RESUMO
Studies have identified genes and molecular pathways regulating cancer metastasis. However, it remains largely unknown whether metastatic potentials of cancer cells from different lineage types are driven by the same or different gene networks. Here, we aim to address this question through integrative analyses of 493 human cancer cells' transcriptomic profiles and their metastatic potentials in vivo. Using an unsupervised approach and considering both gene coexpression and protein-protein interaction networks, we identify different gene networks associated with various biological pathways (i.e. inflammation, cell cycle, and RNA translation), the expression of which are correlated with metastatic potentials across subsets of lineage types. By developing a regularized random forest regression model, we show that the combination of the gene module features expressed in the native cancer cells can predict their metastatic potentials with an overall Pearson correlation coefficient of 0.90. By analyzing transcriptomic profile data from cancer patients, we show that these networks are conserved in vivo and contribute to cancer aggressiveness. The intrinsic expression levels of these networks are correlated with drug sensitivity. Altogether, our study provides novel comparative insights into cancer cells' intrinsic gene networks mediating metastatic potentials across different lineage types, and our results can potentially be useful for designing personalized treatments for metastatic cancers.
Assuntos
Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Metástase Neoplásica , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Mapas de Interação de Proteínas/genética , Transcriptoma , Perfilação da Expressão Gênica , Linhagem da Célula/genéticaRESUMO
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer stimulator of interferon genes (STING) pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single-cell RNA-seq, we show that ENPP1 in both cancer and normal tissues drives primary breast tumor growth and metastasis by dampening extracellular 2'3'-cyclic-GMP-AMP (cGAMP)-STING-mediated antitumoral immunity. ENPP1 loss-of-function in both cancer cells and normal tissues slowed primary tumor growth and abolished metastasis. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied ENPP1 knockout in a STING-dependent manner, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Finally, ENPP1 expression in breast tumors deterministically predicated whether patients would remain free of distant metastasis after pembrolizumab (anti-PD-1) treatment followed by surgery. Altogether, ENPP1 blockade represents a strategy to exploit cancer-produced extracellular cGAMP for controlled local activation of STING and is therefore a promising therapeutic approach against breast cancer.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Imunidade Inata , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismoRESUMO
Metastasis is a major cause of cancer therapy failure and mortality. However, targeting metastatic seeding and colonization remains a significant challenge. In this study, we identified NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, as being overexpressed in metastatic tumors. Our findings suggest that NSD2 overexpression enhances tumor metastasis both in vitro and in vivo. Further analysis revealed that NSD2 promotes tumor metastasis by activating Rac1 signaling. Mechanistically, NSD2 combines with and activates Tiam1 (T lymphoma invasion and metastasis 1) and promotes Rac1 signaling by methylating Tiam1 at K724. In vivo and in vitro studies revealed that Tiam1 K724 methylation could be a predictive factor for cancer prognosis and a potential target for metastasis inhibition. Furthermore, we have developed inhibitory peptide which was proved to inhibit tumor metastasis through blocking the interaction between NSD2 and Tiam1. Our results demonstrate that NSD2-methylated Tiam1 promotes Rac1 signaling and cancer metastasis. These results provide insights into the inhibition of tumor metastasis.
Assuntos
Neoplasias do Colo , Fatores de Troca do Nucleotídeo Guanina , Humanos , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Transdução de Sinais/fisiologia , Invasividade Neoplásica/patologia , Metilação , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
The circulation of tumor cells through the bloodstream is a significant step in tumor metastasis. To better understand the metastatic process, circulating tumor cell (CTC) survival in the circulation must be explored. While immune interactions with CTCs in recent decades have been examined, research has yet to sufficiently explain some CTC behaviors in blood flow. Studies related to CTC mechanical responses in the bloodstream have recently been conducted to further study conditions under which CTCs might die. While experimental methods can assess the mechanical properties and death of CTCs, increasingly sophisticated computational models are being built to simulate the blood flow and CTC mechanical deformation under fluid shear stresses (FSS) in the bloodstream.Several factors contribute to the mechanical deformation and death of CTCs as they circulate. While FSS can damage CTC structure, diverse interactions between CTCs and blood components may either promote or hinder the next metastatic step-extravasation at a remote site. Overall understanding of how these factors influence the deformation and death of CTCs could serve as a basis for future experiments and simulations, enabling researchers to predict CTC death more accurately. Ultimately, these efforts can lead to improved metastasis-specific therapeutics and diagnostics specific in the future.
RESUMO
Lung cancer frequently metastasizes to the bones. An in vivo model is urgently required to identify potential therapeutic targets for the prevention and treatment of lung cancer with bone metastasis. We established a lung adenocarcinoma cell subline (H322L-BO4) that specifically showed metastasis to the leg bones and adrenal glands. This was achieved by repeated isolation of metastatic cells from the leg bones of mice. The cells were intracardially injected into nude mice. Survival was prolonged for mice that received H322L-BO4 cells versus original cells (H322L). H322L-BO4 cells did not exhibit obvious changes in general in vitro properties associated with the metastatic potential (e.g., cell growth, migration, and invasion) compared with H322L cells. However, the phosphorylation of chromosome 9 open reading frame 10/oxidative stress-associated Src activator (C9orf10/Ossa) was increased in H322L-BO4 cells. This result confirmed the increased anchorage independence through C9orf10/Ossa-mediated activation of Src family tyrosine kinase. Reduction of C9orf10/Ossa by shRNA reduced cells' metastasis to the leg bone and prolonged survival in mice. These findings indicate that H322L-BO4 cells can be used to evaluate the effect of candidate therapeutic targets against bone metastatic lung cancer cells. Moreover, C9orf10/Ossa may be a useful target for treatment of lung cancer with bone metastasis.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Ósseas , Neoplasias Pulmonares , Animais , Camundongos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Linhagem Celular Tumoral , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos Nus , Metástase Neoplásica/genética , Quinases da Família src/uso terapêutico , HumanosRESUMO
Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma in vivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.
Assuntos
Carcinoma Hepatocelular , MicroRNAs , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Carcinoma Hepatocelular/patologia , Transdução de Sinais/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Macrófagos/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral/genéticaRESUMO
Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation of epithelial cells into mesenchymal cells with molecular alterations can occur during epithelial-mesenchymal transition (EMT). The EMT mechanism accelerates the cancer metastasis and drug resistance ability in human cancers. Among the different regulators of EMT, Wnt/ß-catenin axis has been emerged as a versatile modulator. Wnt is in active form in physiological condition due to the function of GSK-3ß that destructs ß-catenin, while ligand-receptor interaction impairs GSK-3ß function to increase ß-catenin stability and promote its nuclear transfer. Regarding the oncogenic function of Wnt/ß-catenin, its upregulation occurs in human cancers and it can accelerate EMT-mediated metastasis and drug resistance. The stimulation of Wnt by binding Wnt ligands into Frizzled receptors can enhance ß-catenin accumulation in cytoplasm that stimulates EMT and related genes upon nuclear translocation. Wnt/ß-catenin/EMT axis has been implicated in augmenting metastasis of both solid and hematological tumors. The Wnt/EMT-mediated cancer metastasis promotes the malignant behavior of tumor cells, causing therapy resistance. The Wnt/ß-catenin/EMT axis can be modulated by upstream mediators in which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT axis in metastasis suppression.
Assuntos
Neoplasias , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica , Neoplasias/genéticaRESUMO
Cancer metastasis and therapy resistance are intricately linked with the dynamics of Epithelial-Mesenchymal Transition (EMT) and Circulating Tumor Cells (CTCs). EMT hybrid cells, characterized by a blend of epithelial and mesenchymal traits, have emerged as pivotal in metastasis and demonstrate remarkable plasticity, enabling transitions across cellular states crucial for intravasation, survival in circulation, and extravasation at distal sites. Concurrently, CTCs, which are detached from primary tumors and travel through the bloodstream, are crucial as potential biomarkers for cancer prognosis and therapeutic response. There is a significant interplay between EMT hybrid cells and CTCs, revealing a complex, bidirectional relationship that significantly influences metastatic progression and has a critical role in cancer drug resistance. This resistance is further influenced by the tumor microenvironment, with factors such as tumor-associated macrophages, cancer-associated fibroblasts, and hypoxic conditions driving EMT and contributing to therapeutic resistance. It is important to understand the molecular mechanisms of EMT, characteristics of EMT hybrid cells and CTCs, and their roles in both metastasis and drug resistance. This comprehensive understanding sheds light on the complexities of cancer metastasis and opens avenues for novel diagnostic approaches and targeted therapies and has significant advancements in combating cancer metastasis and overcoming drug resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Metástase Neoplásica , Neoplasias , Células Neoplásicas Circulantes , Microambiente Tumoral , Humanos , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/patologia , Células Neoplásicas Circulantes/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Células MRESUMO
Colorectal cancer (CRC) is the third most common cancer and the prevalence rate of CRC is increasing in the China. In this study, whole-exome sequencing (WES) was performed on primary tissues of 47 CRC Chinese patients including 22 metastatic and 25 non-metastatic patients. By comparison with data from western colorectal cancer patients in the Cancer Genome Atlas (TCGA), we identified a number of genes that are more likely to be mutated in Chinese colorectal cancer patients, such as MUC12, MUC12, MUC2, MUC4, HYDIN and KMT2C. Interestingly, MUC family genes including MUC12, MUC2 and MUC4, have mutation rates of >20%, while the mutation frequency was extremely low in western colorectal cancer patients, which were <3% in TCGA and 0% in Memorial Sloan Kettering Cancer Center (MSKCC). We detected metastasis-specific mutated genes including TCF7L2, MST1L, HRNR and SMAD4, while MUC4, NEB, FLG and RFPL4A alteration is more prevalent in the non-metastasis group. Further analysis reveals mutation genes in metastasis group are more focus in the Wnt and Hippo signaling pathway. APC, SMAD4 and TCF7L2 accounted for the major genetic abnormalities in this pathway. In conclusion, this study identified the unique characteristics of gene mutations in Chinese patients with colorectal cancer, and is a valuable reference for personalized treatment in Chinese CRC patients.
Assuntos
Neoplasias Colorretais , Sequenciamento do Exoma , Mutação , Metástase Neoplásica , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Via de Sinalização Hippo , Mucina-4/genética , Mucina-4/metabolismo , China , Mucina-2/genética , Mucina-2/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteínas Filagrinas , Proteínas Serina-Treonina Quinases/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Via de Sinalização Wnt , Povo Asiático/genética , População do Leste Asiático , Proteínas de Ligação a DNARESUMO
Metastatic spread of tumour cells to tissues and organs around the body is the most frequent cause of death from breast cancer. This has been modelled mainly using mouse models such as syngeneic mammary cancer or human in mouse xenograft models. These have limitations for modelling human disease progression and cannot easily be used for investigation of drug resistance and novel therapy screening. To complement these approaches, advances are being made in ex vivo and 3D in vitro models, which are becoming progressively better at reliably replicating the tumour microenvironment and will in the future facilitate drug development and screening. These approaches include microfluidics, organ-on-a-chip and use of advanced biomaterials. The relevant tissues to be modelled include those that are frequent and clinically important sites of metastasis such as bone, lung, brain, liver for invasive ductal carcinomas and a distinct set of common metastatic sites for lobular breast cancer. These sites all have challenges to model due to their unique cellular compositions, structure and complexity. The models, particularly in vivo, provide key information on the intricate interactions between cancer cells and the native tissue, and will guide us in producing specific therapies that are helpful in different context of metastasis.
Assuntos
Neoplasias da Mama , Metástase Neoplásica , Microambiente Tumoral , Humanos , Neoplasias da Mama/patologia , Animais , Feminino , Metástase Neoplásica/patologia , Modelos Biológicos , Modelos Animais de Doenças , CamundongosRESUMO
Fibronectin (FN) is a major extracellular matrix (ECM) protein involved in a wide range of physiological processes, including cell migration. These FN-mediated cell migration events are essential to processes such as wound repair, cancer metastasis, and vertebrate development. This review synthesizes mainly current literature to provide an overview of the mechanoregulatory role of FN-mediated cell migration. Background on FN structure and role in mechanotransduction is provided. Cell migration concepts are introduced, including the general cell migration mechanism and classification of cell migration types. Then, FN-mediated events that directly affect cell migration are explored. Finally, a focus on FN in tissue repair and cancer migration is presented, as these topics represent a large amount of current research.
Assuntos
Fibronectinas , Neoplasias , Humanos , Fibronectinas/metabolismo , Matriz Extracelular/metabolismo , Mecanotransdução Celular , Movimento Celular , Proteínas da Matriz Extracelular/metabolismo , Neoplasias/metabolismo , Adesão CelularRESUMO
Nasopharyngeal carcinoma (NPC) is prevalent in Asia and exhibits highly metastatic characteristics, leading to uncontrolled disease progression. Isoliquiritigenin (ISL) have attracted attention due to their diverse biological and pharmacological properties, including anticancer activities. However, the impact of ISL on the invasive and migratory ability of NPC remains poorly understood. Hence, this study aimed to investigate the in vitro anti-metastatic effects of ISL on NPC cells and elucidate the underlying signalling pathways. Human NPC cell NPC-39 and NPC-BM were utilized as cell models. Migratory and invasive capabilities were evaluated through wound healing and invasion assays, respectively. Gelatin zymography was employed to demonstrate matrix metalloproteinase-2 (MMP-2) activity, while western blotting was conducted to analyse protein expression levels and explore signalling cascades. Overexpression of signal transducer and activator of transcription 3 (STAT3) was carried out by transduction of STAT3-expressing vector. Our findings revealed that ISL effectively suppressed the migration and invasion of NPC cells. Gelatin zymography and Western blotting assays demonstrated that ISL treatment led to a reduction in MMP-2 enzyme activity and protein expression. Investigation of signalling cascades revealed that ISL treatment resulted in the inhibition of STAT3 phosphorylation. Moreover, overexpression of STAT3 restored the migratory ability of NPC cells in the presence of ISL. Collectively, these findings indicate that ISL inhibits the migration and invasion of NPC cells associating with MMP-2 downregulation through suppressing STAT3 activation. This suggests that ISL has an anti-metastatic effect on NPC cells and has potential therapeutic benefit for NPC treatment.
Assuntos
Movimento Celular , Chalconas , Metaloproteinase 2 da Matriz , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Invasividade Neoplásica , Fator de Transcrição STAT3 , Transdução de Sinais , Humanos , Fator de Transcrição STAT3/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Chalconas/farmacologia , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Transdução de Sinais/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Breast cancer (BC) remains a significant health concern worldwide, with metastasis being a primary contributor to patient mortality. While advances in understanding the disease's progression continue, the underlying mechanisms, particularly the roles of long non-coding RNAs (lncRNAs), are not fully deciphered. In this study, we examined the influence of the lncRNA LINC00524 on BC invasion and metastasis. Through meticulous analyses of TCGA and GEO data sets, we observed a conspicuous elevation of LINC00524 expression in BC tissues. This increased expression correlated strongly with a poorer prognosis for BC patients. A detailed Gene Ontology analysis suggested that LINC00524 likely exerts its effects through RNA-binding proteins (RBPs) mechanisms. Experimentally, LINC00524 was demonstrated to amplify BC cell migration, invasion and proliferation in vitro. Additionally, in vivo tests showed its potent role in promoting BC cell growth and metastasis. A pivotal discovery was LINC00524's interaction with TDP43, which leads to the stabilization of TDP43 protein expression, an element associated with unfavourable BC outcomes. In essence, our comprehensive study illuminates how LINC00524 accelerates BC invasion and metastasis by binding to TDP43, presenting potential avenues for therapeutic interventions.
Assuntos
Neoplasias da Mama , RNA Longo não Codificante , Feminino , Humanos , Bioensaio , Neoplasias da Mama/genética , Transformação Celular Neoplásica , Ontologia Genética , RNA Longo não Codificante/genéticaRESUMO
Circulating hybrid cells (CHCs) are a newly discovered, tumor-derived cell population found in the peripheral blood of cancer patients and are thought to contribute to tumor metastasis. However, identifying CHCs by immunofluorescence (IF) imaging of patient peripheral blood mononuclear cells (PBMCs) is a time-consuming and subjective process that currently relies on manual annotation by laboratory technicians. Additionally, while IF is relatively easy to apply to tissue sections, its application to PBMC smears presents challenges due to the presence of biological and technical artifacts. To address these challenges, we present a robust image analysis pipeline to automate the detection and analysis of CHCs in IF images. The pipeline incorporates quality control to optimize specimen preparation protocols and remove unwanted artifacts, leverages a ß-variational autoencoder (VAE) to learn meaningful latent representations of single-cell images, and employs a support vector machine (SVM) classifier to achieve human-level CHC detection. We created a rigorously labeled IF CHC data set including nine patients and two disease sites with the assistance of 10 annotators to evaluate the pipeline. We examined annotator variation and bias in CHC detection and provided guidelines to optimize the accuracy of CHC annotation. We found that all annotators agreed on CHC identification for only 65% of the cells in the data set and had a tendency to underestimate CHC counts for regions of interest (ROIs) containing relatively large amounts of cells (>50,000) when using the conventional enumeration method. On the other hand, our proposed approach is unbiased to ROI size. The SVM classifier trained on the ß-VAE embeddings achieved an F1 score of 0.80, matching the average performance of human annotators. Our pipeline enables researchers to explore the role of CHCs in cancer progression and assess their potential as a clinical biomarker for metastasis. Further, we demonstrate that the pipeline can identify discrete cellular phenotypes among PBMCs, highlighting its utility beyond CHCs.
Assuntos
Imunofluorescência , Processamento de Imagem Assistida por Computador , Leucócitos Mononucleares , Células Neoplásicas Circulantes , Máquina de Vetores de Suporte , Humanos , Leucócitos Mononucleares/citologia , Processamento de Imagem Assistida por Computador/métodos , Células Neoplásicas Circulantes/patologia , Imunofluorescência/métodos , Neoplasias/patologia , Neoplasias/diagnóstico , Neoplasias/sangue , Análise de Célula Única/métodosRESUMO
BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARG) is a member of the nuclear receptor family. It is involved in the regulation of adipogenesis, lipid metabolism, insulin sensitivity, vascular homeostasis and inflammation. In addition, PPARG agonists, known as thiazolidinediones, are well established in the treatment of type 2 diabetes mellitus. PPARGs role in cancer is a matter of debate, as pro- and anti-tumour properties have been described in various tumour entities. Currently, the specific role of PPARG in patients with colorectal cancer (CRC) is not fully understood. MATERIAL AND METHODS: The prognostic impact of PPARG expression was investigated by immunohistochemistry in a case-control study using a matched pair selection of CRC tumours (n = 246) with either distant metastases to the liver (n = 82), lung (n = 82) or without distant metastases (n = 82). Its effect on proliferation as well as the sensitivity to the chemotherapeutic drug 5-fluorouracil (5-FU) was examined after activation, inhibition, and transient gene knockdown of PPARG in the CRC cell lines SW403 and HT29. RESULTS: High PPARG expression was significantly associated with pulmonary metastasis (p = 0.019). Patients without distant metastases had a significantly longer overall survival with low PPARG expression in their tumours compared to patients with high PPARG expression (p = 0.045). In the pulmonary metastasis cohort instead, a trend towards longer survival was observed for patients with high PPARG expression in their tumour (p = 0.059). Activation of PPARG by pioglitazone and rosiglitazone resulted in a significant dose-dependent increase in proliferation of CRC cell lines. Inhibition of PPARG by its specific inhibitor GW9662 and siRNA-mediated knockdown of PPARG significantly decreased proliferation. Activating PPARG significantly increased the CRC cell lines sensitivity to 5-FU while its inhibition decreased it. CONCLUSION: The prognostic effect of PPARG expression depends on the metastasis localization in advanced CRC patients. Activation of PPARG increased malignancy associated traits such as proliferation in CRC cell lines but also increases sensitivity towards the chemotherapeutic agent 5-FU. Based on this finding, a combination therapy of PPARG agonists and 5-FU-based chemotherapy constitutes a promising strategy which should be further investigated.
Assuntos
Neoplasias Colorretais , Diabetes Mellitus Tipo 2 , Humanos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , PPAR gama/agonistas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão GênicaRESUMO
Integrinß-1 (ITGB1) is a crucial member of the transmembrane glycoprotein signaling receptor family and is also central to the integrin family. It forms heterodimers with other ligands, participates in intracellular signaling and controls a variety of cellular processes, such as angiogenesis and the growth of neurons; because of its role in bidirectional signaling regulation both inside and outside the membrane, ITGB1 must interact with a multitude of substances, so a variety of interfering factors can affect ITGB1 and lead to changes in its function. Over the past 20 years, many studies have confirmed a clear causal relationship between ITGB1 dysregulation and cancer development and progression in a wide range of benign diseases and solid tumor types, which may imply that ITGB1 is a prognostic biomarker and a therapeutic target for cancer treatment that warrants further investigation. This review summarizes the biological roles of ITGB1 in benign diseases and cancers, and compiles the current status of ITGB1 function and therapy in various aspects of tumorigenesis and progression. Finally, future research directions and application prospects of ITGB1 are suggested. Video Abstract.
Assuntos
Integrina beta1 , Neoplasias , Linhagem Celular Tumoral , Integrina beta1/metabolismo , Transdução de Sinais , Proteínas de Transporte , Neoplasias/terapiaRESUMO
The naturally occurring bile acid lithocholic acid (LCA) has been a crucial core structure for many non-sugar-containing sialyltranferase (ST) inhibitors documented in literature. With the aim of elucidating the impact of the terminal carboxyl acid substituent of LCA on its ST inhibition, in this present study, we report the (bio)isosteric replacement-based design and synthesis of sulfonate and sulfate analogues of LCA. Among these compounds, the sulfate analogue SPP-002 was found to selectively inhibit N-glycan sialylation by at least an order of magnitude, indicating a substantial improvement in both potency and selectivity when compared to the unmodified parent bile acid. Molecular docking analysis supported the stronger binding of the synthetic analogue in the enzyme active site. Treatment with SPP-002 also hampered the migration, adhesion, and invasion of MDA-MB-231 cells in vitro by suppressing the expression of signaling proteins involved in the cancer metastasis-associated integrin/FAK/paxillin pathway. In totality, these findings offer not only a novel structural scaffold but also valuable insights for the future development of more potent and selective ST inhibitors with potential therapeutic effects against tumor cancer metastasis.
Assuntos
Ácido Litocólico , Simulação de Acoplamento Molecular , Sialiltransferases , Ácido Litocólico/farmacologia , Ácido Litocólico/química , Ácido Litocólico/síntese química , Ácido Litocólico/análogos & derivados , Humanos , Sialiltransferases/antagonistas & inibidores , Sialiltransferases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , Sulfatos/química , Sulfatos/farmacologia , Sulfatos/síntese química , Metástase Neoplásica , Ácidos Sulfônicos/farmacologia , Ácidos Sulfônicos/química , Ácidos Sulfônicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Estrutura Molecular , Adesão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Paxilina/metabolismo , Paxilina/antagonistas & inibidores , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/metabolismo , Descoberta de DrogasRESUMO
BACKGROUND: The metastasis accounts for most deaths from breast cancer (BRCA). Understanding the molecular mechanisms of BRCA metastasis is urgently demanded. Flap Endonuclease 1 (FEN1), a pivotal factor in DNA metabolic pathways, contributes to tumor growth and drug resistance, however, little is known about the role of FEN1 in BRCA metastasis. METHODS AND RESULTS: In this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α). CONCLUSIONS: These results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.
Assuntos
Neoplasias da Mama , Endonucleases Flap , Fator de Transcrição STAT3 , Feminino , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Endonucleases Flap/genética , Endonucleases Flap/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Animais , CamundongosRESUMO
Rho-associated coiled-coil kinase (ROCK) is involved in multiple cellular activities regulating the actin cytoskeleton, such as cell morphology, adhesion, and migration. The inhibition of ROCK is a feasible strategy to suppress breast cancer metastasis. Herein, based on Belumosudil, a series of pyrazolo[1,5-a]pyrimidine derivatives as selective ROCK2 inhibitors were designed and synthesized. Through systematic investigation of SARs, the piperazine analog 7u was identified with optimum ROCK2 inhibitory activity (IC50 = 36.8 nM) and excellent selectivity over the isoform protein ROCK1 (>250-fold). Intriguingly, upon treatment with 7u, the arrangement of the MDA-MB-231 cytoskeleton was affected accompanied by the alteration of morphology. Furthermore, cell scratch and transwell assays indicated that 7u inhibited MDA-MB-231 cell migration and invasion in a dose-dependent manner. Ultimately, the binding model of 7u with ROCK2 well accounted for the superior activities of 7u as a promising ROCK2 inhibitor with the potential application in breast cancer metastasis treatment.
RESUMO
The inhibition of transforming growth factor-ß1 (TGF-ß1) signaling by targeting TGF-ß receptor 1 (TßR1) has been considered as an ideal approach for the prevention of pancreatic cancer metastasis. Utilizing a pharmacophore model for TßR1 inhibitors, candidate compounds with the potential TßR1 binding ability were screened from the U.S. Food and Drug Administration (FDA) database, and riboflavin (RF) with a highest fit value was chosen to investigate its binding ability to TßR1 and effect on TGF-ß1 signaling in pancreatic cancer cells. Molecular docking and cellular thermal shift assay (CETSA) proved that RF at pharmacological concentrations could directly bind to TßR1. Further studies showed that pharmacological concentrations of RF in vitro could block TGF-ß1 signaling, suppress the migration and invasion, and prevent epithelial-mesenchymal transition (EMT) process of pancreatic cancer cells in the absence or presence of TGF-ß1 stimulation, indicating that RF presented anti-metastatic effect in pancreatic cancer cells. Knockdown of TßR1 could significantly attenuate the effects of RF on the migration and EMT process in pancreatic cancer cells, further confirming that the anti-metastatic effect of RF was achieved by blocking TGF-ß1 signaling after binding to TßR1. Moreover, in a mouse model of pancreatic cancer metastasis, it was certified that RF administration could block lung and liver metastases, TGF-ß1 signaling and EMT process of pancreatic cancer in vivo. In summary, our findings showed that RF could block TGF-ß1 signaling by directly binding to TßR1, thereby suppressing the metastasis of pancreatic cancer cells by inhibiting EMT process both in vitro and in vivo.