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Tristetraprolin expression by keratinocytes protects against skin carcinogenesis.

ABSTRACT: Cancer is caused primarily by genomic alterations resulting in deregulation of gene regulatory circuits in key growth, apoptosis, or DNA repair pathways. Multiple genes associated with the initiation and development of tumors are also regulated at the level of mRNA decay, through the recruitment of RNA-binding proteins to AU-rich elements (AREs) located in their 3'-untranslated regions. One of these ARE-binding proteins, tristetraprolin (TTP; encoded by Zfp36), is consistently dysregulated in many human malignancies. Herein, using regulated overexpression or conditional ablation in the context of cutaneous chemical carcinogenesis, we show that TTP represents a critical regulator of skin tumorigenesis. We provide evidence that TTP controlled both tumor-associated inflammation and key oncogenic pathways in neoplastic epidermal cells. We identify Areg as a direct target of TTP in keratinocytes and show that EGFR signaling potentially contributed to exacerbated tumor formation. Finally, single-cell RNA-Seq analysis indicated that ZFP36 was downregulated in human malignant keratinocytes. We conclude that TTP expression by epidermal cells played a major role in the control of skin tumorigenesis.

SUBMITTER: Assabban A

PROVIDER: S-EPMC8021119 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tristetraprolin expression by keratinocytes protects against skin carcinogenesis

Project description:Cancer is caused primarily by somatic mutations of proto-oncogenes, leading to deregulation of gene regulatory circuits in key growth, apoptosis or DNA repair pathways. Multiple genes associated with the initiation and development of tumors are also regulated at the level of mRNA decay, through the recruitment of RNA binding proteins to AU-rich elements (AREs) located in their 3’-untranslated regions. One of these ARE-binding proteins, tristetraprolin (TTP, encoded by Zfp36) is consistently dysregulated in many human malignancies. Herein, using regulated overexpression or conditional ablation in the context of chemical cutaneous carcinogenesis, we show that TTP represents a critical regulator of skin tumorigenesis. We provide evidence that TTP controls both tumor-associated inflammation and key oncogenic pathways in malignant epidermal cells. We identify Areg as a direct target of TTP in keratinocytes, and show that EGFR signaling contributes to exacerbated tumor formation. We conclude that TTP expression by epidermal cells plays a major role in the control of early steps leading to tumorigenesis.

2021-04-13 | GSE151587 | GEO

Tristetraprolin expression by keratinocytes protects against skin carcinogenesis

Project description:Tristetraprolin expression by keratinocytes protects against skin carcinogenesis

| PRJNA636408 | ENA

Tristetraprolin expression by keratinocytes controls local and systemic inflammation.

Project description:Tristetraprolin (TTP, encoded by the Zfp36 gene) regulates the mRNA stability of several important cytokines. Due to the critical role of this RNA-binding protein in the control of inflammation, TTP deficiency leads to the spontaneous development of a complex inflammatory syndrome. So far, this phenotype has been largely attributed to dysregulated production of TNF and IL‑23 by myeloid cells, such as macrophages or DCs. Here, we generated mice with conditional deletion of TTP in keratinocytes (Zfp36fl/flK14-Cre mice, referred to herein as Zfp36ΔEP mice). Unlike DC-restricted (CD11c-Cre) or myeloid cell-restricted (LysM-Cre) TTP ablation, these mice developed exacerbated inflammation in the imiquimod-induced psoriasis model. Furthermore, Zfp36ΔEP mice progressively developed a spontaneous pathology with systemic inflammation, psoriatic-like skin lesions, and dactylitis. Finally, we provide evidence that keratinocyte-derived TNF production drives these different pathological features. In summary, these findings expand current views on the initiation of psoriasis and related arthritis by revealing the keratinocyte-intrinsic role of TTP.

| S-EPMC5453703 | biostudies-literature

IL-13 from intraepithelial lymphocytes regulates tissue homeostasis and protects against carcinogenesis in the skin.

Project description:The skin is under constant renewal and exposure to environmental challenges. How homeostasis is maintained alongside protective mechanisms against damage is unclear. Among the basal epithelial cells (ECs) is a population of resident intraepithelial lymphocytes (IELs) that provide host-protective immune surveillance. Here we show that IELs cross-communicate with ECs via the production of IL-13. Skin ECs are activated by IEL-derived IL-13, enabling a canonical EC stress response. In the absence of IL-13, or canonical IEL, the skin has decreased ability to repair its barrier and increased susceptibility to cutaneous carcinogenesis. IL-13 controls the rate of EC movement through the epidermis, which might explain the importance of IL-13 for epidermal integrity and its suppressive effect on skin carcinogenesis. These findings show that IL-13 acts as a molecular bridge between IELs and ECs, and reveal a critical host-defensive role for type-2 immunity in regulating EC tissue homeostasis and carcinogenesis.

| S-EPMC4931319 | biostudies-literature

Silver nanoparticles protect human keratinocytes against UVB radiation-induced DNA damage and apoptosis: potential for prevention of skin carcinogenesis.

Project description:Ultraviolet (UV)-B radiation from the sun is an established etiological cause of skin cancer, which afflicts more than a million lives each year in the United States alone. Here, we tested the chemopreventive efficacy of silver-nanoparticles (AgNPs) against UVB-irradiation-induced DNA damage and apoptosis in human immortalized keratinocytes (HaCaT). AgNPs were synthesized by reduction-chemistry and characterized for their physicochemical properties. AgNPs were well tolerated by HaCaT cells and their pretreatment protected them from UVB-irradiation-induced apoptosis along with significant reduction in cyclobutane-pyrimidine-dimer formation. Moreover, AgNPs pre-treatment led to G1-phase cell-cycle arrest in UVB-irradiated HaCaT cells. AgNPs were efficiently internalized in UVB-irradiated cells and localized into cytoplasmic and nuclear compartments. Furthermore, we observed an altered expression of various genes involved in cell-cycle, apoptosis and nucleotide-excision repair in HaCaT cells treated with AgNPs prior to UVB-irradiation. Together, these findings provide support for potential utility of AgNPs as novel chemopreventive agents against UVB-irradiation-induced skin carcinogenesis.From the clinical editorExcessive exposure to the sun is known to increase the risk of skin cancer due to DNA damage. In this work, the authors tested the use of silver nanoparticles as protective agents against ultraviolet radiation. The positive results may open a door for the use of silver nanoparticle as novel agents in the future.

| S-EPMC4476928 | biostudies-literature

Expression of Bioactive Chemerin by Keratinocytes Inhibits Late Stages of Tumor Development in a Chemical Model of Skin Carcinogenesis.

Project description:Chemerin is a multifunctional protein acting mainly through the G protein-coupled receptor ChemR23/CMKLR1/Chemerin1. Its expression is frequently downregulated in human tumors, including in melanoma and squamous cell carcinoma of the skin and anti-tumoral properties of chemerin were reported in mouse tumor graft models. In the present study, we report the development of spontaneous skin tumors in aged ChemR23-deficient mice. In order to test the potential therapeutic benefit of chemerin analogs, a transgenic model in which bioactive chemerin is over-expressed by basal keratinocytes was generated. These animals are characterized by increased levels of chemerin immunoreactivity and bioactivity in the skin and the circulation. In a chemical carcinogenesis model, papillomas developed later, were less numerous, and their progression to carcinomas was delayed. Temporal control of chemerin expression by doxycycline allowed to attribute its effects to late stages of carcinogenesis. The protective effects of chemerin were partly abrogated by ChemR23 invalidation. These results demonstrate that chemerin is able to delay very significantly tumor progression in a model that recapitulates closely the evolution of solid cancer types in human and suggest that the chemerin-ChemR23 system might constitute an interesting target for therapeutic intervention in the cancer field.

| S-EPMC6873210 | biostudies-literature

Macrophage autophagy protects against hepatocellular carcinogenesis in mice.

Project description:Autophagy is a lysosomal degradation pathway of cellular components that regulates macrophage properties. Macrophages are critically involved in tumor growth, metastasis, angiogenesis and immune suppression. Here, we investigated whether macrophage autophagy may protect against hepatocellular carcinoma (HCC). Experiments were performed in mice with deletion of the autophagy gene Atg5 in the myeloid lineage (ATG5Mye-/- mice) and their wild-type (WT) littermates. As compared to WT, ATG5Mye-/- mice were more susceptible to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, as shown by enhanced tumor number and volume. Moreover, DEN-treated ATG5Mye-/- mice exhibited compromised immune cell recruitment and activation in the liver, suggesting that macrophage autophagy invalidation altered the antitumoral immune response. RNA sequencing showed that autophagy-deficient macrophages sorted from DEN mice are characterized by an enhanced expression of immunosuppressive markers. In vitro studies demonstrated that hepatoma cells impair the autophagy flux of macrophages and stimulate their expression of programmed cell death-ligand 1 (PD-L1), a major regulator of the immune checkpoint. Moreover, pharmacological activation of autophagy reduces hepatoma cell-induced PD-L1 expression in cultured macrophages while inhibition of autophagy further increases PD-L1 expression suggesting that autophagy invalidation in macrophages induces an immunosuppressive phenotype. These results uncover macrophage autophagy as a novel protective pathway regulating liver carcinogenesis.

| S-EPMC8458469 | biostudies-literature

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice.

Project description:Tristetraprolin (TTP) is a mRNA binding protein that binds to adenylate-uridylate-rich elements within the 3' untranslated regions of certain transcripts, such as tumor necrosis factor (Tnf) mRNA, and increases their rate of decay. Modulation of TTP expression is implicated in inflammation; however, its role in acute lung inflammation remains unknown. Accordingly, we tested the role of TTP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. LPS-challenged TTP-knockout (TTPKO) mice, as well as myeloid cell-specific TTP-deficient (TTPmyeKO) mice, exhibited significant increases in lung injury, although these responses were more robust in the TTPKO. Mice with systemic overexpression of TTP (TTPΔARE) were protected from ALI, as indicated by significantly reduced neutrophilic infiltration, reduced levels of neutrophil chemoattractants, and histological parameters of ALI. Interestingly, while irradiated wild-type (WT) mice reconstituted with TTPKO hematopoietic progenitor cells (HPCs) showed exaggerated ALI, their reconstitution with the TTPΔARE HPCs mitigated ALI. The reconstitution of irradiated TTPΔARE mice with HPCs from either WT or TTPΔARE donors conferred significant protection against ALI. In contrast, irradiated TTPΔARE mice reconstituted with TTPKO HPCs had exaggerated ALI, but the response was milder as compared to WT recipients that received TTPKO HPCs. Finally, the reconstitution of irradiated TTPKO recipient mice with TTPΔARE HPCs did not confer any protection to the TTPKO mice. These data together suggest that non-HPCs-specific overexpression of TTP within the lungs protects against ALI via downregulation of neutrophil chemoattractants and reduction in neutrophilic infiltration.

| S-EPMC7493631 | biostudies-literature

The mRNA binding proteins HuR and tristetraprolin regulate cyclooxygenase 2 expression during colon carcinogenesis.

Project description:Background & aimsDuring tumorigenesis, loss of rapid messenger RNA (mRNA) decay allows for overexpression of cancer-associated genes. The RNA-binding proteins Hu antigen R (HuR) and tristetraprolin (TTP) bind AU-rich elements in the 3' untranslated region of many cancer-associated mRNAs and target them for stabilization or rapid decay, respectively. We examined the functions of HuR and TTP during colon tumorigenesis and their ability to regulate cyclooxygenase (COX-2), a mediator of prostaglandin synthesis that increases in the colon tumor microenvironment.MethodsWe evaluated expression of HuR and TTP during colorectal tumorigenesis and in colon cancer cells and associated them with COX-2 expression. HuR and TTP-inducible cells were created to investigate HuR- and TTP-mediated regulation of COX-2.ResultsIn normal colon tissues, low levels of nuclear HuR and higher levels of TTP were observed. By contrast, increased HuR expression and cytoplasmic localization were observed in 76% of adenomas and 94% of adenocarcinomas, and TTP expression was lost in >75% of adenomas and adenocarcinomas. Similar results were obtained for HuR and TTP mRNA levels in normal and staged tumor samples. In both adenomas and adenocarcinomas, COX-2 overexpression was associated with increased HuR and decreased TTP (P < .0001); similar associations were observed in colon cancer cells. HuR overexpression in cells up-regulated COX-2 expression, whereas overexpression of TTP inhibited it; limited TTP expression antagonized HuR-mediated COX-2 overexpression.ConclusionsIncreased expression of the mRNA stability factor HuR and loss of the decay factor TTP occurs during early stages of colorectal tumorigenesis. These changes promote COX-2 overexpression and could contribute to colon tumorigenesis.

| S-EPMC3742387 | biostudies-literature

Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.

Project description:TREX2 is a 3'-DNA exonuclease specifically expressed in keratinocytes. Here, we investigated the relevance and mechanisms of TREX2 in ultraviolet (UV)-induced skin carcinogenesis. TREX2 expression was up-regulated by chronic UV exposure whereas it was de-regulated or lost in human squamous cell carcinomas (SCCs). Moreover, we identified SNPs in the TREX2 gene that were more frequent in patients with head and neck SCCs than in healthy individuals. In mice, TREX2 deficiency led to enhanced susceptibility to UVB-induced skin carcinogenesis which was preceded by aberrant DNA damage removal and degradation as well as reduced inflammation. Specifically, TREX2 loss diminished the up-regulation of IL12 and IFNγ, key cytokines related to DNA repair and antitumor immunity. In UV-treated keratinocytes, TREX2 promoted DNA repair and passage to late apoptotic stages. Notably, TREX2 was recruited to low-density nuclear chromatin and micronuclei, where it interacted with phosphorylated H2AX histone, which is a critical player in both DNA repair and cell death. Altogether, our data provide new insights in the molecular mechanisms of TREX2 activity and establish cell autonomous and non-cell autonomous functions of TREX2 in the UVB-induced skin response.

| S-EPMC4673170 | biostudies-literature

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