Role of Fra-2 in cancer

Abstract

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.

Fig. 1. Fos-related antigen-2 (Fra-2) is modulated by microRNAs, extracellular signals, environmental stresses, and oncogenes.

MicroRNAs regulate translational efficiency of FOSL2 mRNA, inhibiting its expression. When phosphorylated or activated, Fra-2 forms AP-1 complex by dimerizing with Jun family members. AP-1 heterodimers recognize specific genomic response-elements (ARE, CRE, TRE, MARE I and MARE II) and transcriptionally control, activating or repressing, a wide number of genes. Modulation of those genes contributes to cell survival, cell death, cell proliferation, epithelial-mesenchymal transition, tumor progression and carcinogenesis. Created with BioRender.

Fig. 2. Fra-2 plays a critical role in cancer.

Fra-2 can exert a pro-tumorigenic behavior (labeled in red) in tissues and organs such as liver, lung, breast, and pancreas or can play an oncosuppressive role (labeled in blue) in malignant melanoma, or a dual role as in epithelial ovarian carcinoma. Created with BioRender.

Fig. 3. Role of Fra-2 regulation in breast (BC), non-small cell lung cancer (NSCLC) and malignant melanoma (MM).

In BC, Fra-2 is modulated by ERa and, in turn, transcriptionally activates Cyclin-D1 and -E, supporting pro-growth activity and Relb, promoting cell survival. Fra-2 stimulates epithelial-mesenchymal transition (EMT) and extravasation inducing transcription of ICAM-1, L1-CAM and Integrins. In NSCLC, MET and TGFβ1 signaling induce Fra-2 activation that, in turn, transcriptionally controls SNAI2 and interaction with Smad3, respectively. These extracellular signals promote EMT and cell motility via Fra-2. Moreover, Fra-2 contributes to cell proliferation, acting on cancer susceptibility candidate 9 (CASC9). Fra-2 is also involved in the mechanism of drug resistance: in gefitinib-resistant NSCLC cells upregulation of exosomal lncRNA urothelial carcinoma-associated 1 (UCA1) induces Fra-2 expression. Moreover, in miR-301a-low context, Fra-2 promotes platinum resistance, modulating GLIPR1. In MM, Fra-2 exerts a oncosuppressive role, in fact Fra-2 is downmodulated in human melanoma samples compared to normal skin. Fra-2 low- expression induces Fam212b and in turn promotes cell motility and metastasis and inhibits CyclinD1, controlling cell proliferation. Reduced levels of ROS cause Fra-2 overexpression, leading to a less aggressive phenotype. Created with BioRender.

Fig. 4. Role of Fra-2 in colon rectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC) and epithelial ovarian carcinoma (EOC).

In CRC, different non-coding RNAs regulate Fra-2 expression. In particular, miR-597-5p low expression is not capable to target Fra-2 that in turn transcriptionally activates E-cadherin, Fibronectin and Vimentin, promoting EMT, cell motility and neo-angiogenesis. Circ-FAT-1 and Cir-0005615 overexpression induce Fra-2 transcriptional activity, sponging miR-619-5p and miR-873-5p, respectively. Moreover, Fra-2 activates the expression of EphA2, turning on PI3K/Akt and WNT/β-catenin signaling pathways. In PDAC, Fra-2 expression is modulated by miR-15a and different stressors and, in turn, induces IGF1R upregulation, promoting cell cycle re-entry in serum starved cells. In EOC, Fra-2 regulates BRCA1 expression, protecting mesodermal cells from the transformation in early stage of carcinogenesis. Conversely, LncRNA-UCA1 upregulation, sponging miR-143, induces Fra-2 overexpression and confers platinum resistance in advanced disease. Created with BioRender.

Fig. 5. Role of Fra-2 in T-cell malignancies.

In cutaneous T-cell lymphomas (CTCLs), Fra-2 overexpression transcriptionally activates CCR4, MYB and BCL6 proto-oncogenes. Even in adult T-cell leukemia/lymphoma (ATL), Fra-2 upregulation has a pro-survival role in transformed T-cells. HTLV-1 infection activates JNK that in turn induces Fra-2. The interaction between Tax and AP-1 complex, here represented by Fra-2, promotes the transcription of a various number of oncogenes (MYB, MDM2, BCL6, SOX4), contributing to cell growth and proliferation. Administration of mogamulizumab, an anti-CCR4 antibody, improves the patient outcome in relapsed or refractory ATL. In anaplastic large cell lymphoma (ALCL), characterized by the translocation t(2;5) and the constitutive activation of the NPM-ALK fusion protein, Fra-2 is also overexpressed. AP-1 complex, made of Fra-2 and Jun, inhibits the apoptotic pathway. Created with BioRender.

Fig. 6. Role of Fra-2 in tumor microenvironment.

In primary human breast fibroblasts, the activation of TGFβ1 signaling pathway engages Fra-2 expression via ERK and promotes Fibronectin and αSMA. This mechanism contributes to tumor microenvironment remodeling and tumor progression in breast cancer. In breast cancer-associated fibroblasts (CAFs), Fra-2 transcriptionally activates WNT5A, stimulating endothelial cells and neo-angiogenesis. In tumor-associated macrophages (TAMs), Wnt/β-catenin signaling induces Fra-2 activation that in turn promotes transcription of CD163, Cd206, ILr1 and TGFB1, supporting the switch from TAM1 to pro-tumorigenic macrophages (TAM2). In PDAC, Fra-2 overexpression transcriptionally activates CCL28, recruiting Treg cells. In a SOX2 amplification context, linked to tumor aggressiveness, Fra-2 activation is enhanced. Both these mechanisms eventually promote immune escape, with an increased number of Treg, macrophages and neutrophils and a decrease of activated natural killer (NK) cells. Created with BioRender.