The regulation of interferon type I pathway‐related genes RSAD2 and ETV7 specifically indicates antibody‐mediated rejection after kidney transplantation

Matz, Mareen; Heinrich, Frederik; Zhang, Qiang; Lorkowski, Christine; Seelow, Evelyn; Wu, Kaiyin; Lachmann, Nils; Addo, Richard; Mashreghi, Mir‐Farzin; Budde, Klemens

doi:10.1111/ctr.13429

Cited by 17 publications

(15 citation statements)

References 41 publications

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“…In particular, we chose to use IFN-β as type I IFN, given the previous data in literature suggesting a negative role for IFN-β in breast cancer stemness [ 56 , 57 ], and IFN-γ as type II IFN, being the only member of this subfamily. Since, as mentioned above, ETV7 itself is a well-recognized Interferon-stimulated gene (ISG) [ 26 , 28 ], we first analyzed its expression in response to IFN-β and IFN-γ in MCF7 cells. As expected, we observed a robust and significant induction of ETV7 expression in response to both types of IFNs, with a peak of induction at 8 h for IFN-β and 24 h for IFN-γ, confirming that ETV7 is strongly responsive to IFNs also in the breast cancer-derived MCF7 cell line (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, ETV7 over-expression in human U937 cells was shown to impede monocytic differentiation [ 25 ]. ETV7 is also recognized as an Interferon (IFN)-stimulated gene (ISG), as its expression was shown to be induced by type I, type II, and type III IFN treatment in different cell types [ 26 – 28 ]. Elevated ETV7 expression has been associated with several tumor types; however, the role of ETV7 in cancer has been poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

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ETV7 regulates breast cancer stem-like cell features by repressing IFN-response genes

et al. 2021

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Cancer stem cells (CSCs) represent a population of cells within the tumor able to drive tumorigenesis and known to be highly resistant to conventional chemotherapy and radiotherapy. In this work, we show a new role for ETV7, a transcriptional repressor member of the ETS family, in promoting breast cancer stem-like cells plasticity and resistance to chemo- and radiotherapy in breast cancer (BC) cells. We observed that MCF7 and T47D BC-derived cells stably over-expressing ETV7 showed reduced sensitivity to the chemotherapeutic drug 5-fluorouracil and to radiotherapy, accompanied by an adaptive proliferative behavior observed in different culture conditions. We further noticed that alteration of ETV7 expression could significantly affect the population of breast CSCs, measured by CD44+/CD24low cell population and mammosphere formation efficiency. By transcriptome profiling, we identified a signature of Interferon-responsive genes significantly repressed in cells over-expressing ETV7, which could be responsible for the increase in the breast CSCs population, as this could be partially reverted by the treatment with IFN-β. Lastly, we show that the expression of the IFN-responsive genes repressed by ETV7 could have prognostic value in breast cancer, as low expression of these genes was associated with a worse prognosis. Therefore, we propose a novel role for ETV7 in breast cancer stem cells’ plasticity and associated resistance to conventional chemotherapy and radiotherapy, which involves the repression of a group of IFN-responsive genes, potentially reversible upon IFN-β treatment. We, therefore, suggest that an in-depth investigation of this mechanism could lead to novel breast CSCs targeted therapies and to the improvement of combinatorial regimens, possibly involving the therapeutic use of IFN-β, with the aim of avoiding resistance development and relapse in breast cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ETV7 regulates breast cancer stem-like cell features by repressing IFN-response genes

et al. 2021

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“…These studies have been more commonly performed on renal biopsy samples as they provide sufficient material for RNA extraction. As listed in Table 1, gene signatures associated with fibrosis, i-IFTA, chronic rejection (ABMR and TCMR) and graft failure can be identified by determining gene expression profiling (45)(46)(47)(48)(49)(50)(51)(52)(53). Importantly, the gene set has higher predictive capacity than that of baseline clinical variables, and clinical and pathological variables.…”

Section: Transcriptomic Biomarkersmentioning

confidence: 99%

Tackling Chronic Kidney Transplant Rejection: Challenges and Promises

et al. 2021

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Despite advances in post-transplant management, the long-term survival rate of kidney grafts and patients has not improved as approximately forty percent of transplants fails within ten years after transplantation. Both immunologic and non-immunologic factors contribute to late allograft loss. Chronic kidney transplant rejection (CKTR) is often clinically silent yet progressive allogeneic immune process that leads to cumulative graft injury, deterioration of graft function. Chronic active T cell mediated rejection (TCMR) and chronic active antibody-mediated rejection (ABMR) are classified as two principal subtypes of CKTR. While significant improvements have been made towards a better understanding of cellular and molecular mechanisms and diagnostic classifications of CKTR, lack of early detection, differential diagnosis and effective therapies continue to pose major challenges for long-term management. Recent development of high throughput cellular and molecular biotechnologies has allowed rapid development of new biomarkers associated with chronic renal injury, which not only provide insight into pathogenesis of chronic rejection but also allow for early detection. In parallel, several novel therapeutic strategies have emerged which may hold great promise for improvement of long-term graft and patient survival. With a brief overview of current understanding of pathogenesis, standard diagnosis and challenges in the context of CKTR, this mini-review aims to provide updates and insights into the latest development of promising novel biomarkers for diagnosis and novel therapeutic interventions to prevent and treat CKTR.

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“…In addition, genome-wide transcriptional profiling has demonstrated that the combined treatment of MCF7 breast cancer-derived cells with the chemotherapeutic agent doxorubicin and the inflammatory cytokine TNF-α results in the synergistic induction of ETV7 (21). ETV7 was also identified as an interferon (IFN)-stimulated gene (ISG), and its expression is known to be up-regulated upon the treatment with type I, type II, and type III interferons (22)(23)(24)(25). We have recently shown that ETV7 negatively regulates the type I interferon response, and it is known to be involved in the viral immune response by suppressing a subset of ISGs that are important for the control of influenza and SARS-CoV-2 viruses (26,27).…”

Section: Introductionmentioning

confidence: 99%

ETV7 reduces inflammatory responses in breast cancer cells by repressing TNFR1/NF-κB axis

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et al. 2022

Preprint

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The transcription factor ETV7 is an oncoprotein that is up-regulated in all breast cancer (BC) types. We have recently demonstrated that ETV7 promoted breast cancer progression by increasing cancer cell proliferation and stemness and was also involved in the development of chemo- and radio-resistance. However, the roles of ETV7 in breast cancer inflammation have yet to be studied. Gene ontology analysis previously performed on BC cells stably over-expressing ETV7 demonstrated that ETV7 was involved in the suppression of innate immune and inflammatory responses. To better decipher the involvement of ETV7 in these signaling pathways, in this study, we identified TNFRSF1A, encoding for the main receptor of TNF-alpha, TNFR1, as one of the genes down-regulated by ETV7. We demonstrated that ETV7 directly binds to the intron I of this gene, and we showed that the ETV7-mediated down-regulation of TNFRSF1A reduced the activation of NF-kappaB signaling. Furthermore, in this study, we unveiled a potential crosstalk between ETV7 and STAT3, another master regulator of inflammation. While it is known that STAT3 directly up-regulates the expression of TNFRSF1A, here we demonstrated that ETV7 reduces the ability of STAT3 to bind to the TNFRSF1A gene via a competitive mechanism, leading to the repression of its transcription. These results suggest that ETV7 can reduce the inflammatory responses in breast cancer through the down-regulation of TNFRSF1A.

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The regulation of interferon type I pathway‐related genes RSAD2 and ETV7 specifically indicates antibody‐mediated rejection after kidney transplantation

Cited by 17 publications

References 41 publications

ETV7 regulates breast cancer stem-like cell features by repressing IFN-response genes

ETV7 regulates breast cancer stem-like cell features by repressing IFN-response genes

Tackling Chronic Kidney Transplant Rejection: Challenges and Promises

ETV7 reduces inflammatory responses in breast cancer cells by repressing TNFR1/NF-κB axis

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