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1.
Biomedicines ; 9(6)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073463

RESUMO

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients' selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets.

2.
Sci Adv ; 7(19)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33962944

RESUMO

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210-based therapeutic and diagnostic strategies.

3.
Cancer Lett ; 510: 13-23, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-33862151

RESUMO

An interactive crosstalk between tumor and stroma cells is essential for metastatic melanoma progression. We evidenced that ESDN/DCBLD2/CLCP1 plays a crucial role in endothelial cells during the spread of melanoma. Precisely, increased extravasation and metastasis formation were revealed in ESDN-null mice injected with melanoma cells, even if the primary tumor growth, vessel permeability, and angiogenesis were not enhanced. Interestingly, improved adhesion of melanoma cells to ESDN-depleted endothelial cells was observed, due to the presence of higher levels of E-selectin transcripts/proteins in ESDN-defective cells. In accordance with these results, anticorrelation was observed between ESDN and E-selectin in human endothelial cells. Most importantly, our data revealed that cimetidine, an E-selectin inhibitor, was able to block cell adhesion, extravasation, and metastasis formation in ESDN-null mice, underlying a major role of ESDN in E-selectin transcription upregulation, which according to our data, may presumably be linked to STAT3. Based on our results, we propose a protective role for ESDN during the spread of melanoma and reveal its therapeutic potential.

4.
Cancers (Basel) ; 13(1)2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33401522

RESUMO

The metabolism of cancer cells is generally very different from what is found in normal counterparts. However, in a tumor mass, the continuous crosstalk and competition for nutrients and oxygen among different cells lead to metabolic alterations, not only in cancer cells, but also in the different stromal and immune cells of the tumor microenvironment (TME), which are highly relevant for tumor progression. MicroRNAs (miRs) are small non-coding RNAs that silence their mRNA targets post-transcriptionally and are involved in numerous physiological cell functions as well as in the adaptation to stress situations. Importantly, miRs can also be released via extracellular vesicles (EVs) and, consequently, take part in the bidirectional communication between tumor and surrounding cells under stress conditions. Certain miRs are abundantly expressed in stromal and immune cells where they can regulate various metabolic pathways by directly suppressing enzymes or transporters as well as by controlling important regulators (such as transcription factors) of metabolic processes. In this review, we discuss how miRs can induce metabolic reprogramming in stromal (fibroblasts and adipocytes) and immune (macrophages and T cells) cells and, in turn, how the biology of the different cells present in the TME is able to change. Finally, we debate the rebound of miR-dependent metabolic alterations on tumor progression and their implications for cancer management.

5.
Cell Mol Life Sci ; 78(4): 1355-1367, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33079227

RESUMO

The p140Cap adaptor protein is a scaffold molecule encoded by the SRCIN1 gene, which is physiologically expressed in several epithelial tissues and in the neurons. However, p140Cap is also strongly expressed in a significant subset of cancers including breast cancer and neuroblastoma. Notably, cancer patients with high p140Cap expression in their primary tumors have a lower probability of developing a distant event and ERBB2-positive breast cancer sufferers show better survival. In neuroblastoma patients, SRCIN1 mRNA levels represent an independent risk factor, which is inversely correlated to disease aggressiveness. Consistent with clinical data, SRCIN1 gain or loss of function mouse models demonstrated that p140Cap may affect tumor growth and metastasis formation by controlling the signaling pathways involved in tumorigenesis and metastatic features. This study reviews data showing the relevance of SRCIN1/p140Cap in cancer patients, the impact of SRCIN1 status on p140Cap expression, the specific mechanisms through which p140Cap can limit cancer progression, the molecular functions regulated by p140Cap, along with the p140Cap interactome, to unveil its key role for patient stratification in clinics.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Neoplasias da Mama/genética , Carcinogênese/genética , Neuroblastoma/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Metástase Neoplásica , Neuroblastoma/patologia , Receptor ErbB-2/genética , Transdução de Sinais/genética
6.
Int J Biol Sci ; 16(7): 1238-1251, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32174798

RESUMO

microRNAs (miRNAs) are small non-coding RNAs acting as negative regulators of gene expression and involved in tumor progression. We recently showed that inhibition of the pro-metastatic miR-214 and simultaneous overexpression of its downstream player, the anti-metastatic miR-148b, strongly reduced metastasis formation. To explore the therapeutic potential of miR-148b, we generated a conjugated molecule aimed to target miR-148b expression selectively to tumor cells. Precisely, we linked miR-148b to GL21.T, an aptamer able to specifically bind to AXL, an oncogenic tyrosine kinase receptor highly expressed on cancer cells. Axl-148b conjugate was able to inhibit migration and invasion of AXL-positive, but not AXL-negative, cancer cells, demonstrating high efficacy and selectivity in vitro. In parallel, expression of ALCAM and ITGA5, two miR-148b direct targets, was reduced. More importantly, axl-148b chimeric aptamers were able to inhibit formation and growth of 3D-mammospheres, to induce necrosis and apoptosis of treated xenotransplants, as well as to block breast cancer and melanoma dissemination and metastatization in mice. Relevantly, axl aptamer acted as specific delivery tool for miR-148b, but it also actively contributed to inhibit metastasis formation, together with miR-148b. In conclusion, our data show that axl-148b conjugate is able to inhibit tumor progression in an axl- and miR-148b-dependent manner, suggesting its potential development as therapeutic molecule.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/metabolismo , Melanoma/fisiopatologia , MicroRNAs/metabolismo , Células Neoplásicas Circulantes , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/fisiologia
7.
PLoS One ; 15(2): e0228062, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32012171

RESUMO

Melatonin, a hormone secreted by pineal gland, exerts antimetastatic effects by reducing tumor cell proliferation, migration and invasion. MicroRNAs (miRNAs) are small, non-coding RNAs that play a crucial role in regulation of gene expression and biological processes of the cells. Herein, we search for a link between the tumor/metastatic-suppressive actions of melatonin and miRNA expression in triple-negative breast cancer cells. We demonstrated that melatonin exerts its anti-tumor actions by reducing proliferation, migration and c-Myc expression of triple negative breast cancer cells. By using Taqman-based assays, we analyzed the expression levels of a set of miRNAs following melatonin treatment of triple negative breast cancer cells and we identified 17 differentially expressed miRNAs, 6 down-regulated and 11 up-regulated. We focused on the anti-metastatic miR-148b and the oncogenic miR-210 both up-regulated by melatonin treatment and studied the effect of their modulation on melatonin-mediated impairment of tumor progression. Surprisingly, when miR-148b or miR-210 were depleted in triple-negative breast cancer cells, using a specific miR-148b sponge or anti-miR-210, melatonin effects on migration inhibition and c-myc downregulation were still visible suggesting that the increase of miR-148b and miR-210 expression observed following melatonin treatment was not required for the efficacy of melatonin action. Nevertheless, ours results suggest that melatonin exhibit a compound for metastatic trait inhibition, especially in MDA-MB-231 breast cancer cells even if a direct link between modulation of expression of certain proteins or miRNAs and melatonin effects has still to be established.


Assuntos
Melatonina/farmacologia , MicroRNAs/genética , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-myc/metabolismo
8.
Semin Cancer Biol ; 60: 214-224, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31386907

RESUMO

Cancer is a multistep disease based on crucial interactions between tumor cells and the microenvironment (extracellular matrix and stroma/immune cells). In fact, during dissemination, tumor cells have to escape from the primary tumor mass, cross the basal membrane, interact with endothelial cells to enter blood vessels (intravasation), survive in the bloodstream, get in contact with endothelial cells again to exit the bloodstream (extravasation) and seed in distant organs. Interactions between tumor and stroma cells are strongly coordinated by microRNAs (miRNAs), small non-coding RNAs able to silence protein coding genes by binding to specific recognition sites, mostly located at the 3' UTR of mature mRNAs. Relevantly, miRNA expression is often altered (overexpression or downregulation) in tumor cells and influenced by stroma cells. At the same time, miRNAs are abundant and essential in stroma cells during tumor cell dissemination and their expression is influenced by tumor cells. In fact, for instance, conditional ablation of Dicer in the endothelium of tumor bearing-mice leads to reduced tumor growth and microvessel density. In this review, we specifically focus on the role of miRNAs in endothelial cells regarding their positive or negative intervention on tumor angiogenesis or lymphoangiogenesis or when tumor cells detach from the tumor mass and intravasate or extravasate in/out of the blood vessels. Examples of pro-angiogenic miRNAs are miR-9 or miR-494, often overexpressed in tumors, which accumulate in tumor cell microvescicles and, therefore, get transferred to endothelial cells where they induce migration and angiogenesis. Differently, miR-200 and miR-128 are often downregulated in tumors and inhibit angiogenesis and lymphoangiogenesis. Instead, miR-126 controls intravasation while miR-146a, miR-214, miR-148b govern extravasation, in a positive or negative manner. Finally, at the end, we summarize opportunities for therapeutic interventions based on miRNAs acting on endothelial cells.


Assuntos
Comunicação Celular/genética , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/etiologia , Neoplasias/metabolismo , Microambiente Tumoral/genética , Animais , Comunicação Celular/imunologia , Progressão da Doença , Humanos , Estadiamento de Neoplasias , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Microambiente Tumoral/imunologia
9.
Epigenomics ; 11(14): 1581-1599, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31693439

RESUMO

Aim: Growing evidence shows a strong interplay between post-transcriptional regulation, mediated by miRNAs (miRs) and epigenetic regulation. Nevertheless, the number of experimentally validated miRs (called epi-miRs) involved in these regulatory circuitries is still very small. Material & methods: We propose a pipeline to prioritize candidate epi-miRs and to identify potential epigenetic interactors of any given miR starting from miR transfection experiment datasets. Results & conclusion: We identified 34 candidate epi-miRs: 19 of them are known epi-miRs, while 15 are new. Moreover, using an in-house generated gene expression dataset, we experimentally proved that a component of the polycomb-repressive complex 2, the histone methyltransferase enhancer of zeste homolog 2 (EZH2), interacts with miR-214, a well-known prometastatic miR in melanoma and breast cancer, highlighting a miR-214-EZH2 regulatory axis potentially relevant in tumor progression.


Assuntos
Epigênese Genética/genética , MicroRNAs/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Melanoma/genética , Complexo Repressor Polycomb 2/genética , Transfecção/métodos
11.
Oncogene ; 38(19): 3756-3762, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30664692

RESUMO

Attenuated Listeria monocytogenes (Lmat-LLO) represents a valuable anticancer vaccine and drug delivery platform. Here we show that in vitro Lmat-LLO causes ROS production and, in turn, apoptotic killing of a wide variety of melanoma cells, irrespectively of their stage, mutational status, sensitivity to BRAF inhibitors or degree of stemness. We also show that, when administered in the therapeutic setting to Braf/Pten genetically engineered mice, Lmat-LLO causes a strong decrease in the size and volume of primary melanoma tumors, as well as a reduction of the metastatic burden. At the molecular level, we confirm that the anti-melanoma activity exerted in vivo by Lmat-LLO depends also on its ability to potentiate the immune response of the organism against the infected tumor. Our data pave the way to the preclinical testing of listeria-based immunotherapeutic strategies against metastatic melanoma, using a genetically engineered mouse rather than xenograft models.


Assuntos
Vacinas Anticâncer/farmacologia , Listeria monocytogenes/imunologia , Melanoma Experimental/tratamento farmacológico , Animais , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos Transgênicos , Vacinas Atenuadas/farmacologia
12.
EMBO Rep ; 20(2)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30591524

RESUMO

Telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) constitute the core telomerase enzyme that maintains the length of telomeres. Telomere maintenance is affected in a broad range of cancer and degenerative disorders. Taking advantage of gain- and loss-of-function approaches, we show that Argonaute 2 (AGO2) promotes telomerase activity and stimulates the association between TERT and TERC AGO2 depletion results in shorter telomeres as well as in lower proliferation rates in vitro and in vivo We also demonstrate that AGO2 interacts with TERC and with a newly identified sRNA (terc-sRNA), arising from the H/ACA box of TERC Notably, terc-sRNA is sufficient to enhance telomerase activity when overexpressed. Analyses of sRNA-Seq datasets show that terc-sRNA is detected in primary human tissues and increases in tumors as compared to control tissues. Collectively, these data uncover a new layer of complexity in the regulation of telomerase activity by AGO2 and might lay the foundation for new therapeutic targets in tumors and telomere diseases.


Assuntos
Proteínas Argonauta/metabolismo , RNA/genética , RNA/metabolismo , Telomerase/metabolismo , Animais , Proteínas Argonauta/genética , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Ativação Enzimática , Expressão Gênica , Loci Gênicos , Xenoenxertos , Humanos , Camundongos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Conformação de Ácido Nucleico , Ligação Proteica , RNA/química , Telomerase/química , Telomerase/genética
13.
Mol Ther ; 26(8): 2008-2018, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29929788

RESUMO

We previously demonstrated that miR-214 is upregulated in malignant melanomas and triple-negative breast tumors and promotes metastatic dissemination by affecting a complex pathway including the anti-metastatic miR-148b. Importantly, tumor dissemination could be reduced by blocking miR-214 function or increasing miR-148b expression or by simultaneous interventions. Based on this evidence, with the intent to explore the role of miR-214 as a target for therapy, we evaluated the capability of new chemically modified anti-miR-214, R97/R98, to inhibit miR-214 coordinated metastatic traits. Relevantly, when melanoma or breast cancer cells were transfected with R97/R98, anti-miR-214 reduced miR-214 expression and impaired transendothelial migration were observed. Noteworthy, when the same cells were injected in the tail vein of mice, cell extravasation and metastatic nodule formation in lungs were strongly reduced. Thus, suggesting that R97/R98 anti-miR-214 oligonucleotides were able to inhibit tumor cell escaping through the endothelium. More importantly, when R97/R98 anti-miR-214 compounds were systemically delivered to mice carrying melanomas or breast or neuroendocrine pancreatic cancers, a reduced number of circulating tumor cells and lung or lymph node metastasis formation were detected. Similar results were also obtained when AAV8-miR-214 sponges were used in neuroendocrine pancreatic tumors. Based on this evidence, we propose miR-214 as a promising target for anti-metastatic therapies.


Assuntos
Antagomirs/administração & dosagem , MicroRNAs/genética , Neoplasias/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Animais , Antagomirs/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Camundongos , MicroRNAs/antagonistas & inibidores , Metástase Neoplásica/tratamento farmacológico , Neoplasias/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cell Death Differ ; 25(7): 1224-1238, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29568059

RESUMO

The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.


Assuntos
MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Microambiente Tumoral , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Células HCT116 , Células HeLa , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , MicroRNAs/genética , Proteínas de Neoplasias/genética , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Neoplásico/genética , Peixe-Zebra , Proteínas Ativadoras de ras GTPase/genética
15.
Oncogene ; 37(9): 1175-1191, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29238040

RESUMO

The proangiogenic cytokine Interleukin-3 (IL-3) is released by inflammatory cells in breast and ovarian cancer tissue microenvironments and also acts as an autocrine factor for human breast and kidney tumor-derived endothelial cells (TECs). We have previously shown that IL-3-treated endothelial cells (ECs) release extracellular vesicles (EVs), which serve as a paracrine mechanism for neighboring ECs, by transferring active molecules. The impact of an anti-IL-3R-alpha blocking antibody on the proangiogenic effect of EVs released from TECs (anti-IL-3R-EVs) has therefore been investigated in this study. We have found that anti-IL-3R-EV treatment prevented neovessel formation and, more importantly, also induced the regression of in vivo TEC-derived neovessels. Two miRs that target the canonical wingless (Wnt)/ß-catenin pathway, at different levels, were found to be differentially regulated when comparing the miR-cargo of naive TEC-derived EVs (EVs) and anti-IL-3R-EVs. miR-214-3p, which directly targets ß-catenin, was found to be upregulated, whereas miR-24-3p, which targets adenomatous polyposis coli (APC) and glycogen synthase kinase-3ß (GSK3ß), was found to be downregulated. In fact, upon their transfer into the cell, low ß-catenin content and high levels of the two members of the "ß-catenin destruction complex" were detected. Moreover, c-myc downregulation was found in TECs treated with anti-IL-3R-EVs, pre-miR-214-3p-EVs and antago-miR-24-3p-EVs, which is consistent with network analyses of miR-214-3p and miR-24-3p gene targeting. Finally, in vivo studies have demonstrated the impaired growth of vessels in pre-miR-214-3p-EV- and antago-miR-24-3p-EV-treated animals. These effects became much more evident when combo treatment was applied. The results of the present study identify the canonical Wnt/ß-catenin pathway as a relevant mechanism of TEC-derived EV proangiogenic action. Furthermore, we herein provide evidence that IL-3R blockade may yield some significant advantages, than miR targeting, in inhibiting the proangiogenic effects of naive TEC-derived EVs by changing TEC-EV-miR cargo.


Assuntos
Anticorpos Monoclonais/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Células Endoteliais/patologia , Vesículas Extracelulares/patologia , Subunidade alfa de Receptor de Interleucina-3/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-3/genética , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Camundongos , Camundongos SCID , MicroRNAs/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética , beta Catenina/metabolismo
16.
Oncotarget ; 8(41): 69204-69218, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-29050198

RESUMO

BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated. MerTK overexpression was demonstrated not only in melanomas resistant to BRAFi monotherapy (5 out of 10 samples from melanoma patients) but also in melanoma resistant to BRAFi+MEKi (1 out of 3), although MEKi alone does not affect MerTK. Mechanistically, BRAFi-induced activation of Zeb2 stimulates MerTK in BRAFV600 melanoma through mTORC1-triggered activation of autophagy. Co-targeting MerTK and BRAFV600 significantly reduced tumour burden in xenografted mice, which was pheno-copied by co-inhibition of autophagy and mutant BRAFV600.

17.
Sci Rep ; 7(1): 1145, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28442738

RESUMO

ErbB2 overexpression is detected in approximately 20% of breast cancers and is correlated with poor survival. It was previously shown that the adaptor protein p130Cas/BCAR1 is a crucial mediator of ErbB2 transformation and that its overexpression confers invasive properties to ErbB2-positive human mammary epithelial cells. We herein prove, for the first time, that the transcriptional repressor Blimp1 is a novel mediator of p130Cas/ErbB2-mediated invasiveness. Indeed, high Blimp1 expression levels are detected in invasive p130Cas/ErbB2 cells and correlate with metastatic status in human breast cancer patients. The present study, by using 2D and 3D breast cancer models, shows that the increased Blimp1 expression depends on both MAPK activation and miR-23b downmodulation. Moreover, we demonstrate that Blimp1 triggers cell invasion and metastasis formation via its effects on focal adhesion and survival signaling. These findings unravel the previously unidentified role that transcriptional repressor Blimp1 plays in the control of breast cancer invasiveness.


Assuntos
Neoplasias da Mama/patologia , Proteína Substrato Associada a Crk/metabolismo , Regulação da Expressão Gênica , Invasividade Neoplásica , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Receptor ErbB-2/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Camundongos
18.
Oncotarget ; 8(9): 15894-15911, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28199980

RESUMO

PD-L1 is expressed by a subset of patients with metastatic melanoma (MM) with an unfavorable outcome. Its expression is increased in cells resistant to BRAF or MEK inhibitors (BRAFi or MEKi). However, the function and regulation of expression of PD-L1 remain incompletely understood.After generating BRAFi- and MEKi-resistant cell lines, we observed marked up-regulation of PD-L1 expression. These cells were characterized by a common gene expression profile with up-regulation of genes involved in cell movement. Consistently, in vitro they showed significantly increased invasive properties. This phenotype was controlled in part by PD-L1, as determined after silencing the molecule. Up-regulation of PD-L1 was due to post-transcriptional events controlled by miR-17-5p, which showed an inverse correlation with PD-L1 mRNA. Direct binding between miR-17-5p and the 3'-UTR of PD-L1 mRNA was demonstrated using luciferase reporter assays.In a cohort of 80 BRAF-mutated MM patients treated with BRAFi or MEKi, constitutive expression of PD-L1 in the absence of immune infiltrate, defined the patient subset with the worst prognosis. Furthermore, PD-L1 expression increased in tissue biopsies after the metastatic lesions became resistant to BRAFi or MEKi. Lastly, plasmatic miR-17-5p levels were higher in patients with PD-L1+ than PD-L1- lesions.In conclusion, our findings indicate that PD-L1 expression induces a more aggressive behavior in melanoma cells. We also show that PD-L1 up-regulation in BRAFi or MEKi-resistant cells is partly due to post-transcriptional mechanisms that involve miR-17-5p, suggesting that miR-17-5p may be used as a marker of PD-L1 expression by metastatic lesions and ultimately a predictor of responses to BRAFi or MEKi.


Assuntos
Antígeno B7-H1/genética , Expressão Gênica/genética , MicroRNAs/genética , Progressão da Doença , Feminino , Humanos , Melanoma/genética , Transfecção , Regulação para Cima
19.
Oncotarget ; 8(6): 10007-10024, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-28052020

RESUMO

Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific RNA binding protein that controls several key cellular processes, like alternative splicing and translation. Previous studies have demonstrated a tumor suppressor role for this protein. Recently, however, a pro-metastatic function of ESRP1 has been reported. We thus aimed at clarifying the role of ESRP1 in Colorectal Cancer (CRC) by performing loss- and gain-of-function studies, and evaluating tumorigenesis and malignancy with in vitro and in vivo approaches. We found that ESRP1 plays a role in anchorage-independent growth of CRC cells. ESRP1-overexpressing cells grown in suspension showed enhanced fibroblast growth factor receptor (FGFR1/2) signalling, Akt activation, and Snail upregulation. Moreover, ESRP1 promoted the ability of CRC cells to generate macrometastases in mice livers. High ESRP1 expression may thus stimulate growth of cancer epithelial cells and promote colorectal cancer progression. Our findings provide mechanistic insights into a previously unreported, pro-oncogenic role for ESRP1 in CRC, and suggest that fine-tuning the level of this RNA-binding protein could be relevant in modulating tumor growth in a subset of CRC patients.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Células CACO-2 , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Camundongos Endogâmicos NOD , Camundongos SCID , Micrometástase de Neoplasia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Proteínas de Ligação a RNA/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Tempo , Transfecção , Carga Tumoral
20.
EMBO Mol Med ; 9(2): 219-237, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27974353

RESUMO

The development of resistance remains a major obstacle to long-term disease control in cancer patients treated with targeted therapies. In BRAF-mutant mouse models, we demonstrate that although targeted inhibition of either BRAF or VEGF initially suppresses the growth of BRAF-mutant tumors, combined inhibition of both pathways results in apoptosis, long-lasting tumor responses, reduction in lung colonization, and delayed onset of acquired resistance to the BRAF inhibitor PLX4720. As well as inducing tumor vascular normalization and ameliorating hypoxia, this approach induces remodeling of the extracellular matrix, infiltration of macrophages with an M1-like phenotype, and reduction in cancer-associated fibroblasts. At the molecular level, this therapeutic regimen results in a de novo transcriptional signature, which sustains and explains the observed efficacy with regard to cancer progression. Collectively, our findings offer new biological rationales for the management of clinical resistance to BRAF inhibitors based on the combination between BRAFV600E inhibitors with anti-angiogenic regimens.


Assuntos
Antineoplásicos/administração & dosagem , Indóis/administração & dosagem , Proteínas Mutantes/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Sulfonamidas/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
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