Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin carcinogenesis, we found a proinflammatory gene signature in CAFs isolated from dysplastic skin. This signature was maintained in CAFs from subsequent skin carcinomas and was evident in mammary and pancreatic tumors in mice and in cognate human cancers. The inflammatory signature was already activated in CAFs isolated from the initial hyperplastic stage in multistep skin tumorigenesis. CAFs from this pathway promoted macrophage recruitment, neovascularization, and tumor growth, activities that are abolished when NF-kappaB signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be "educated" by carcinoma cells to express proinflammatory genes.
Summary
Protein misfolding stimulates a signaling pathway involving noncoding RNAs to promote cell death.
The endoplasmic reticulum (ER) is the primary organelle for folding and maturation of secretory and transmembrane proteins. Inability to meet protein-folding demand leads to “ER stress,” and activates IRE1α, an ER transmembrane kinase-endoribonuclease (RNase). IRE1α promotes adaptation through splicing Xbp1 mRNA or apoptosis through incompletely understood mechanisms. Here we found that sustained IRE1α RNase activation caused rapid decay of select microRNAs (miRs -17, -34a, -96, -125b) that normally repress translation of Caspase-2 mRNA, and thus sharply elevates protein levels of this initiator protease of the mitochondrial apoptotic pathway. In cell-free systems, recombinant IRE1α endonucleolytically cleaved microRNA precursors at sites distinct from DICER. Thus, IRE1α regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response.
Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is postulated to cause Autism Spectrum Disorders (ASD). The mammalian target of rapamycin (mTOR) is strongly implicated in ASD via upstream signaling. However, downstream regulatory mechanisms are ill-defined. We show that knockout (KO) of the eukaryotic translation Initiation Factor 4E-Binding Protein 2 (4E-BP2), an eIF4E-repressor downstream of mTOR, or eIF4E overexpression lead to increased translation of neuroligins, which are post-synaptic proteins that are causally linked to ASD. 4E-BP2-KO mice exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviors: social interaction deficits, altered communication and repetitive/stereotyped behaviors. Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2 protein amounts, restore the normal excitation/inhibition ratio and rectify the social behavior deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation to inhibition balance, and its dysregulation engenders ASD-like phenotypes.
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