be profibrotic or antifibrotic. Induction of autophagy in tubular cells, particularly in the proximal tubular epithelial cells (PTECs) protects cells against stresses such as proteinuria-induced apoptosis and ischemia-induced acute kidney injury (AKI), whereas the loss of autophagy in renal cells scores a significant increase in sensitivity to several renal diseases. In this review, we discuss new findings that emphasize the various functions of TGF-β1 in producing not just renal fibrosis but also the beneficial TGF-β1 signaling mechanisms in autophagy.