scholarly journals IL-1R–MyD88 signaling in keratinocyte transformation and carcinogenesis

2012 ◽  
Vol 209 (9) ◽  
pp. 1689-1702 ◽  
Author(s):  
Christophe Cataisson ◽  
Rosalba Salcedo ◽  
Shakeeb Hakim ◽  
B. Andrea Moffitt ◽  
Lisa Wright ◽  
...  
Keyword(s):  
Human Cancer ◽  
Tumor Formation ◽  
Skin Carcinogenesis ◽  
Differentiation Markers ◽  
Autocrine Loop ◽  
Oncogenic Ras ◽  
Cytokines And Chemokines ◽  
A Cell ◽  
Proinflammatory Gene ◽  
Myd88 Signaling

Constitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. In this study, we report that mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective wild-type (WT) controls. MyD88−/− or IL-1R−/− keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Although RAS-expressing MyD88−/− keratinocytes form only a few small tumors in orthotopic grafts, IL-1R–deficient RAS-expressing keratinocytes retain the ability to form tumors in orthotopic grafts. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1α, IL-1R, and MyD88 leading to phosphorylation of IκBα and NF-κB activation. Blocking IL-1α–mediated NF-κB activation in RAS-expressing WT keratinocytes reverses the differentiation defect and inhibits proinflammatory gene expression. Collectively, these results demonstrate that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes.

scholarly journals Signal Transduction Involving the Dmp1 Transcription Factor and its Alteration in Human Cancer

2008 ◽  
Vol 2 ◽  
pp. CMO.S548 ◽  
Author(s):  
Takayuki Sugiyama ◽  
Donna P. Frazier ◽  
Pankaj Taneja ◽  
Robert D. Kendig ◽  
Rachel L. Morgan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Human Cancer ◽  
Synergistic Effects ◽  
Tumor Formation ◽  
Binding Property ◽  
Lung Cancers ◽  
Myc Oncogene ◽  
Oncogenic Ras ◽  
Cycle Arrest ◽  
Dependent Cell

Summary Dmp1 (cyclin D-interacting myb-like protein 1; also called Dmtf1) is a transcription factor that has been isolated in a yeast two-hybrid screen through its binding property to cyclin D2. Dmp1 directly binds to and activates the Arf promoter and induces Arf-p53-dependent cell cycle arrest in primary cells. D-type cyclins usually inhibit Dmp1-mediated transcription in a Cdk-independent fashion; however, Dmp1 shows synergistic effects with D-cyclins on the Arf promoter. Ras or Myc oncogene-induced tumor formation is accelerated in both Dmp1+/- and Dmp1-/- mice with no significant differences between Dmp1+/- and Dmp1-/-. Thus, Dmp1 is haplo-insufficient for tumor suppression. Tumors from Dmp1-/- or Dmp1+/- mice often retain wild-type Arf and p53, suggesting that Dmp1 is a physiological regulator of the Arf-p53 pathway. The Dmp1 promoter is activated by oncogenic Ras-Raf signaling, while it is repressed by physiological mitogenic stimuli, overexpression of E2F proteins, and genotoxic stimuli mediated by NF-κB. The human DMP1 gene (h DMP1) is located on chromosome 7q21 and is hemizygously deleted in approximately 40% of human lung cancers, especially those that retain normal INK4a/ARF and P53 loci. Thus, h DMP1 is clearly involved in human carcinogenesis, and tumors with h DMP1 deletion may constitute a discrete disease entity.

scholarly journals MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 940
Author(s):  
Chi-Yu Lai ◽  
Kun-Yun Yeh ◽  
Chiu-Ya Lin ◽  
Yang-Wen Hsieh ◽  
Hsin-Hung Lai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Stellate Cell ◽  
Human Cancer ◽  
Tumor Formation ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Lipid Metabolism Disorder ◽  
Full Spectrum ◽  
Stat3 Signaling

MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)-inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR-21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibrosis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR-21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)-related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR-21 regulatory proteins (i.e., PTEN, SMAD7, p-AKT, p-SMAD3, and p-STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demonstrated that miR-21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of ptenb, pparaa, and activation of the PI3K/AKT pathway; second, miR-21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF-β/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, inflammation, fibrosis and activation of the PI3K/AKT, TGF-β/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR-21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.

scholarly journals Ultraviolet Radiation and Chronic Inflammation—Molecules and Mechanisms Involved in Skin Carcinogenesis: A Narrative Review

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 326
Author(s):  
Magdalena Ciążyńska ◽  
Irmina Olejniczak-Staruch ◽  
Dorota Sobolewska-Sztychny ◽  
Joanna Narbutt ◽  
Małgorzata Skibińska ◽  
...  
Keyword(s):  
Ultraviolet Radiation ◽  
Chronic Inflammation ◽  
Potential Role ◽  
Tumor Formation ◽  
Skin Carcinogenesis ◽  
Molecular Networks ◽  
Cancer Therapies ◽  
Inflammatory Microenvironment ◽  
Skin Cancers

The process of skin carcinogenesis is still not fully understood. Both experimental and epidemiological evidence indicate that chronic inflammation is one of the hallmarks of microenvironmental-agent-mediated skin cancers and contributes to its development. Maintaining an inflammatory microenvironment is a condition leading to tumor formation. Multiple studies focus on the molecular pathways activating tumorigenesis by inflammation and indicate several biomarkers and factors that can improve diagnostic and prognostic processes in oncology and dermatology. Reactive oxygen species produced by ultraviolet radiation, oxidizers, or metabolic processes can damage cells and initiate pro-inflammatory cascades. Considering the potential role of inflammation in cancer development and metastasis, the identification of early mechanisms involved in carcinogenesis is crucial for clinical practice and scientific research. Moreover, it could lead to the progress of advanced skin cancer therapies. We focus on a comprehensive analysis of available evidence and on understanding how chronic inflammation and ultraviolet radiation can result in skin carcinogenesis. We present the inflammatory environment as complex molecular networks triggering tumorigenesis and constituting therapeutic targets.

scholarly journals CRISPR enriches for cells with mutations in a p53-related interactome, and this can be inhibited

2021 ◽  
Author(s):  
Long Jiang ◽  
Katrine Ingelshed ◽  
Yunbing Shen ◽  
Sanjaykumar V. Boddul ◽  
Vaishnavi Srinivasan Iyer ◽  
...  
Keyword(s):  
Cellular Response ◽  
Human Cancer ◽  
Genetic Alterations ◽  
Dna Breaks ◽  
Data Set ◽  
Human Cancer Cell Lines ◽  
Cycle Arrest ◽  
Double Stranded Dna ◽  
A Cell

CRISPR/Cas9 can be used to inactivate or modify genes by inducing double-stranded DNA breaks1–3. As a protective cellular response, DNA breaks result in p53-mediated cell cycle arrest and activation of cell death programs4,5. Inactivating p53 mutations are the most commonly found genetic alterations in cancer, highlighting the important role of the gene6–8. Here, we show that cells deficient in p53, as well as in genes of a core CRISPR-p53 tumor suppressor interactome, are enriched in a cell population when CRISPR is applied. Such enrichment could pose a challenge for clinical CRISPR use. Importantly, we identify that transient p53 inhibition suppresses the enrichment of cells with these mutations. Furthermore, in a data set of >800 human cancer cell lines, we identify parameters influencing the enrichment of p53 mutated cells, including strong baseline CDKN1A expression as a predictor for an active CRISPR-p53 axis. Taken together, our data identify strategies enabling safe CRISPR use.

scholarly journals DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop

2019 ◽  
Vol 26 (1) ◽  
pp. 197-214 ◽  
Author(s):  
Veronica Vella ◽  
Maria Luisa Nicolosi ◽  
Patrizia Cantafio ◽  
Michele Massimino ◽  
Rosamaria Lappano ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Differentiation ◽  
Epithelial To Mesenchymal Transition ◽  
Human Thyroid ◽  
Autocrine Signaling ◽  
Differentiation Markers ◽  
Autocrine Loop ◽  
Mesenchymal Transition ◽  
Poorly Differentiated ◽  
Induced Changes

Patients with thyroid cancers refractory to radioiodine (RAI) treatment show a limited response to various therapeutic options and a low survival rate. The recent use of multikinase inhibitors has also met limited success. An alternative approach relies on drugs that induce cell differentiation, as the ensuing increased expression of the cotransporter for sodium and iodine (NIS) may partially restore sensitivity to radioiodine. The inhibition of the ERK1/2 pathway has shown some efficacy in this context. Aggressive thyroid tumors overexpress the isoform-A of the insulin receptor (IR-A) and its ligand IGF-2; this IGF-2/IR-A loop is associated with de-differentiation and stem-like phenotype, resembling RAI-refractory tumors. Importantly, IR-A has been shown to be positively modulated by the non-integrin collagen receptor DDR1 in human breast cancer. Using undifferentiated human thyroid cancer cells, we now evaluated the effects of DDR1 on IGF-2/IR-A loop and on markers of cell differentiation and stemness. DDR1 silencing or downregulation caused significant reduction of IR-A and IGF-2 expression, and concomitant increased levels of differentiation markers (NIS, Tg, TSH, TPO). Conversely, markers of epithelial-to-mesenchymal transition (Vimentin, Snail-2, Zeb1, Zeb2 and N-Cadherin) and stemness (OCT-4, SOX-2, ABCG2 and Nanog) decreased. These effects were collagen independent. In contrast, overexpression of either DDR1 or its kinase-inactive variant K618A DDR1-induced changes suggestive of less differentiated and stem-like phenotype. Collagen stimulation was uneffective. In conclusion, in poorly differentiated thyroid cancer, DDR1 silencing or downregulation blocks the IGF-2/IR-A autocrine loop and induces cellular differentiation. These results may open novel therapeutic approaches for thyroid cancer.

scholarly journals A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer

2019 ◽  
Vol 116 (13) ◽  
pp. 6435-6440 ◽  
Author(s):  
Natasha C. Lucki ◽  
Genaro R. Villa ◽  
Naja Vergani ◽  
Michael J. Bollong ◽  
Brittney A. Beyer ◽  
...  
Keyword(s):  
Small Molecule ◽  
Brain Cancer ◽  
Critical Role ◽  
Tumor Formation ◽  
Tumor Xenograft ◽  
Drug Candidate ◽  
Cell Type ◽  
Caspase 1 ◽  
A Cell

Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

scholarly journals PDTM-09. Yap1 FUNCTION IN SEX-BIASED MEDULLOBLASTOMA FORMATION AND ANTI-TUMOR IMMUNITY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi188-vi188
Author(s):  
Nourhan Abdelfattah ◽  
Sivaraman Natarajan ◽  
Yaohui Chen ◽  
Kin-Hoe Chow ◽  
Shu-hsia Chen ◽  
...  
Keyword(s):  
Cytotoxic T Cells ◽  
Therapeutic Benefit ◽  
Tumor Formation ◽  
Normal Brain ◽  
A Cell ◽  
Developing Mouse Brain ◽  
Pediatric Brain ◽  
Normal Brain Development ◽  
Extended Survival

Abstract Immunotherapies offer remarkable potential to provide robust therapeutic benefit. Patients suffering from medulloblastoma (MB), the most frequent pediatric brain malignancy, can especially benefit from this approach, minimizing the devastating side effects of aggressive radiation and chemotherapies that disrupt normal brain development. However, regulators of the immune landscape remain poorly understood and no effective immunotherapies exist yet for MB. Here, we describe a sex-dependent Yap1 function in fSmoM2;GFAPcre SHH-MB (SG) mouse model. We show that Yap1 is both a cell-autonomous regulator of MB stem-cells and a non-cell-autonomous regulator of immune infiltrates in SHH-MB. Yap1 deletion in SG mice results in increased neuronal differentiation, significantly extended survival, and enhanced infiltration of peripheral blood immune cells (including cytotoxic T-cells, neutrophils, and macrophages). Additionally, this rescue phenotype is observed in a sex-biased manner: 65% of Yap1f/f;fSmoM2;GFAPcre males are rescued in contrast to 35% of females. These observations implicate Yap1 as a mediator of sex-biased brain-tumor formation, either through direct modulation of MB cells and/or through indirectly mediating the MB immune landscape. We are currently testing the role of sex-specific differences in the developing mouse brain to elucidate context-dependent function of Yap1 in MB genesis and maintenance.

Oncogenic NRAS, KRAS, and HRAS Induce Distinct Hematological Diseases in Mice.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1444-1444
Author(s):  
Chaitali Parikh ◽  
Ramesh Subrahmanyam ◽  
Ruibao Ren
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Small Gtpases ◽  
Mouse Bone Marrow ◽  
Ras Proteins ◽  
Myeloid Malignancies ◽  
Oncogenic Ras ◽  
Ras Oncogenes

Abstract RAS family proteins (NRAS, HRAS and KRAS 4B/4A) are small GTPases that play a central role in transducing signals that regulate cell proliferation, survival and differentiation. The RAS proteins interact with a common set of activators and effectors and, therefore, share many biochemical and biological functions. However, the RAS proteins associate with different microdomains of the plasma membrane as well as other internal cell membranes and are capable of generating distinct signal outputs. Mutations that result in constitutive activation of RAS proteins are associated with approximately 30% of all human cancers, including 20–30% acute myeloid leukemia (AML) and 50–70% chronic myelomonocytic leukemia (CMML). Different RAS oncogenes are preferentially associated with different types of human cancer. In myeloid malignancies, NRAS mutations occur (in approximately 70% of cases), more frequently than KRAS mutations, while HRAS mutations are rare. The mechanism underlying the different frequencies of RAS isoforms mutated in myeloid leukemia is not known. One possibility is that oncogenic RAS proteins have different leukemogenic potentials. To test this possibility, we compared the ability of the three oncogenic RAS proteins to induce leukemias using the same animal model. We have shown previously that oncogenic NRAS rapidly and efficiently induces CMML- or AML-like disease in an improved mouse bone marrow transduction and transplantation model. We found here that in the same model system, oncogenic KRAS invariably induces a CMML-like disease that is similar to what has been shown in a mouse conditional knock in model for oncogenic KRAS. Surprisingly, all mice receiving oncogenic HRAS infected bone marrow cells develop an AML-like disease. The HRAS mice have the shortest disease latency, followed by NRAS and then KRAS. HRAS induced disease also appears to be more aggressive than N or KRAS and is usually accompanied by massive pulmonary infiltration and hemorrhages. These studies demonstrate that all three RAS oncogenes have the potential to induce myeloid leukemias, yet have distinct leukemogenic potentials. The underlying mechanism of the discrepancy between the frequency of HRAS mutation in human myeloid leukemia and its leukemogenic potential in mice is not clear, but the models established here provide a system for further studying the molecular mechanisms in the pathogenesis of myeloid malignancies and for testing targeted therapies.

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