Progress in the Study of Fra-2 in Respiratory Diseases.

Fos-related antigen-2 (Fra-2) is a member of the activating protein-1 (AP-1) family of transcription factors. It is involved in controlling cell growth and differentiation by regulating the production of the extracellular matrix (ECM) and coordinating the balance of signals within and outside the cell. Fra-2 is not only closely related to bone development, metabolism, and immune system and eye development but also in the progression of respiratory conditions like lung tumors, asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). The increased expression and activation of Fra-2 in various lung diseases has been shown in several studies. However, the specific molecular mechanisms through which Fra-2 affects the development of respiratory diseases are not yet understood. The purpose of this research is to summarize and delineate advancements in the study of the involvement of transcription factor Fra-2 in disorders related to the respiratory system.

Catalpol improves insulin resistance and lipid metabolism disorder in diabetic mice by inhibiting microRNA-101-3p to up-regulate FOS-related antigen 2.

Disorders of glucose and lipid metabolism are important causes of type 2 diabetes mellitus (T2DM). Defining the molecular mechanisms of metabolic disorders and exploring drug targets are key to the treatment of T2DM. The study discovered the effects of catalpol on insulin resistance (IR) and lipid metabolism disorder (LMD) in type 2 diabetes mellitus (T2DM). A T2DM mouse model was established by a high-fat diet and a single intraperitoneal injection of streptozotocin. and injected with catalpol at 10 mg/kg for 12 weeks, and the lentiviral vector of miR-101-3p or Fos-related antigen 2 (FOSL2) expression was interfered with intravenously mouse insulin resistance (IR) and lipid metabolism disorder (LMD)-related indices were then measured. Pancreatic histopathology was observed by hematoxylin and eosin (HE) staining and TUNEL staining. The miR-101-3p and FOSL2 were detected by RT-qPCR or Western blot. In results: catalpol improved IR and LMD (both P<0.05) in diabetic mice, and alleviated the histopathological changes in the pancreas. miR-101-3p was upregulated (P<0.05), and FOSL2 was downregulated (P<0.05) in T2DM mice, while catalpol rescued their expression pattern (both P<0.05). The miR-101-3p targeted FOSL2. Down-regulating miR-101-3p or up-regulating FOSL2 improved IR and LMD (all P<0.05) in diabetic mice, and alleviated pancreatic histopathological changes. Overexpressing miR-101-3p or suppressing FOSL2 weakened the ameliorative effects of catalpol in T2DM mice (all P<0.05). We conclude that catalpol improves IR and LMD in diabetic mice by inhibiting miR-101-3p to up-regulate FOSL2.

BACH1 transcriptionally upregulates FOSL2 to induce M2 macrophages phenotype by activating TGFß/SMAD signaling to promote the transformation of lung fibroblasts into myofibroblasts.

Pulmonary fibrosis is a chronic and progressive lung disorder. The pro-fibrosis factors induced by M2 macrophage phenotype promote the differentiation of fibroblasts into myofibroblasts, which is essential for pulmonary fibrosis. We aimed to explore the role and mechanism of BTB domain and CNC homology 1 (BACH1) in pulmonary fibrosis. BACH1 was knocked down in THP-1 polarized M2 macrophages with or without FOS-like antigen 2 (FOSL2) overexpression, the expression of M2 macrophage markers was detected. Cell viability, migration, invasion and extracellular matrix (ECM) accumulation were estimated by CCK-8, wound healing, transwell, western bot and immunofluorescence staining. Luciferase reporter and chromatin immunoprecipitation assays were used to verify the binding of BACH1 to FOSL2 promotor region. In vivo, a bleomycin (BLM)-induced pulmonary fibrosis mice model was established to evaluate the effect of BACH1 silencing on the histopathological changes, M2 macrophage phenotype and extracellular matrix (ECM) deposition. Expression of proteins was assessed with western blot. Results indicated that BACH1 expression was upregulated in M2 macrophages polarized from THP-1 cells. BACH1 deficiency inhibited the polarization of THP-1 to the M2 macrophage phenotype to promote the transformation of lung fibroblasts into myofibroblasts. Additionally, BACH1 could transcriptionally activate FOSL2 expression in THP-1-derived macrophages to upregulate TGFß/SMAD signaling in HFL-1 cells. The animal experiments indicated that BACH1 knockdown alleviated BLM-induced pulmonary fibrosis, M2 macrophage polarization and inactivated FOSL2/TGFß/SMAD signaling in mice lung tissues. Together, this finding suggests BACH1/FOSL2 may be useful therapeutic targets for the treatment of pulmonary fibrosis.

Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the Activator Protein-1 (AP-1) (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens (Fra-) 1 and 2 is unknown. Here, we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis, and Pparγ-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently under direct regulation by AP-1 through a conserved distal 3' enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the Bromodomain and Extra-Terminal motif inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.

AP-1/C-FOS and AP-1/FRA2 differentially regulate early and late adipogenic differentiation of mesenchymal stem cells.

Obesity is defined as an abnormal accumulation of adipose tissue in the body and is a major global health problem due to increased morbidity and mortality. Adipose tissue is made up of adipocytes, which are fat-storing cells, and the differentiation of these fat cells is known as adipogenesis. Several transcription factors (TFs) such as CEBPß, CEBPα, PPARγ, GATA, and KLF have been reported to play a key role in adipogenesis. In this study, we report one more TF AP-1, which is found to be involved in adipogenesis. Human mesenchymal stem cells  were differentiated into adipocytes, and the expression pattern of different subunits of AP-1 was examined during adipogenesis. It was observed that C-FOS was predominantly expressed at an early stage (Day 2), whereas FRA2 expression peaked at later stages (Days 6 and 8) of adipogenesis. Chromatin immunoprecipitation-sequencing analysis revealed that C-FOS binds mainly to the promoters of WNT1, miR-30a, and ANAPC7 and regulates their expression during mitotic clonal expansion. In contrast, FRA2 binds to the promoters of CIDEA, NOTCH1, ARAF, and MYLK, regulating their expression and lipid metabolism. Data obtained clearly indicate that the differential expression of C-FOS and FRA2 is crucial for different stages of adipogenesis. This also raises the possibility of considering AP-1 as a therapeutic target for treating obesity and related disorders.

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.

Fosl2 Deficiency Predisposes Mice to Osteopetrosis, Leading to Bone Marrow Failure.

Arthritis causes Fos-like 2 (Fosl2) inactivation, and various immune cells contribute to its pathogenesis. However, little is known about the role of Fosl2 in hematopoiesis and the possible pathological role of Fosl2 inactivation in the hematopoietic system in arthritis. In this study, we show that Fosl2 maintains hematopoietic stem cell (HSC) quiescence and differentiation while controlling the inflammatory response via macrophages. Fosl2-specific deletion in the hematopoietic system caused the expansion of HSCs and myeloid cell growth while affecting erythroid and B cell differentiation. Fosl2 inactivation enhanced macrophage M1 polarization and stimulated proinflammatory cytokines and myeloid growth factors, skewing HSCs toward myeloid cell differentiation, similar to hematopoietic alterations in arthritic mice. Loss of Fosl2 mediated by Vav-iCre also displays an unexpected deletion in embryonic erythro-myeloid progenitor-derived osteoclasts, leading to osteopetrosis and anemia. The reduced bone marrow cellularity in Vav-iCreFosl2f/f mice is a consequence of the reduced bone marrow space in osteopetrotic mice rather than a direct role of Fosl2 in hematopoiesis. Thus, Fosl2 is indispensable for erythro-myeloid progenitor-derived osteoclasts to maintain the medullary cavity to ensure normal hematopoiesis. These findings improve our understanding of the pathogenesis of bone-destructive diseases and provide important implications for developing therapeutic approaches for these diseases.

RUNX1/NPM1/H3K4me3 complex contributes to extracellular matrix remodeling via enhancing FOSL2 transcriptional activation in glioblastoma.

Extracellular matrix (ECM) remodeling has been implicated in the tumor malignant progression and immune escape in glioblastoma (GBM). Runt-related transcription factor 1 (RUNX1) is a vital transcriptional factor for promoting tumorigenesis and invasion in mesenchymal subtype of GBM. But the correlation between RUNX1 and ECM genes expression and regulatory mechanism of RUNX1 on ECM genes expression remain poorly understood to date. In this study, by using integral analysis of chromatin immunoprecipitation-sequencing and RNA sequencing, we reported that RUNX1 positively regulated the expression of various ECM-related genes, including Fibronectin 1 (FN1), Collagen type IV alpha 1 chain (COL4A1), and Lumican (LUM), in GBM. Mechanistically, we demonstrated that RUNX1 interacted with Nucleophosmin 1 (NPM1) to maintain the chromatin accessibility and facilitate FOS Like 2, AP-1 Transcription Factor Subunit (FOSL2)-mediated transcriptional activation of ECM-related genes, which was independent of RUNX1's transcriptional function. ECM remodeling driven by RUNX1 promoted immunosuppressive microenvironment in GBM. In conclusion, this study provides a novel mechanism of RUNX1 binding to NPM1 in driving the ECM remodeling and GBM progression.

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.

Iron homeostasis proteins Grx4 and Fra2 control activity of the Schizosaccharomyces pombe iron repressor Fep1 by facilitating [2Fe-2S] cluster removal.

The Bol2 homolog Fra2 and monothiol glutaredoxin Grx4 together play essential roles in regulating iron homeostasis in Schizosaccharomyces pombe. In vivo studies indicate that Grx4 and Fra2 act as coinhibitory partners that inactivate the transcriptional repressor Fep1 in response to iron deficiency. In Saccharomyces cerevisiae, Bol2 is known to form a [2Fe-2S]-bridged heterodimer with the monothiol Grxs Grx3 and Grx4, with the cluster ligands provided by conserved residues in Grx3/4 and Bol2 as well as GSH. In this study, we characterized this analogous [2Fe-2S]-bridged Grx4-Fra2 complex in S. pombe by identifying the specific residues in Fra2 that act as ligands for the Fe-S cluster and are required to regulate Fep1 activity. We present spectroscopic and biochemical evidence confirming the formation of a [2Fe-2S]-bridged Grx4-Fra2 heterodimer with His66 and Cys29 from Fra2 serving as Fe-S cluster ligands in S. pombe. In vivo transcription and growth assays confirm that both His66 and Cys29 are required to fully mediate the response of Fep1 to low iron conditions. Furthermore, we analyzed the interaction between Fep1 and Grx4-Fra2 using CD spectroscopy to monitor changes in Fe-S cluster coordination chemistry. These experiments demonstrate unidirectional [2Fe-2S] cluster transfer from Fep1 to Grx4-Fra2 in the presence of GSH, revealing the Fe-S cluster dependent mechanism of Fep1 inactivation mediated by Grx4 and Fra2 in response to iron deficiency.

Long non-coding RNA MIR17HG impedes FOSL2-mediated transcription activation of HIC1 to maintain a pro-inflammatory phenotype of microglia during intracerebral haemorrhage.

Activation and polarization of microglia play decisive roles in the progression of intracerebral haemorrhage (ICH), and lactate exposure correlates with microglia polarization. This study explores molecules influencing lactate production and microglia phenotype alteration following ICH. A murine model of ICH was induced by intracerebral injection of collagenase. The mice experienced autonomous neurological function recovery, haematoma resolution and rapid lactate production, along with a gradual increase in angiogenesis activity, neuronal recovery and an M1-to-M2 phenotype change of microglia. Galloflavin, a lactate dehydrogenase antagonist, suppressed this phenotype change and the functional recovery in mice. FOS like 2 (FOSL2) was significantly upregulated in the brain tissues from day 7 post-ICH. Overexpression of FOSL2 induced an M1-to-M2 phenotype shift in microglia and accelerated lactate production in vivo and in haemoglobin-treated microglia in vitro. Long non-coding RNA MIR17HG impeded FOSL2-mediated transcription activation of hypermethylated in cancer 1 (HIC1). MIR17HG overexpression induced pro-inflammatory activation of microglia in mice, which was blocked by further HIC1 overexpression. Overall, this study demonstrates that MIR17HG maintains a pro-inflammatory phenotype of microglia during ICH progression by negating FOSL2-mediated transcription activation of HIC1. Specific inhibition of MIR17HG or upregulation of FOSL2 or HIC1 may favour inflammation inhibition and haematoma resolution in ICH.

LncRNA ITGB2-AS1 promotes cisplatin resistance of non-small cell lung cancer by inhibiting ferroptosis via activating the FOSL2/NAMPT axis.

Cisplatin resistance is a major therapeutic challenge in non-small cell lung cancer (NSCLC). Herein, the regulatory role of long non-coding RNA (lncRNA) ITGB2-AS1 in regulating NSCLC cisplatin resistance was investigated. NSCLC cisplatin resistance cells were constructed using A549 and H1975 cells. Cell viability and proliferation were detected by MTT assay and colony formation assay, respectively. Cell apoptosis and cell cycle were examined by flow cytometry. GSH, MDA, ROS, and Fe2+ levels were measured by the corresponding kits. The expressions of ferroptosis-negative regulation genes (GPX4 and SLC7A11) were determined by qRT-PCR and western blot. Molecular interactions were analyzed by RNA pull-down, RIP, ChIP, and dual-luciferase reporter assays. The effects of ITGB2-AS1 silencing on NSCLC cisplatin resistance in vivo were elevated by the tumor xenograft experiment. ITGB2-AS1 expression was increased in NSCLC patients and cisplatin-resistant NSCLC cells, which was positively correlated with ferroptosis-negative regulation genes. ITGB2-AS1 knockdown suppressed resistant cell proliferation and promoted cell apoptosis and ferroptosis. ITGB2-AS1 increased NAMPT expression by binding to FOSL2, thereby repressing p53 expression. The ITGB2-AS1 knockdown also inhibited NSCLC cisplatin resistance in vivo. ITGB2-AS1 promoted NSCLC cisplatin resistance by inhibiting p53-mediated ferroptosis via activating the FOSL2/NAMPT axis.

Chromatin accessibility uncovers KRAS-driven FOSL2 promoting pancreatic ductal adenocarcinoma progression through up-regulation of CCL28.

BACKGROUND: The epigenetic mechanisms involved in the progression of pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. This study aimed to identify key transcription factors (TFs) through multiomics sequencing to investigate the molecular mechanisms of TFs that play critical roles in PDAC. METHODS: To characterise the epigenetic landscape of genetically engineered mouse models (GEMMs) of PDAC with or without KRAS and/or TP53 mutations, we employed ATAC-seq, H3K27ac ChIP-seq, and RNA-seq. The effect of Fos-like antigen 2 (FOSL2) on survival was assessed using the Kaplan-Meier method and multivariate Cox regression analysis for PDAC patients. To study the potential targets of FOSL2, we performed Cleavage Under Targets and Tagmentation (CUT&Tag). To explore the functions and underlying mechanisms of FOSL2 in PDAC progression, we employed several assays, including CCK8, transwell migration and invasion, RT-qPCR, Western blotting analysis, IHC, ChIP-qPCR, dual-luciferase reporter, and xenograft models. RESULTS: Our findings indicated that epigenetic changes played a role in immunosuppressed signalling during PDAC progression. Moreover, we identified FOSL2 as a critical regulator that was up-regulated in PDAC and associated with poor prognosis in patients. FOSL2 promoted cell proliferation, migration, and invasion. Importantly, our research revealed that FOSL2 acted as a downstream target of the KRAS/MAPK pathway and recruited regulatory T (Treg) cells by transcriptionally activating C-C motif chemokine ligand 28 (CCL28). This discovery highlighted the role of an immunosuppressed regulatory axis involving KRAS/MAPK-FOSL2-CCL28-Treg cells in the development of PDAC. CONCLUSION: Our study uncovered that KRAS-driven FOSL2 promoted PDAC progression by transcriptionally activating CCL28, revealing an immunosuppressive role for FOSL2 in PDAC.

Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by chronic low-grade inflammation. Previous studies have demonstrated that the gut microbiome can affect the host tissue cells' mRNA N6-methyladenosine (m6A) modifications. This study aimed to understand the role of intestinal flora in ovarian cells inflammation by regulating mRNA m6A modification particularly the inflammatory state in PCOS. The gut microbiome composition of PCOS and Control groups was analyzed by 16S rRNA sequencing, and the short chain fatty acids were detected in patients' serum by mass spectrometry methods. The level of butyric acid was found to be decreased in the serum of the obese PCOS group (FAT) compared to other groups, and this was correlated with increased Streptococcaceae and decreased Rikenellaceae based on the Spearman's rank test. Additionally, we identified FOSL2 as a potential METTL3 target using RNA-seq and MeRIP-seq methodologies. Cellular experiments demonstrated that the addition of butyric acid led to a decrease in FOSL2 m6A methylation levels and mRNA expression by suppressing the expression of METTL3, an m6A methyltransferase. Additionally, NLRP3 protein expression and the expression of inflammatory cytokines (IL-6 and TNF-α) were downregulated in KGN cells. Butyric acid supplementation in obese PCOS mice improved ovarian function and decreased the expression of local inflammatory factors in the ovary. Taken together, the correlation between the gut microbiome and PCOS may unveil crucial mechanisms for the role of specific gut microbiota in the pathogenesis of PCOS. Furthermore, butyric acid may present new prospects for future PCOS treatments.

Integration of ATAC-Seq and RNA-Seq reveals FOSL2 drives human liver progenitor-like cell aging by regulating inflammatory factors.

BACKGROUND: Human primary hepatocytes (PHCs) are considered to be the best cell source for cell-based therapies for the treatment of end-stage liver disease and acute liver failure. To obtain sufficient and high-quality functional human hepatocytes, we have established a strategy to dedifferentiate human PHCs into expandable hepatocyte-derived liver progenitor-like cells (HepLPCs) through in vitro chemical reprogramming. However, the reduced proliferative capacity of HepLPCs after long-term culture still limits their utility. Therefore, in this study, we attempted to explore the potential mechanism related to the proliferative ability of HepLPCs in vitro culture. RESULTS: In this study, analysis of assay for transposase accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed for PHCs, proliferative HepLPCs (pro-HepLPCs) and late-passage HepLPCs (lp-HepLPCs). Genome-wide transcriptional and chromatin accessibility changes during the conversion and long-term culture of HepLPCs were studied. We found that lp-HepLPCs exhibited an aged phenotype characterized by the activation of inflammatory factors. Epigenetic changes were found to be consistent with our gene expression findings, with promoter and distal regions of many inflammatory-related genes showing increased accessibility in the lp-HepLPCs. FOSL2, a member of the AP-1 family, was found to be highly enriched in the distal regions with increased accessibility in lp-HepLPCs. Its depletion attenuated the expression of aging- and senescence-associated secretory phenotype (SASP)-related genes and resulted in a partial improvement of the aging phenotype in lp-HepLPCs. CONCLUSIONS: FOSL2 may drive the aging of HepLPCs by regulating inflammatory factors and its depletion may attenuate this phenotypic shift. This study provides a novel and promising approach for the long-term in vitro culture of HepLPCs.

SOX2 dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating the FOSL2/IL6 axis.

BACKGROUND: Inflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and the consequences on disease aggressiveness are insufficiently understood. METHODS: Data of 27 tumor entities (about 5000 samples) were downloaded from the TCGA and GEO databases. Multi-omic analyses were performed on these and in-house data to investigate molecular determinants of tumor aggressiveness. Using molecular loss-of-function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness were addressed. Patient specimens and in vivo disease models were subsequently used to validate findings. RESULTS: There was significant association between somatic copy number alterations (sCNAs) and tumor aggressiveness. SOX2 amplification was the most important feature among novel and known aggressiveness-associated alterations. Mechanistically, SOX2 regulates a group of genes, in particular the AP1 transcription factor FOSL2, to sustain pro-inflammatory signaling pathways, such as IL6-JAK-STAT3, TNFA and IL17. FOSL2 was found overexpressed in tumor sections of specifically aggressive cancers. In consequence, prolonged inflammation induces immunosuppression and activates cytidine deamination and thus DNA damage as evidenced by related mutational signatures in aggressive tumors. The DNA damage affects tumor suppressor genes such as TP53, which is the most mutated gene in aggressive tumors compared to less aggressive ones (38% vs 14%), thereby releasing cell cycle control. These results were confirmed by analyzing tissues from various tumor types and in vivo studies. CONCLUSION: Our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.

Circ_0005615 Regulates the Progression of Colorectal Cancer Through the miR-873-5p/FOSL2 Signaling Pathway.

To determine the effects of circ_0005615 in CRC development and underneath mechanism. The expression levels of circ_0005615, microRNA-873-5p (miR-873-5p) and FOS-like antigen 2 (FOSL2) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of exosome makers, proliferation-related makers and FOSL2 were detected by western blot or immunohistochemistry assay. Cell proliferation was evaluated by cell counting kit-8 (CCK-8) and cell colony formation assays. Cell migration and invasion were demonstrated by a transwell assay. Cell apoptosis was investigated by flow cytometry analysis. The binding relationship between miR-873-5p and circ_0005615 or FOSL2 was predicted by circular RNA interactome and targetscan online databases, respectively, and identified by dual-luciferase reporter assay. The impacts of circ_0005615 silencing on tumor formation were determined by in vivo tumor formation assay. Circ_0005615 expression was dramatically upregulated in serum exosomes of CRC patients compared with the control group. The CRC patients with a high circ_0005615 expression had a poor survival rate. Circ_0005615 and FOSL2 expressions were apparently increased, while miR-873-5p was decreased in CRC tissues or cells relative to control groups. Circ_0005615 knockdown inhibited cell proliferation, migration, and invasion, whereas promoted cell apoptosis in CRC; however, miR-873-5p inhibitor attenuated these impacts. Additionally, circ_0005615 acted as a sponge of miR-873-5p and miR-873-5p bound to FOSL2. FOSL2 overexpression restrained the effects of miR-873-5p mimic on CRC progression. Furthermore, circ_0005615 knockdown suppressed tumor growth in vivo. Circ_0005615 modulated CRC malignant progression by controlling FOSL2 expression through sponging miR-873-5p. This finding lays a foundation for the study on circRNA-mediated CRC therapy.

FOSL2 promotes intertumoral infiltration of T cells and increases pathological complete response rates in locally advanced rectal cancer patients.

The outcome of neoadjuvant chemoradiotherapy (nCRT) remains highly unpredictable for individuals with locally advanced rectal cancer (LARC). We set out to characterize effective biomarkers that promote a pathological complete response (pCR). We quantified the abundances of 6483 high-confidence proteins in pre-nCRT biopsies of 58 LARC patients from two hospitals with pressure cycling technology (PCT)-assisted pulse data-independent acquisition (PulseDIA) mass spectrometry. Compared with non-pCR patients, pCR patients achieved long-term disease-free survival (DFS) and had higher tumor immune infiltration, especially CD8+ T cell infiltration, before nCRT. FOSL2 was selected as the candidate biomarker for predicting pCR and was found to be significantly upregulated in pCR patients, which was verified in another 54 pre-nCRT biopsies of LARC patients by immunohistochemistry. FOSL2 expression was able to predict pCR by multiple reaction monitoring (MRM) with high efficiency (Area under curve (AUC) = 0.939, specificity = 1.000, sensitivity = 0.850), and high FOSL2 expression was associated with long-term DFS (p = 0.044). When treated with simulated nCRT, FOSL2 sufficiency resulted in more significant inhibition of cell proliferation, and more significant promotion of cell cycle arrest and cell apoptosis. Moreover, CXCL10 secretion with abnormal cytosolic dsDNA accumulation was found in FOSL2-wildtype (FOSL2-WT) tumor cells over nCRT, which might elevate CD8+ T-cell infiltration and CD8+ T-cell-mediated cytotoxicity to promote nCRT-induced antitumor immunity. Our study revealed proteomic profiles in LARC patients before nCRT and highlighted immune activation in the tumors of patients who achieved pCR. We identified FOSL2 as a promising biomarker to predict pCR and promote long-term DFS by contributing to CD8+ T-cell infiltration.

FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects.

PURPOSE: We aimed to investigate the molecular basis of a novel recognizable neurodevelopmental syndrome with scalp and enamel anomalies caused by truncating variants in the last exon of the gene FOSL2, encoding a subunit of the AP-1 complex. METHODS: Exome sequencing was used to identify genetic variants in all cases, recruited through Matchmaker exchange. Gene expression in blood was analyzed using reverse transcription polymerase chain reaction. In vitro coimmunoprecipitation and proteasome inhibition assays in transfected HEK293 cells were performed to explore protein and AP-1 complex stability. RESULTS: We identified 11 individuals from 10 families with mostly de novo truncating FOSL2 variants sharing a strikingly similar phenotype characterized by prenatal growth retardation, localized cutis scalp aplasia with or without skull defects, neurodevelopmental delay with autism spectrum disorder, enamel hypoplasia, and congenital cataracts. Mutant FOSL2 messenger RNAs escaped nonsense-mediated messenger RNA decay. Truncated FOSL2 interacts with c-JUN, thus mutated AP-1 complexes could be formed. CONCLUSION: Truncating variants in the last exon of FOSL2 associate a distinct clinical phenotype by altering the regulatory degradation of the AP-1 complex. These findings reveal a new role for FOSL2 in human pathology.