Follicular helper T (TFH) cells mediate germinal center reactions to generate high affinity antibodies against specific pathogens, and their excessive production is associated with the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). ETV5, a member of the ETS transcription factor family, promotes TFH cell differentiation in mice. In this study, we examined the role of ETV5 in the pathogenesis of lupus in mice and humans. T cell-specific deletion of Etv5 alleles ameliorated TFH cell differentiation and autoimmune phenotypes in lupus mouse models. Further, we identified SPP1 as an ETV5 target that promotes TFH cell differentiation in both mice and humans. Notably, extracellular osteopontin (OPN) encoded by SPP1 enhances TFH cell differentiation by activating the CD44-AKT signaling pathway. Furthermore, ETV5 and SPP1 levels were increased in CD4+ T cells from patients with SLE and were positively correlated with disease activity. Taken together, our findings demonstrate that ETV5 is a lupus-promoting transcription factor, and secreted OPN promotes TFH cell differentiation.

E26 transformation-specific translocation variant 5 (ETV5) has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). However, the exact roles of ETV5 in regulating CD4+ T cell-mediated intestinal inflammation and fibrosis formation remain unclear. Here, we reveal that ETV5 overexpression induced interleukin (IL)-9 and its transcription factor IRF4 expression in IBD CD4+ T cells under T helper type 9 (Th9) cells-polarizing conditions. The silencing of IRF4 inhibited ETV5-induced IL-9 expression. CD4+ T cell-specific ETV5 deletion ameliorated intestinal inflammation and fibrosis in trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis and CD4+ T cell-transferred recombination-activating gene-1 knockout (Rag1-/-) colitis mice, characterized by less CD4+ T cell infiltration and lower fibroblast activation and collagen deposition in the colonic tissues. Furthermore, IL-9 treatment aggressive TNBS-induced intestinal fibrosis in CD4+ T cell-specific ETV5 deletion and wild-type control mice. In vitro, human intestinal fibroblasts cocultured with ETV5 overexpressed-Th9 cells expressed higher levels of collagen I and III, whereas an inclusion of anti-IL-9 antibody could reverse this effect. Ribonucleic acid sequencing analysis demonstrated that IL-9 upregulated TAF1 expression in human intestinal fibroblasts. Clinical data showed that number of α-smooth muscle actin+TAF1+ fibroblasts are higher in inflamed mucosa of patients with IBD. Importantly, TAF1 small interfering ribonucleic acid treatment suppressed IL-9-mediated profibrotic effect in vitro. These findings reveal that CD4+ T cell-derived ETV5 promotes intestinal inflammation and fibrosis through upregulating IL-9-mediated intestinal inflammatory and fibrotic response in IBD. Thus, the ETV5/IL-9 signal pathway in T cells might represent a novel therapeutic target for intestinal inflammation and fibrosis in IBD.

Atractylodes macrocephala III (ATL III), with anti-inflammatory and antitumor effects, is the main compound of Atractylodes macrocephala. Whether ATL III has an effect on cervical cancer and the specific mechanism are still unclear. Here, we investigated the effects of ATL III on cervical cancer cells at different concentrations and found that ATL III downregulates insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), which was found to be highly expressed in cervical cancer tissue by RNA-Seq. In this study, we found that ATL III promotes apoptosis and regulates epithelial-mesenchymal transition (EMT) in cervical cancer cells (HeLa and SiHa cells) and that IGF2BP3 is a common target gene of ATL III in HeLa and SiHa cells. The expression level of IGF2BP3 in cervical cancer cells was proportional to their migration and invasion abilities. This was verified by transfection of cells with a small interfering RNA and an IGF2BP3 overexpression plasmid. After ATL III treatment, the migration and invasion abilities of cervical cancer cells were obviously reduced, but these effects were attenuated after overexpression of IGF2BP3. In addition, the transcription factor IGF2BP3 was predicted by the JASPAR system. After intersection with our sequencing results, we verified the promotional effect of ETV5 (ETS translocation variant 5) on IGF2BP3 and found that ALT III inhibited ETV5. In general, our research showed that ATL III inhibits the migration and invasion of cervical cancer cells by regulating IGF2BP3 through ETV5.

N6-methyladenosine (m6A) modification orchestrates cancer formation and progression by affecting the tumor microenvironment (TME). For hepatocellular carcinoma (HCC), immune evasion and angiogenesis are characteristic features of its TME. The role of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), as an m6A reader, in regulating HCC TME are not fully understood. Herein, it is discovered that trimethylated histone H3 lysine 4 and H3 lysine 27 acetylation modification in the promoter region of YTHDF2 enhanced its expression in HCC, and upregulated YTHDF2 in HCC predicted a worse prognosis. Animal experiments demonstrated that Ythdf2 depletion inhibited spontaneous HCC formation, while its overexpression promoted xenografted HCC progression. Mechanistically, YTHDF2 recognized the m6A modification in the 5\'-untranslational region of ETS variant transcription factor 5 (ETV5) mRNA and recruited eukaryotic translation initiation factor 3 subunit B to facilitate its translation. Elevated ETV5 expression induced the transcription of programmed death ligand-1 and vascular endothelial growth factor A, thereby promoting HCC immune evasion and angiogenesis. Targeting YTHDF2 via small interference RNA-containing aptamer/liposomes successfully both inhibited HCC immune evasion and angiogenesis. Together, this findings reveal the potential application of YTHDF2 in HCC prognosis and targeted treatment.

The morbidity and mortality of NSCLC remains high worldwide. However, the molecular mechanisms of NSCLC still largely unclear. Ets variant 5 (ETV5) is a transcription factor that found to be overexpressed in multiple cancers. However, the role of ETV5 in NSCLC remains unknown. We aim to explore the role and mechanisms of ETV5 in NSCLC development. The expression of ETV5 was evaluated in NSCLC tissues and cell lines. ETV5 overexpressing and downregulation cell lines were established according to the endogenous expression of ETV5. Functional studies were performed by transwell assay. The downstream targets of ETV5 were screened by PCR array and were confirmed by luciferase reporter assay. We found that overexpression of ETV5 indicates worse prognosis of NSCLC patients. Elevated ETV5 expression promotes NSCLC cell invasion and migration via transcriptional activates of TGFβ1. Therefore, ETV5/TGFβ signaling may serve as a therapeutic target for NSCLS patients.

E26 transformation-specific (ETS) factors have emerged as key mediators underlying human tumorigenesis. Here, we sought to characterize the expression pattern, biological roles, and clinical significance of ETS Variant Transcription Factor 5 (ETV5) in head neck squamous cell carcinoma (HNSCC).
ETV5 expression pattern in HNSCC was determined by bioinformatics interrogations and immunohistochemical staining in primary samples. The associations between its abundance with clinicopathological parameters, and patient survival were evaluated. Colony formation, CCK-8, flow cytometry, wound healing, and Transwell invasion assays, as well as xenograft models, were utilized to determine the phenotypic changes after ETV5 silencing in vitro and vivo. The potential binding of ETV5 in the Slug promoter was determined by ChIP-qPCR.
ETV5 was significantly overexpressed in HNSCC samples. Its overexpression is significantly associated with aggressiveness features and reduced survival. ETV5 knockdown significantly inhibited cell proliferation, migration, invasion, and induced apoptosis in vitro, and impaired tumor growth in vivo. Moreover, ETV5-activated Slug transcription by binding its promoter region in HNSCC cells. Patients with ETV5highSlughigh had the worst survival across multiple HNSCC cohorts.
Our findings reveal that ETV5 serves as a novel prognostic biomarker and putative oncogene for HNSCC progression likely by activating Slug transcription.

E26 transformation-specific (ETS) transcription variant 5 (ETV5), also known as ETS-related molecule (ERM), exerts versatile functions in normal physiological processes, including branching morphogenesis, neural system development, fertility, embryonic development, immune regulation, and cell metabolism. In addition, ETV5 is repeatedly found to be overexpressed in multiple malignant tumors, where it is involved in cancer progression as an oncogenic transcription factor. Its roles in cancer metastasis, proliferation, oxidative stress response and drug resistance indicate that it is a potential prognostic biomarker, as well as a therapeutic target for cancer treatment. Post-translational modifications, gene fusion events, sophisticated cellular signaling crosstalk and non-coding RNAs contribute to the dysregulation and abnormal activities of ETV5. However, few studies to date systematically summarized the role and molecular mechanisms of ETV5 in benign diseases and in oncogenic progression. In this review, we specify the molecular structure and post-translational modifications of ETV5. In addition, its critical roles in benign and malignant diseases are summarized to draw a panorama for specialists and clinicians. The updated molecular mechanisms of ETV5 in cancer biology and tumor progression are delineated. Finally, we prospect the further direction of ETV5 research in oncology and its potential translational applications in the clinic.

Esophageal squamous cell carcinoma (ESCC) is notorious for the rapid progression especially early tumor metastasis due to the unclear mechanism. Recently, ETV5 attracts much attention for its potential role as an oncogenic transcription factor involved in multiple cancers. However, no one reported the mechanism behind the association between ETV5 expression and esophageal squamous cell carcinoma progression. In this study, we found that ETV5 was upregulated in ESCC both from online database and our ESCC tissues and ETV5 was associated with tumor staging and prognosis. Knockdown of ETV5 or its downstream genes SKA1 and TRPV2 significantly suppress ESCC cells migration and invasion, respectively. Additionally, in vivo study showed knockdown of ETV5 inhibited tumor metastasis. Further experiments unveiled ETV5 could transcriptionally upregulate the expression of SKA1 and TRPV2 and further activate MMPs in ESCC progression. In conclusion, ETV5 was associated with ESCC tumor staging and ESCC prognosis clinically. ETV5 promoted metastasis of ESCC by activating MMPs through augmenting the transcription of SKA1 and TRPV2. ETV5 was likely to be a novel oncogene and therapeutic target in ESCC.

BACKGROUND: ETS transcription factors are known to act as either positive or negative regulators of the expression of genes involved in various biological processes. It was reported that ETS variant transcription factor 5 (ETV5), a key member of the ETS family, mainly plays a role as an potential oncogene in various malignant tumors. However, the role and mechanism of ETV5 in high-grade serous ovarian cancer (HGSOC) have not been elucidated.
METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to detect ETV5 messenger ribonucleic acid (mRNA) expression in 87 HGSOC tissues and 35 normal fallopian tube tissues. Western blotting and qRT-PCR were used to detect the protein and mRNA expression of ETV5 in six ovarian cancer (OC) and human embryonic cell lines. Knockdown or overexpression of ETV5 in HGSOC cell lines, Cell Counting Kit-8, colony formation, and transwell assays were used to detect HGSOC cell proliferation, invasion, and migration capabilities. The chi-square test was used to analyze the clinicopathological characteristics of HGSOC patients. Survival analysis was performed using the Kaplan-Meier method, and the log-rank test was used to analyze the correlation between ETV5 expression and HGSOC patient prognosis. Univariate and multivariate analyses using the Cox regression model were conducted to determine the independent significance of relevant clinical covariates.
RESULTS: Bioinformatic analysis demonstrated that ETV5 expression was significantly upregulated in OC (p < 0.05). qRT-PCR showed that ETV5 was significantly overexpressed in HGSOC tissues than in fallopian tube tissues (p < 0.05). qRT-PCR and western blotting assays demonstrated that ETV5 was relatively highly expressed in OC cell lines. ETV5 overexpression was positively associated with poor survival in HGSOC patients, therefore making it a high-risk factor for HGSOC progression. Furthermore, ETV5 promoted the proliferation, migration, and invasion capabilities of HGSOC cells.
CONCLUSIONS: ETV5 has a carcinogenic effect in HGSOC and can be used as a clinically effective biomarker to determine the prognosis of HGSOC patients.

In vitro induction of human primordial germ cell-like cells (hPGCLCs) provides an ideal platform to recapitulate hPGC development. However, the detailed molecular mechanisms regulating the induction of hPGCLCs remain largely uncharacterized. Here, we profiled the chromatin accessibility and transcriptome dynamics throughout the process of hPGCLC induction. Genetic ablation of SOX15 indicated the crucial roles of SOX15 in the maintenance of hPGCLCs. Mechanistically, SOX15 exerted its roles via suppressing somatic gene expression and sustaining latent pluripotency. Notably, ETV5, a downstream regulator of SOX15, was also uncovered to be essential for hPGCLC maintenance. Finally, a stepwise switch of OCT4/SOX2, OCT4/SOX17, and OCT4/SOX15 binding motifs were found to be enriched in closed-to-open regions of human embryonic stem cells, and early- and late-stage hPGCLCs, respectively. Collectively, our data characterized the chromatin accessibility and transcriptome landscapes throughout hPGCLC induction and defined the SOX15-mediated regulatory networks underlying this process.