Tristetraprolin expression by keratinocytes protects against skin carcinogenesis

Assabban, Assiya; Dubois-Vedrenne, Ingrid; Maele, Laurye Van; Salcedo, Rosalba; Snyder, Brittany L.; Zhou, Lecong; Azouz, Abdulkader; Toeuf, Bérengère de; Lapouge, Gaëlle; La, Caroline; Melchior, Maxime; Nguyen, Muriel; Thomas, Séverine; Wu, Shu Fen; Hu, Wenqian; Kruys, Véronique; Blanpain, Cédric; Trinchieri, Giorgio; Gueydan, Cyril; Blackshear, Perry J.; Goriely, Stanislas

doi:10.1172/jci.insight.140669

Cited by 10 publications

(4 citation statements)

References 47 publications

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“…28 However, TTPDARE mice are resistant to experimental models of imiquimod-induced dermatitis, collagen antibody-induced arthritis, experimental autoimmune encephalomyelitis, bacterial gingivitis and dental bone erosion, inflammatory lung damage, experimental autoimmune uveitis, and chemically induced skin carcinogenesis. [29][30][31][32] We previously showed that glucocorticoids are master regulators of gastric inflammation. Systemic removal of endogenous glucocorticoids by ADX triggers massive, spontaneous gastric inflammation and SPEM.…”

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confidence: 99%

Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation

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Khadka

Peterson

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Aberrant gastric inflammation damages the stomach and induces gastric metaplasia (spasmolytic polypeptideexpressing metaplasia). Increased expression of the RNA binding protein tristetraprolin suppresses adrenalectomyinduced gastric inflammation and spasmolytic polypeptideexpressing metaplasia development. BACKGROUND & AIMS:Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a wellestablished sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNAbinding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. METHODS:We used a TTP-overexpressing model, the TTPDadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. RESULTS:We found that TTPDadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from highdose-tamoxifen-induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. CONCLUSIONS:Our results show that TTP exerts broad antiinflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling:

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confidence: 99%

Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation

Busada

Khadka

Peterson

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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“…These 3 markers, KRT5, KRT6A, and APOE, are part of a tight correlation network (Figure 4E and Supplementary Figure 3) that includes other genes and whose expression levels track with SSc severity and are involved in a range of functional processes. ZFP36 encodes tristetraprolin, an AU‐rich element RNA binding protein that is up‐regulated in wounded skin and controls inflammatory cytokines as well as neoplastic processes in keratinocytes (18,19). S100A2 regulates keratinocyte differentiation through its interaction with p53 (20), and expression of the alarmin S100A8 is associated with increased keratinocyte proliferation and epithelial–mesenchymal transition (21).…”

Section: Resultsmentioning

confidence: 99%

Cell Type–Specific Biomarkers of Systemic Sclerosis Disease Severity Capture Cell‐Intrinsic and Cell‐Extrinsic Circuits

Berkowitz

Tabib

Xiao

et al. 2023

Arthritis & Rheumatology

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ObjectiveSystemic sclerosis (SSc) is a multifactorial autoimmune fibrotic disorder involving complex rewiring of cell‐intrinsic and cell‐extrinsic signaling coexpression networks involving a range of cell types. However, the rewired circuits as well as corresponding cell–cell interactions remain poorly understood. To address this, we used a predictive machine learning framework to analyze single‐cell RNA‐sequencing data from 24 SSc patients across the severity spectrum as quantified by the modified Rodnan skin score (MRSS).MethodsWe used a least absolute shrinkage and selection operator (LASSO)–based predictive machine learning approach on the single‐cell RNA‐sequencing data set to identify predictive biomarkers of SSc severity, both across and within cell types. The use of L1 regularization helps prevent overfitting on high‐dimensional data. Correlation network analyses were coupled to the LASSO model to identify cell‐intrinsic and cell‐extrinsic co‐correlates of the identified biomarkers of SSc severity.ResultsWe found that the uncovered cell type–specific predictive biomarkers of MRSS included previously implicated genes in fibroblast and myeloid cell subsets (e.g., SFPR2+ fibroblasts and monocytes), as well as novel gene biomarkers of MRSS, especially in keratinocytes. Correlation network analyses revealed novel cross‐talk between immune pathways and implicated keratinocytes in addition to fibroblast and myeloid cells as key cell types involved in SSc pathogenesis. We then validated the uncovered association of key gene expression and protein markers in keratinocytes, KRT6A and S100A8, with SSc skin disease severity.ConclusionOur global systems analyses reveal previously uncharacterized cell‐intrinsic and cell‐extrinsic signaling coexpression networks underlying SSc severity that involve keratinocytes, myeloid cells, and fibroblasts.image

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“…These findings support the potential benefit of targeting chemotherapy-induced senescent cells as a strategy to reduce occurrence of second cancer in the future. A recent study demonstrated that RNA-binding protein tristetraprolin that binds to AU-rich elements (AREs) in the 3′-untranslated regions of mRNAs and targets ARE-containing mRNAs for degradation, is an important regulator of skin carcinogenesis and may represent a useful therapeutic target ( 219 ). Of note, the critical role of the interleukin (IL)-33/regulatory T cell (Treg) axis in chronic inflammation-induced tumor-promoting environment both in the skin and colon has been recently elucidated, suggesting a promising therapeutic strategy for the treatment and prevention of cancers associated with chronic inflammation ( 220 ).…”

Section: In Vivo Modelsmentioning

confidence: 99%

Investigating Cutaneous Squamous Cell Carcinoma in vitro and in vivo: Novel 3D Tools and Animal Models

et al. 2022

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Cutaneous Squamous Cell Carcinoma (cSCC) represents the second most common type of skin cancer, which incidence is continuously increasing worldwide. Given its high frequency, cSCC represents a major public health problem. Therefore, to provide the best patients’ care, it is necessary having a detailed understanding of the molecular processes underlying cSCC development, progression, and invasion. Extensive efforts have been made in developing new models allowing to study the molecular pathogenesis of solid tumors, including cSCC tumors. Traditionally, in vitro studies were performed with cells grown in a two-dimensional context, which, however, does not represent the complexity of tumor in vivo. In the recent years, new in vitro models have been developed aiming to mimic the three-dimensionality (3D) of the tumor, allowing the evaluation of tumor cell-cell and tumor-microenvironment interaction in an in vivo-like setting. These models include spheroids, organotypic cultures, skin reconstructs and organoids. Although 3D models demonstrate high potential to enhance the overall knowledge in cancer research, they lack systemic components which may be solved only by using animal models. Zebrafish is emerging as an alternative xenotransplant model in cancer research, offering a high-throughput approach for drug screening and real-time in vivo imaging to study cell invasion. Moreover, several categories of mouse models were developed for pre-clinical purpose, including xeno- and syngeneic transplantation models, autochthonous models of chemically or UV-induced skin squamous carcinogenesis, and genetically engineered mouse models (GEMMs) of cSCC. These models have been instrumental in examining the molecular mechanisms of cSCC and drug response in an in vivo setting. The present review proposes an overview of in vitro, particularly 3D, and in vivo models and their application in cutaneous SCC research.

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Tristetraprolin expression by keratinocytes protects against skin carcinogenesis

Cited by 10 publications

References 47 publications

Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation

Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation

Cell Type–Specific Biomarkers of Systemic Sclerosis Disease Severity Capture Cell‐Intrinsic and Cell‐Extrinsic Circuits

Investigating Cutaneous Squamous Cell Carcinoma in vitro and in vivo: Novel 3D Tools and Animal Models

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