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1.
Clin Transl Med ; 14(5): e1694, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38797942

RESUMO

BACKGROUND: BRAFV600E is the most common genetic mutation in differentiated thyroid cancer (DTC) occurring in 60% of patients and drives malignant tumour cell phenotypes including proliferation, metastasis and immune-escape. BRAFV600E-mutated papillary thyroid cancer (PTC) also displays greatly reduced expression of thyroid differentiation markers, thus tendency to radioactive iodine (RAI) refractory and poor prognosis. Therefore, understanding the molecular mechanisms and main oncogenic events underlying BRAFV600E will guide future therapy development. METHODS: Bioinformatics and clinical specimen analyses, genetic manipulation of BRAFV600E-induced PTC model, functional and mechanism exploration guided with transcriptomic screening, as well as systematic rescue experiments were applied to investigate miR-31 function within BRAFV600E-induced thyroid cancer development. Besides, nanoparticles carrying miR-31 antagomirs were testified to alleviate 131I iodide therapy on PTC models. RESULTS: We identify miR-31 as a significantly increased onco-miR in BRAFV600E-associated PTC that promotes tumour progression, metastasis and RAI refractoriness via sustained Wnt/ß-catenin signalling. Mechanistically, highly activated BRAF/MAPK pathway induces miR-31 expression via c-Jun-mediated transcriptional regulation across in vitro and transgenic mouse models. MiR-31 in turn facilitates ß-catenin stabilisation via directly repressing tumour suppressors CEBPA and DACH1, which direct the expression of multiple essential Wnt/ß-catenin pathway inhibitors. Genetic functional assays showed that thyroid-specific knockout of miR-31 inhibited BRAFV600E-induced PTC progression, and strikingly, enhanced expression of sodium-iodide symporter and other thyroid differentiation markers, thus promoted 131I uptake. Nanoparticle-mediated application of anti-miR-31 antagomirs markedly elevated radio-sensitivity of BRAFV600E-induced PTC tumours to 131I therapy, and efficiently suppressed tumour progression in the pre-clinical mouse model. CONCLUSIONS: Our findings elucidate a novel BRAF/MAPK-miR-31-Wnt/ß-catenin regulatory mechanism underlying clinically BRAFV600E-associated DTC tumourigenesis and dedifferentiation, also highlight a potential adjuvant therapeutic strategy for advanced DTC.


Assuntos
MicroRNAs , Proteínas Proto-Oncogênicas B-raf , Neoplasias da Glândula Tireoide , Animais , Humanos , Camundongos , Carcinogênese/genética , Desdiferenciação Celular/genética , Desdiferenciação Celular/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo
3.
Carcinogenesis ; 44(7): 549-561, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37466677

RESUMO

Immunotherapy is the only approved systemic therapy for advanced cutaneous squamous cell carcinoma (cSCC), however, roughly 50% of patients do not respond to the therapy and resistance often occurs over time to those who initially respond. Immunosuppression could have a critical role in developing treatment resistance, thus, understanding the mechanisms of how immunosuppression is developed and regulated may be the key to improving clinical diagnosis and treatment strategies for cSCC. Here, through using a series of immunocompetent genetically engineered mouse models, we demonstrate that miR-22 promotes cSCC development by establishing regulatory T cells (Tregs)-mediated immunosuppressive tumor microenvironment (TME) in a tumor cell autonomous manner. Mechanism investigation revealed that miR-22 elicits the constitutive activation of JAK/STAT3 signaling by directly targeting its suppressor SOCS3, which augments cancer cell-derived chemokine secretion and Tregs recruitment. Epithelial-specific and global knockouts of miR-22 repress papilloma and cSCC development and progression, manifested with reduced Tregs infiltration and elevated CD8+ T cell activation. Transcriptomic analysis and functional rescue study confirmed CCL17, CCL20 and CCL22 as the main affected chemokines that mediate the chemotaxis between miR-22 highly expressing keratinocyte tumor cells and Tregs. Conversely, overexpression of SOCS3 reversed miR-22-induced Tregs recruitment toward tumor cells. Clinically, gradually increasing Tregs infiltration during cSCC progression was negatively correlated with SOCS3 abundance, supported by previously documented elevated miR-22 levels. Thus, our study uncovers a novel miR-22-SOCS3-JAK/STAT3-chemokines regulatory mechanism in defining the immunosuppressive TME and highlights the promising clinical application value of miR-22 as a common targeting molecule against JAK/STAT3 signaling and immune escape in cSCC.

5.
Nat Commun ; 13(1): 1588, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35332119

RESUMO

MAPK signaling inhibitor (MAPKi) therapies show limited efficacy for advanced thyroid cancers despite constitutive activation of the signaling correlates with disease recurrence and persistence. Understanding how BRAF pathway stimulates tumorigenesis could lead to new therapeutic targets. Here, through genetic and pathological approaches, we demonstrate that BRAFV600E promotes thyroid cancer development by increasing myeloid-derived suppressor cells (MDSCs) penetrance. This BRAFV600E-induced immune suppression involves re-activation of the developmental factor TBX3, which in turn up-regulates CXCR2 ligands in a TLR2-NFκB dependent manner, leading to MDSCs recruitment into the tumor microenvironment. CXCR2 inhibition or MDSCs repression improves MAPKi therapy effect. Clinically, high TBX3 expression correlates with BRAFV600E mutation and increased CXCR2 ligands, along with abundant MDSCs infiltration. Thus, our study uncovers a BRAFV600E-TBX3-CXCLs-MDSCs axis that guides patient stratification and could be targeted to improve the efficacy of MAPKi therapy in advanced thyroid cancer patients.


Assuntos
Células Supressoras Mieloides , Neoplasias da Glândula Tireoide , Humanos , Ligantes , Mutação , Células Supressoras Mieloides/metabolismo , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/tratamento farmacológico , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Microambiente Tumoral/genética
7.
Oncogene ; 40(39): 5799-5813, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34345013

RESUMO

Emerging evidence suggests that the cancer stem cells (CSCs) are key culprits of cancer metastasis and drug resistance. Understanding mechanisms regulating the critical oncogenic pathways and CSCs function could reveal new diagnostic and therapeutic strategies. We now report that miR-22, a miRNA critical for hair follicle stem/progenitor cell differentiation, promotes tumor initiation, progression, and metastasis by maintaining Wnt/ß-catenin signaling and CSCs function. Mechanistically, we find that miR-22 facilitates ß-catenin stabilization through directly repressing citrullinase PAD2. Moreover, miR-22 also relieves DKK1-mediated repression of Wnt/ß-catenin signaling by targeting a FosB-DDK1 transcriptional axis. miR-22 knockout mice showed attenuated Wnt/ß-catenin activity and Lgr5+ CSCs penetrance, resulting in reduced occurrence, progression, and metastasis of chemically induced cutaneous squamous cell carcinoma (cSCC). Clinically, miR-22 is abundantly expressed in human cSCC. Its expression is even further elevated in the CSCs proportion, which negatively correlates with PAD2 and FosB expression. Inhibition of miR-22 markedly suppressed cSCC progression and increased chemotherapy sensitivity in vitro and in xenograft mice. Together, our results revealed a novel miR-22-WNT-CSCs regulatory mechanism in cSCC and highlight the important clinical application prospects of miR-22, a common target molecule for Wnt/ß-catenin signaling and CSCs, for patient stratification and therapeutic intervention.


Assuntos
Carcinoma de Células Escamosas , Animais , Humanos , Camundongos , Neoplasias Cutâneas , beta Catenina
8.
Oncogene ; 40(29): 4832-4845, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34155343

RESUMO

Metastasis is the main cause of death in breast cancer patients. The initial step of metastasis is invadopodia-mediated extracellular matrix (ECM) degradation, which enables local breast tumor cells to invade surrounding tissues. However, the molecular mechanism underlying invadopodia-mediated metastasis remains largely unknown. Here we found that the RNA-binding protein Musashi1 (Msi1) exhibited elevated expression in invasive breast tumors and promoted lung metastasis of mammary cancer cells. Suppression of Msi1 reduced invadopodia formation in mammary cancer cells. Furthermore, Msi1 deficiency decreased the expression and activity of Mmp9, an important enzyme in ECM degradation. Mechanistically, Msi1 directly suppressed Timp3, an endogenous inhibitor of Mmp9. In clinical breast cancer specimens, TIMP3 and MSI1 levels were significantly inversely correlated both in normal breast tissue and breast cancer tissues and associated with overall survival in breast cancer patients. Taken together, our findings demonstrate that the MSI1-TIMP3-MMP9 cascade is critical for invadopodia-mediated onset of metastasis in breast cancer, providing novel insights into a promising therapeutic strategy for breast cancer metastasis.


Assuntos
Neoplasias da Mama , Humanos , Podossomos , Inibidor Tecidual de Metaloproteinase-3
9.
Biomark Med ; 14(18): 1683-1692, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33346697

RESUMO

Background: The clinical value of antithyroglobulin antibodies (TgAb) as a tumor marker for differentiated thyroid cancer (DTC) is still controversial. Materials & methods: We studied 110 TgAb positive DTC patients who underwent total thyroidectomy and 131I therapies. Multivariate logistic regression was conducted to analyze the association between prognostic factors and disease outcomes. Results & conclusion: Pre-ablation TgAb levels and the changes of TgAb in 6-12 months after the first 131I therapy were risk factors for disease outcome in patients younger than 55, while extrathyroid extension was a risk factor in patients older than 55. The median TgAb half-life was 7.7 months and the median time for TgAb positivity to become negative was 15.8 months. The dynamics of TgAb within the first year after remnant ablation could predict disease outcome for DTC patients.


Assuntos
Soro Antilinfocitário/imunologia , Neoplasias da Glândula Tireoide/imunologia , Adulto , Anticorpos/imunologia , Autoanticorpos/imunologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia/métodos
11.
iScience ; 13: 173-189, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30849621

RESUMO

Epithelial morphogenesis is a common feature in various organs and contributes to functional formation. However, the molecular mechanisms behind epithelial morphogenesis remain largely unknown. Mammary gland is an excellent model system to investigate the molecular mechanisms of epithelial morphogenesis. In this study, we found that cysteine dioxygenase (CDO), a key enzyme in cysteine oxidative metabolism, was involved in mammary epithelial morphogenesis. CDO knockout (KO) females exhibited severe defects in mammary branching morphogenesis and ductal elongation, resulting in poor lactation. CDO contributes to the luminal epithelial cell differentiation, proliferation, and apoptosis mainly through its downstream product cysteine sulfinic acid (CSA). Exogenous supplementation of CSA not only rescued the defects in CDO KO mouse but also enhanced ductal growth in wild-type mouse. It suggests that CDO regulates luminal epithelial differentiation and regeneration via CSA and consequently contributes to mammary development, which raises important implications for epithelial morphogenesis and pathogenesis of breast cancer.

12.
J Invest Dermatol ; 138(10): 2253-2263, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29605672

RESUMO

Wound healing is essential for skin repair after injury, and it consists of hemostasis, inflammation, re-epithelialization, and remodeling phases. Successful re-epithelialization, which relies on proliferation and migration of epidermal keratinocytes, requires a reduction in tissue inflammation. Therefore, understanding the molecular mechanism underlying the transition from inflammation to re-epithelialization will help to better understand the principles of wound healing. Currently, the in vivo functions of specific microRNAs in wound healing are not fully understood. We observed that miR-31 expression is strongly induced in wound edge keratinocytes, and is directly regulated by the activity of NF-κB and signal transducer and activator of transcription 3 signaling pathways during the inflammation phase. We used miR-31 loss-of-function mouse models to demonstrate that miR-31 promotes keratinocyte proliferation and migration. Mechanistically, miR-31 activates the Ras/mitogen-activated protein kinase signaling by directly targeting Rasa1, Spred1, Spred2, and Spry4, which are negative regulators of the Ras/mitogen-activated protein kinase pathway. Knockdown of these miR-31 targets at least partially rescues the delayed scratch wound re-epithelialization phenotype observed in vitro in miR-31 knockdown keratinocytes. Taken together, these findings identify miR-31 as an important cell-autonomous mediator during the transition from inflammation to re-epithelialization phases of wound healing, suggesting a therapeutic potential for miR-31 in skin injury repair.


Assuntos
Queratinócitos/metabolismo , MicroRNAs/genética , Reepitelização/fisiologia , Cicatrização/genética , Ferimentos e Lesões/patologia , Animais , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Hibridização In Situ , Queratinócitos/patologia , Camundongos , Camundongos Knockout , MicroRNAs/metabolismo , Transdução de Sinais , Ferimentos e Lesões/genética , Ferimentos e Lesões/metabolismo
13.
Oncogene ; 37(21): 2773-2792, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29511350

RESUMO

The T-box transcription factor TBX3 has been implicated in the patterning and differentiation of a number of tissues during embryonic development, and is overexpressed in a variety of cancers; however, the precise function of TBX3 in papillary thyroid carcinoma (PTC) development remains to be determined. In the current study, we report downregulation of TBX3 in PTC cells delays the G1/S-phase transition, decreases cell growth in vitro, and inhibits tumor formation in vivo. We identified p57KIP2 as a novel downstream target that serves as the key mediator of TBX3's control over PTC cell proliferation. Reduced expression of TBX3 resulted in increased p57KIP2 level, while knockdown of p57KIP2 rescues the cell-cycle arrest phenotype. In clinical PTC specimens, the expression of TBX3 is markedly upregulated and significantly correlated with advanced tumor grade, but negatively correlated with the expression of p57KIP2. Mechanism investigation revealed that TBX3 directly binds to the CDKN1C gene promoter region, the coding gene of p57KIP2, and represses its transcription. Furthermore, recruitment of main components of the PRC2 complex as well as class I histone deacetylases, HDAC1 and HDAC2, is required for TBX3 to fulfill the transcriptional repression function. Our findings illustrate the previously unknown function and mechanism in cell proliferation regulation by the TBX3-p57KIP2 axis and provide evidence for the contribution of the PRC2 complex and HDAC1/2. Targeting of this pathway may present a novel and molecular defined strategy against PTC development.


Assuntos
Inibidor de Quinase Dependente de Ciclina p57/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas com Domínio T/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima , Animais , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/metabolismo , Humanos , Masculino , Camundongos , Estadiamento de Neoplasias , Transplante de Neoplasias , Regiões Promotoras Genéticas , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo
14.
Nat Commun ; 8(1): 1036, 2017 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-29051494

RESUMO

MicroRNA-mediated post-transcriptional regulation plays key roles in stem cell self-renewal and tumorigenesis. However, the in vivo functions of specific microRNAs in controlling mammary stem cell (MaSC) activity and breast cancer formation remain poorly understood. Here we show that miR-31 is highly expressed in MaSC-enriched mammary basal cell population and in mammary tumors, and is regulated by NF-κB signaling. We demonstrate that miR-31 promotes mammary epithelial proliferation and MaSC expansion at the expense of differentiation in vivo. Loss of miR-31 compromises mammary tumor growth, reduces the number of cancer stem cells, as well as decreases tumor-initiating ability and metastasis to the lung, supporting its pro-oncogenic function. MiR-31 modulates multiple signaling pathways, including Prlr/Stat5, TGFß and Wnt/ß-catenin. Particularly, it activates Wnt/ß-catenin signaling by directly targeting Wnt antagonists, including Dkk1. Importantly, Dkk1 overexpression partially rescues miR31-induced mammary defects. Together, these findings identify miR-31 as the key regulator of MaSC activity and breast tumorigenesis.


Assuntos
Neoplasias da Mama/metabolismo , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/citologia , Células-Tronco/metabolismo , Proteínas Wnt/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células , Autorrenovação Celular , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Glândulas Mamárias Humanas/citologia , Glândulas Mamárias Humanas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco/citologia , Proteínas Wnt/genética , Via de Sinalização Wnt , beta Catenina/metabolismo
15.
PLoS Genet ; 11(5): e1005253, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26020521

RESUMO

Hair follicles (HF) undergo precisely regulated recurrent cycles of growth, cessation, and rest. The transitions from anagen (growth), to catagen (regression), to telogen (rest) involve a physiological involution of the HF. This process is likely coordinated by a variety of mechanisms including apoptosis and loss of growth factor signaling. However, the precise molecular mechanisms underlying follicle involution after hair keratinocyte differentiation and hair shaft assembly remain poorly understood. Here we demonstrate that a highly conserved microRNA, miR-22 is markedly upregulated during catagen and peaks in telogen. Using gain- and loss-of-function approaches in vivo, we find that miR-22 overexpression leads to hair loss by promoting anagen-to-catagen transition of the HF, and that deletion of miR-22 delays entry to catagen and accelerates the transition from telogen to anagen. Ectopic activation of miR-22 results in hair loss due to the repression a hair keratinocyte differentiation program and keratinocyte progenitor expansion, as well as promotion of apoptosis. At the molecular level, we demonstrate that miR-22 directly represses numerous transcription factors upstream of phenotypic keratin genes, including Dlx3, Foxn1, and Hoxc13. We conclude that miR-22 is a critical post-transcriptional regulator of the hair cycle and may represent a novel target for therapeutic modulation of hair growth.


Assuntos
Diferenciação Celular/genética , Folículo Piloso/metabolismo , Queratinócitos/metabolismo , MicroRNAs/biossíntese , Alopecia/genética , Apoptose/genética , Proliferação de Células/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Folículo Piloso/crescimento & desenvolvimento , Humanos , Queratinas/biossíntese , Queratinas/genética , MicroRNAs/genética , Transdução de Sinais/genética , Células-Tronco/metabolismo , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
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