Role of Fra-2 in cancer.

Fos-related antigen-2 (Fra-2) is the most recently discovered member of the Fos family and, by dimerizing with Jun proteins, forms the activator protein 1 (AP-1) transcription factor. By inducing or repressing the transcription of several target genes, Fra-2 is critically involved in the modulation of cell response to a variety of extracellular stimuli, stressors and intracellular changes. In physiological conditions, Fra-2 has been found to be ubiquitously expressed in human cells, regulating differentiation and homeostasis of bone, muscle, nervous, lymphoid and other tissues. While other AP-1 members, like Jun and Fos, are well characterized, studies of Fra-2 functions in cancer are still at an early stage. Due to the lack of a trans-activating domain, which is present in other Fos proteins, it has been suggested that Fra-2 might inhibit cell transformation, eventually exerting an anti-tumor effect. In human malignancies, however, Fra-2 activity is enhanced (or induced) by dysregulation of microRNAs, oncogenes and extracellular signaling, suggesting a multifaceted role. Therefore, Fra-2 can promote or prevent transformation, proliferation, migration, epithelial-mesenchymal transition, drug resistance and metastasis formation in a tumor- and context-dependent manner. Intriguingly, recent data reports that Fra-2 is also expressed in cancer associated cells, contributing to the intricate crosstalk between neoplastic and non-neoplastic cells, that leads to the evolution and remodeling of the tumor microenvironment. In this review we summarize three decades of research on Fra-2, focusing on its oncogenic and anti-oncogenic effects in tumor progression and dissemination.

Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies. PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment. Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC. Here, we identified the transcription factor Fos-related antigen-2 (Fra-2) as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation. We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients. Mechanistically, we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting. In miR-15a-low context, IGF1R hyperactivated mTOR, modulated the autophagic flux and sustained PDAC growth in nutrient deprivation. In a genetic mouse model, Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction. Consistently, nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner. Overall, our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.