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In this issue of Molecular Cell, Yang et al.1 find that arginine-to-cysteine substitutants are enriched in a subset of lung cancer proteomes, potentiated by arginine deprivation, and promote resistance to chemotherapy.
Assuntos
Arginina , Cisteína , Neoplasias Pulmonares , Proteoma , Humanos , Cisteína/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Arginina/metabolismo , Proteoma/metabolismo , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Enzimas de Conjugação de Ubiquitina/metabolismo , Quinases raf/metabolismo , Proteínas ras/metabolismo , Animais , Células CACO-2 , Carcinogênese , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Genes ras , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Transplante de Neoplasias , Interferência de RNA , RNA Interferente Pequeno/metabolismoRESUMO
Cancers with Ras mutations represent a major therapeutic problem. Recent RNAi screens have uncovered multiple nononcogene addiction pathways that are necessary for the survival of Ras mutant cells. Here, we identify the evolutionarily conserved gene enhancer of rudimentary homolog (ERH), in which depletion causes greater toxicity in cancer cells with mutations in the small GTPase KRAS compared with KRAS WT cells. ERH interacts with the spliceosome protein SNRPD3 and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E and consequently, chromosome congression defects. Gene expression profiling indicates that ERH is required for the expression of multiple cell cycle genes, and the gene expression signature resulting from ERH down-regulation inversely correlates with KRAS signatures. Clinically, tumor ERH expression is inversely associated with survival of colorectal cancer patients whose tumors harbor KRAS mutations. Together, these findings identify a role of ERH in mRNA splicing and mitosis, and they provide evidence that KRAS mutant cancer cells are dependent on ERH for their survival.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Sequência Conservada , Evolução Molecular , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Splicing de RNA/genética , Fatores de Transcrição/metabolismo , Proteínas ras/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos Humanos/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Oncogenes , Ligação Proteica , Proteínas Proto-Oncogênicas p21(ras) , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sobrevida , Proteínas Centrais de snRNP/metabolismoRESUMO
KRAS mutations are common driver oncogenes associated with the development of several solid tumors. KRAS oncogene has been considered a highly challenging target for drug development because of structural features, including the lack of deep groove on its catalytic unit. However, by leveraging cysteine residues, covalent KRAS inhibitors irreversibly trap KRAS G12C mutants in their inactive GDP-bound state. These agents have resulted in significant clinical responses among patients with KRAS G12C-mutant solid tumors, including patients with colorectal cancer (CRC). Other allele-specific inhibitors of KRAS oncogene and panKRAS and panRAS inhibitors are also currently being investigated in clinical trials. This review article overviews recent clinical progress on KRAS G12C targeting for the management of patients with KRAS G12C-mutant CRC and provides an update on other RAS targeting approaches. We also discuss the unique biological features of RAS-mutant CRC, which require the combination of KRAS inhibitors and anti-epidermal growth factor receptor therapy, and elaborate on resistance mechanisms and novel therapeutic avenues that may define future treatment paradigms of patients with RAS-mutant CRC.
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Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer secreted protein that becomes over-expressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis. NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia induced factor-1a (HIF1a) nuclear retention and function. NPTX1 is over-expressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1a hypoxic response in PDAC.
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Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential transfer RNA (tRNA) modification enzyme in GSCs. YRDC catalyzes the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNA species (A denotes adenosine, and N denotes any nucleotide). Targeting YRDC reduced t6A formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated t6A formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon bias. Dietary threonine restriction (TR) reduced tumor t6A formation, slowed xenograft growth and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment.
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Glioblastoma , Treonina , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/metabolismo , Humanos , Animais , Camundongos , Treonina/metabolismo , Treonina/genética , Biossíntese de Proteínas , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Códon/genética , RNA de Transferência/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismoRESUMO
Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine limitation-a feature of tumor microenvironments-is sufficient to induce arginine codon-switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced an adaptive proteomic shift toward low-arginine codon-containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons-reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.
Assuntos
Arginina , Neoplasias Colorretais , Humanos , Sequência de Bases , Arginina/genética , Arginina/metabolismo , Biossíntese de Proteínas , Proteômica , Escherichia coli/metabolismo , Códon/metabolismo , Neoplasias Colorretais/genética , Microambiente TumoralRESUMO
Utilization of specific codons varies significantly across organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine restriction-a feature of tumor microenvironments-is sufficient to induce arginine codon-switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced a proteomic shift towards low arginine codon containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons-reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.
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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm of mismatch repair-deficient/microsatellite instability-high (MMMR-D/MSI-H) colorectal cancer (CRC). Unique molecular features of MMR-D/MSI-H CRC with frameshift alterations, which result in mutation-associated neoantigen (MANA) generation, create an ideal molecular framework for MANA-driven T-cell priming and antitumor immunity. These biologic characteristics of MMR-D/MSI-H CRC resulted in rapid drug development with ICIs for patients with MMR-D/MSI-H CRC. Observed deep and durable responses with the use of ICIs in advanced-stage disease have stimulated the development of clinical trials with ICIs for patients with early-stage MMR-D/MSI-H CRC. Most recently, neoadjuvant dostarlimab monotherapy for nonoperative management of MMR-D/MSI-H rectal cancer and neoadjuvant NICHE trial with nivolumab and ipilimumab for MMR-D/MSI-H colon cancer resulted in groundbreaking results. Although nonoperative management of patients with MMR-D/MSI-H rectal cancer with ICIs will potentially define our current therapeutic approach, therapeutic goals of neoadjuvant ICI therapy for patients with MMR-D/MSI-H colon cancer may differ given that nonoperative management has not been well established for colon cancer. Herein, we overview recent advancements in ICI-based therapies for patients with early-stage MMR-D/MSI-H colon and rectal cancer and elaborate on the future treatment paradigm of this unique subgroup of CRC.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Instabilidade de Microssatélites , Terapia Neoadjuvante , Reparo de Erro de Pareamento de DNA , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genéticaRESUMO
Recent trials provide evidence that HER2 is a potential new target for patients with colorectal cancer. While HER2-positive tumors do not show a very encouraging response to anti-HER2-positive agents like trastuzumab alone, promising results have been observed when combined with other synergistically acting tyrosine kinase inhibitors (TKIs). Our meta-analysis was conducted following the Cochrane Handbook and written following the PRISMA guidelines. The protocol was registered on PROSPERO with the registration number CRD42022338935. After a comprehensive search for relevant articles, 14 CTs were identified and uploaded to Rayyan, and six trials were ultimately selected for inclusion. The meta-analysis revealed that a median of three prior lines of therapy was used before enrolling in the six trials comprising 238 patients with HER2-positive metastatic colorectal cancer (mCRC). The pooled objective response rate (ORR) and disease control rate (DCR) were 31.33% (95% confidence interval [CI] 24.27-38.39) and 74.37% (95% CI 64.57-84.17), respectively. The pooled weighted progression-free survival (PFS) was 6.2 months. The pooled ORR and DCR meta-analysis indicate a significant response to HER2-targeted therapy in this patient in HER2-positive mCRC. Additionally, a pooled PFS of 6.2 months suggests that HER2-targeted treatment regimens are associated with a meaningful improvement in survival outcomes in this population.
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Neoplasias Colorretais , Humanos , Trastuzumab , Intervalo Livre de Progressão , Neoplasias Colorretais/tratamento farmacológicoRESUMO
PURPOSE: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy can improve the limited efficacy of colorectal cancer (CRC) immunotherapy. CX-5461 causes substantial DNA damage and genomic instability and can increase ICIs' therapeutic efficacies through tumor microenvironment alteration. RESULTS: We analyzed whether CX-5461 enhances ICIs' effects in CRC and discovered that CX-5461 causes severe DNA damage, including cytosolic dsDNA appearance, in various human and mouse CRC cells. Our bioinformatics analysis predicted CX-5461-based interferon (IFN) signaling pathway activation in these cells, which was verified by the finding that CX-5461 induces IFN-α and IFN-ß secretion in these cells. Next, cGAMP, phospho-IRF3, CCL5, and CXCL10 levels exhibited significant posttreatment increases in CRC cells, indicating that CX-5461 activates the cGAS-STING-IFN pathway. CX-5461 also enhanced PD-L1 expression through STAT1 activation. CX-5461 alone inhibited tumor growth and prolonged survival in mice. CX-5461+anti-PD-1 or anti-PD-L1 alone exhibited synergistic growth-suppressive effects against CRC and breast cancer. CX-5461 alone or CX-5461+anti-PD-1 increased cytotoxic T-cell numbers and reduced myeloid-derived suppressor cell numbers in mouse spleens. CONCLUSIONS: Therefore, clinically, CX-5461 combined with ICIs for CRC therapy warrants consideration because CX-5461 can turn cold tumors into hot ones.
Assuntos
Neoplasias Colorretais , Inibidores de Checkpoint Imunológico , Humanos , Camundongos , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno B7-H1/metabolismo , Naftiridinas , Benzotiazóis , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Microambiente TumoralRESUMO
From financial improprieties to fraudulent claims, scandals and trust transgressions can incite feelings of betrayal. Can these negative reactions spillover and taint other entities that were not involved in the original transgression? We conducted six studies to investigate this question directly. Results consistently demonstrated that people who had perceived a recent betrayal by a transgressing trustee were significantly less likely to trust a new entity that shared nominal group membership with the previous trust transgressor. This betrayal spillover effect occurs both in economic game environments and can be applied to real-world charitable contexts in which people made actual donation decisions or assessed the likelihood that a charity would be embroiled in a scandal in the future. Importantly, the betrayal spillover effect only spilled over to those that shared a nominal group identity with the original trust transgressor, and this behavior was driven by a sense of distrust stemming from people's expectations having been violated. By systematically investigating whether and to what extent betrayals can contaminate subsequent trust development, this research provides a deeper and broadened understanding on how one may be vicariously affected by other entities' trust indiscretions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Traição , Confiança , Emoções , HumanosRESUMO
The human genome contains 61 codons encoding 20 amino acids. Synonymous codons representing a given amino acid are decoded by a set of transfer RNAs (tRNAs) called isoacceptors. We report the surprising observation that two isoacceptor tRNAs that decode synonymous codons become modulated in opposing directions during breast cancer progression. Specifically, tRNAIleUAU became upregulated, whereas tRNAIleGAU became repressed as breast cancer cells attained enhanced metastatic capacity. Functionally, tRNAIleUAU promoted and tRNAIleGAU suppressed metastatic colonization in mouse xenograft models. These tRNAs mediated opposing effects on codon-dependent translation of growth-promoting genes, consistent with genomic enrichment or depletion of their cognate codons in mitotic genes. Our findings uncover a specific isoacceptor tRNA pair that act in opposition, divergently impacting growth-regulating genes and a disease phenotype. Degeneracy of the genetic code can thus be biologically exploited by human cancer cells via tRNA isoacceptor shifts that causally facilitate the transition toward a growth-promoting state.
Assuntos
Neoplasias da Mama , Animais , Camundongos , Humanos , Feminino , Neoplasias da Mama/genética , RNA de Transferência de Isoleucina , Códon/genética , RNA de Transferência/genética , RNA de Transferência/química , RNA de Transferência/metabolismo , Aminoácidos/genética , Proliferação de Células/genéticaRESUMO
BACKGROUND: Compared with the precise targeting of drug-resistant mutant cancer cells, strategies for eliminating non-genetic adaptation-mediated resistance are limited. The pros and cons of the existence of inflammasomes in cancer have been reported. Nevertheless, the dynamic response of inflammasomes to therapies should be addressed. METHODS: Tumor-derived exosomes were purified by differential ultracentrifugation and validated by nanoparticle tracking analysis and transmission electron microscopy. A proximity ligation assay and interleukin-1ß (IL-1ß) level were used for detecting activation of NLRP3 inflammasomes. RNA sequencing was used to analyze the exosomal RNAs. MIR21 knocked out human monocytic THP cells and mir21 knocked out murine oral cancer MTCQ1 cells were generated for confirming the exosomal delivery of microRNA (miR)-21. Syngeneic murine models for head and neck cancer (C57BLJ/6J), breast cancer (BALB/C) and lung cancer (C57BL/6J) were applied for examining the impact of Snail-miR21 axis on inflammasome activation in vivo. Single-cell RNA sequencing was used for analyzing the tumor-infiltrated immune cells. Head and neck patient samples were used for validating the findings in clinical samples. RESULTS: We demonstrated that in cancer cells undergoing Snail-induced epithelial-mesenchymal transition (EMT), tumor cells suppress NLRP3 inflammasome activities of tumor-associated macrophages (TAMs) in response to chemotherapy through the delivery of exosomal miR-21. Mechanistically, miR-21 represses PTEN and BRCC3 to facilitate NLRP3 phosphorylation and lysine-63 ubiquitination, inhibiting NLRP3 inflammasome assembly. Furthermore, the Snail-miR-21 axis shapes the post-chemotherapy tumor microenvironment (TME) by repopulating TAMs and by activating CD8+ T cells. In patients with head and neck cancer, the Snail-high cases lacked post-chemotherapy IL-1ß surge and were correlated with a worse response. CONCLUSIONS: This finding reveals the mechanism of EMT-mediated resistance beyond cancer stemness through modulation of post-treatment inflammasome activity. It also highlights the dynamic remodeling of the TME throughout metastatic evolution.
Assuntos
Neoplasias de Cabeça e Pescoço , MicroRNAs , Fatores de Transcrição da Família Snail/metabolismo , Animais , Linfócitos T CD8-Positivos , Cisplatino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Inflamassomos , Camundongos , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Microambiente TumoralRESUMO
From employees' point of view, changes in ethical leadership perceptions can signal important changes in the nature of the employment relationship. Guided by social exchange theory, this study proposes that changes in ethical leadership perceptions shape how employees appraise their exchange relationship with the organization and affect their pride in or contempt for the organization. Changes in these associative/dissociative emotions, in turn, precipitate changes in behaviors that serve or hurt the organization, notably voice and turnover. Experimental data collected from 900 subjects (Study 1) and field data collected from 470 employees across 4 waves over 14 months (Study 2) converged to show that changes in ethical leadership perceptions were related to same-direction changes in employees' pride in the organization and to opposite-direction changes in their contempt for the organization above and beyond the effect of the present ethical leadership level. Changes in pride were in turn related to same-direction changes in functional voice, whereas changes in contempt were related to same-direction changes in dysfunctional voice. The field study also provided evidence that when pride increased (decreased), employees were less (more) likely to leave the organization 6 months after. These results suggest that changes in ethical leadership perceptions are meaningful on their own, that they may alter employees' organization-targeted behaviors, and that changes in associative/dissociative emotions are the mediating mechanism. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Assuntos
Liderança , Princípios Morais , Emprego , Humanos , Percepção , Comportamento SocialRESUMO
Guided by cognitive appraisal theory, we argue that wish-making is a conceptually distinct type of coping strategy and that wish-making during the COVID-19 pandemic has functional cognitive-affective consequences. Specifically, it facilitates positive appraisals of the pandemic, which then facilitate job satisfaction. Enhanced job satisfaction in turn reduces counterproductive work behavior during the pandemic. These arguments were tested via two empirical studies involving 546 Hong Kong employees surveyed on two consecutive working days during the pandemic. The individuals who made wishes during the pandemic reported more positive appraisals of the pandemic, which in turn promoted their job satisfaction and lowered their counterproductive work behavior. Crucially, wish-making had significant effects on positive appraisals above and beyond other coping strategies. Thus, we contribute to the employee coping literature by highlighting one relatively easy way for employees to combat the psychological effects of the pandemic (and other challenges in life) and regulate their affective well-being and behaviors at work. Namely, making wishes that envision a better future can enhance employees' job satisfaction, which in turn lowers counterproductive work behavior.
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Therapeutic combinations of VEGFR tyrosine kinase inhibitor plus immune checkpoint blockade now represent a standard in the first-line management of patients with advanced renal cell carcinoma. Tumor molecular profiling has shown notable heterogeneity when it comes to activation states of relevant pathways, and it is not clear that concurrent pursuit of two mechanisms of action is needed in all patients. Here, we applied an in silico drug model to simulate combination therapy by integrating previously reported findings from individual monotherapy studies. Clinical data was collected from prospective clinical trials of axitinib, cabozantinib, pembrolizumab and nivolumab. Efficacy of two-drug combination regimens (cabozantinib plus nivolumab, and axitinib plus pembrolizumab) was then modeled assuming independent effects of each partner. Reduction in target lesions, objective response rates (ORR), and progression-free survival (PFS) were projected based on previously reported activity of each agent, randomly pairing efficacy data from two source trials for individual patients and including only the superior effect of each pair in the model. In silico results were then contextualized to register phase III studies of these combinations with similar ORR, PFS, and best tumor response. As increasingly complex therapeutic strategies emerge, computational tools like this could help define benchmarks for trial designs and precision medicine efforts. Summary statement: In silico drug modeling provides meaningful insights into the effects of combination immunotherapy for patients with advanced kidney cancer.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Simulação por Computador/normas , Imunoterapia/métodos , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Intervalo Livre de ProgressãoRESUMO
Cholangiocarcinoma is the most common primary malignant tumor of the bile duct. The current standard first-line treatment for advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin. However, few effective treatment choices exist for refractory cholangiocarcinoma, and additional therapeutic drugs are urgently required. Our previous work demonstrated that the ALDH isoform 1A3 plays a vital role in the malignant behavior of cholangiocarcinoma and may serve as a new therapeutic target. In this study, we found a positive correlation between ALDH1A3 protein expression levels and the cell migration abilities of three cholangiocarcinoma cell lines, which was verified using ALDH1A3-overexpressing and ALDH1A3-knockdown clones. We also used ALDH1A3-high and ALDH1A3-low populations of cholangiocarcinoma cell lines from the library of integrated network-based cellular signatures (LINCS) program and assessed the effects of ruxolitinib, a commercially available JAK2 inhibitor. Ruxolitinib had a higher cytotoxic effect when combined with gemcitabine. Furthermore, the nuclear translocation STAT1 and STAT3 heterodimers were markedly diminished by ruxolitinib treatment, possibly resulting in decreased ALDH1A3 activation. Notably, ruxolitinib alone or combined with gemcitabine led to significantly reduced tumor size and weight. Collectively, our studies suggest that ruxolitinib might suppress the ALDH1A3 activation through the JAK2/STAT1/3 pathway in cholangiocarcinoma, and trials should be undertaken to evaluate its efficacy in clinical therapy.
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The actin-binding protein filamin links membrane receptors to the underlying cytoskeleton. The cytoplasmic domains of these membrane receptors have been shown to bind to various filamin immunoglobulin repeats. Notably, among 24 human filamin repeats, repeat 17 was reported to specifically bind to platelet receptor glycoprotein Ibalpha and repeat 21 to integrins. However, a complete sequence alignment of all 24 human filamin repeats reveals that repeats 17 and 21 actually belong to a distinct filamin repeat subgroup (containing repeats 4, 9, 12, 17, 19, 21, and 23) that shares a conserved ligand-binding site. Using isothermal calorimetry and NMR analyses, we show that all repeats in this subgroup can actually bind glycoprotein Ibalpha, integrins, and a cytoskeleton regulator migfilin in similar manners. These data provide a new view on the ligand specificity of the filamin repeats. They also suggest a multiple ligand binding mechanism where similar repeats within a filamin monomer may promote receptor clustering or receptor cross-talking for regulation of the cytoskeleton organization and diverse filamin-mediated cellular activities.
Assuntos
Proteínas Contráteis/metabolismo , Proteínas dos Microfilamentos/metabolismo , Transdução de Sinais/fisiologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Calorimetria , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Proteínas Contráteis/química , Proteínas Contráteis/classificação , Proteínas Contráteis/genética , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Filaminas , Humanos , Integrinas/genética , Integrinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/classificação , Proteínas dos Microfilamentos/genética , Modelos Moleculares , Dados de Sequência Molecular , Ressonância Magnética Nuclear Biomolecular , Filogenia , Complexo Glicoproteico GPIb-IX de Plaquetas , Isoformas de Proteínas/química , Isoformas de Proteínas/classificação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Alinhamento de SequênciaRESUMO
Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide; however, accurate molecular markers to predict its prognosis are still limited. We previously demonstrated that overexpression of the DNA double-strand break repair protein NBS1 is a prognostic marker of advanced head and neck squamous cell carcinoma (HNSCC). Therefore, we aimed to investigate the feasibility of using NBS1 as a biomarker in OSCC. In this study, we enrolled 148 OSCC for immunohistochemical (IHC) and clinical analysis. Data from 58 advanced non-oral-cavity HNSCC (NO-HNSCC) cases were also included for comparison due to the biological and clinical discrepancy between OSCC and HNSCC originated from the other sites (e.g. pharynx or larynx). First, we validated the NBS1 IHC results by real-time RT-PCR analysis, and an excellent correlation between the results of these two assays confirmed the reliability and robustness of IHC procedures and interpretation. NBS1 overexpression was an independent prognostic marker in both OSCC and NO-HNSCC cases. In OSCC, the prognostic significance of NBS1 was shown regardless of T stage and lymph node status. Increased NBS1 expression correlated with advanced T stage and recurrence/metastasis. NBS1 overexpression correlated with the phosphorylation levels of Akt and its downstream target mammalian target of rapamycin (mTOR). These results clearly illustrate the expression profile of NBS1 in OSCC and NO-HNSCC, and highlight the role of NBS1 in HNSCC irrespective of the primary sites. It also indicates the practicability of application of NBS1 as a marker in OSCC.