RESUMEN
Evidence from physical sciences in oncology increasingly suggests that the interplay between the biophysical tumor microenvironment and genetic regulation has significant impact on tumor progression. Especially, tumor cells and the associated stromal cells not only alter their own cytoskeleton and physical properties but also remodel the microenvironment with anomalous physical properties. Together, these altered mechano-omics of tumor tissues and their constituents fundamentally shift the mechanotransduction paradigms in tumorous and stromal cells and activate oncogenic signaling within the neoplastic niche to facilitate tumor progression. However, current findings on tumor biophysics are limited, scattered, and often contradictory in multiple contexts. Systematic understanding of how biophysical cues influence tumor pathophysiology is still lacking. This review discusses recent different schools of findings in tumor biophysics that have arisen from multi-scale mechanobiology and the cutting-edge technologies. These findings range from the molecular and cellular to the whole tissue level and feature functional crosstalk between mechanotransduction and oncogenic signaling. We highlight the potential of these anomalous physical alterations as new therapeutic targets for cancer mechanomedicine. This framework reconciles opposing opinions in the field, proposes new directions for future cancer research, and conceptualizes novel mechanomedicine landscape to overcome the inherent shortcomings of conventional cancer diagnosis and therapies.
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Mecanotransducción Celular , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/patología , Transducción de Señal , Microambiente Tumoral , BiofisicaRESUMEN
Despite recent advances in molecular therapeutics, lung cancer is still a leading cause of cancer deaths. Currently, limited targeted therapy options and acquired drug resistance present significant barriers in the treatment of patients with lung cancer. New strategies in drug development, including those that take advantage of the intracellular ubiquitin-proteasome system to induce targeted protein degradation, have the potential to advance the field of personalized medicine for patients with lung cancer. Specifically, small molecule proteolysis targeting chimeras (PROTACs), consisting of two ligands connected by a linker that bind to a target protein and an E3 ubiquitin ligase, have been developed against many cancer targets, providing promising opportunities for advanced lung cancer. In this review, we focus on the rationale for PROTAC therapy as a new targeted therapy and the current status of PROTAC development in lung cancer.
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Neoplasias Pulmonares , Complejo de la Endopetidasa Proteasomal , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas/metabolismo , Proteolisis , Ubiquitina-Proteína Ligasas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genéticaRESUMEN
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been spreading globally and threatening public health. Advanced in vitro models that recapitulate the architecture and functioning of specific tissues and organs are in high demand for COVID-19-related pathology studies and drug screening. Three-dimensional (3D) in vitro cultures such as self-assembled and engineered organoid cultures surpass conventional two-dimensional (2D) cultures and animal models with respect to the increased cellular complexity, better human-relevant environment, and reduced cost, thus presenting as promising platforms for understanding viral pathogenesis and developing new therapeutics. This review highlights the recent advances in self-assembled and engineered organoid technologies that are used for COVID-19 studies. The challenges and future perspectives are also discussed.
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Epithelial-mesenchymal transition (EMT) is implicated in tumor metastasis and therapeutic resistance. It remains a challenge to target cancer cells that have undergone EMT. The Snail family of key EMT-inducing transcription factors directly binds to and transcriptionally represses not only epithelial genes but also a myriad of additional genomic targets that may carry out significant biological functions. Therefore, we reasoned that EMT inherently causes various concomitant phenotypes, some of which may create targetable vulnerabilities for cancer treatment. In the present study, we found that Snail transcription factors bind to the promoters of multiple genes encoding subunits of the AMP-activated protein kinase (AMPK) complex, and expression of AMPK genes was markedly downregulated by EMT. Accordingly, high AMPK expression in tumors correlated with epithelial cell markers and low AMPK expression in tumors was strongly associated with adverse prognosis. AMPK is the principal sensor of cellular energy status. In response to energy stress, AMPK is activated and critically reprograms cellular metabolism to restore energy homeostasis and maintain cell survival. We showed that activation of AMPK by energy stress was severely impaired by EMT. Consequently, EMT cancer cells became hypersensitive to a variety of energy stress conditions and primarily underwent pyroptosis, a regulated form of necrotic cell death. Collectively, the study suggests that EMT impedes the activation of AMPK signaling induced by energy stress and sensitizes cancer cells to pyroptotic cell death under energy stress conditions. Therefore, while EMT promotes malignant progression, it concurrently induces collateral vulnerabilities that may be therapeutically exploited.
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Transición Epitelial-Mesenquimal , Neoplasias , Piroptosis , Proteínas Quinasas Activadas por AMP/metabolismo , Transición Epitelial-Mesenquimal/genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Factores de Transcripción de la Familia Snail , Estrés FisiológicoRESUMEN
OBJECTIVES: Assess well-being among older adults through secondary analysis measured during an annual survey in 2018, 2019, and 2020, to determine trends from before and during the COVID-19 pandemic. METHODS: Mailed surveys sent annually included measures related to various psychosocial factors. MAIN FINDINGS: Response rates were 29% in 2018, 25% in 2019, and 24% in 2020. Most respondents reported average or high resilience (89% 2018-2020), high purpose (64% in 2018 and 2019, 63% in 2020), moderate optimism (46% in 2019, 44% in 2020) and low stress (88% in 2019 and 2020). Reported loneliness increased 13% from 2018 to 2020. In 2020, only 45% reported high comfort with technology, decreasing with age (>75). PRINCIPAL CONCLUSION: Psychosocial well-being of respondents were doing well despite changes related to COVID-19. However, increased loneliness may negatively impact long-term health outcomes; thus, a focus on technology options to stay socially connected and access healthcare are needed.
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COVID-19/psicología , Soledad , Resiliencia Psicológica , Anciano , Humanos , Soledad/psicología , Pandemias , Encuestas y CuestionariosRESUMEN
Lung cancer with loss-of-function of the LKB1 tumor suppressor is a common aggressive subgroup with no effective therapies. LKB1-deficiency induces constitutive activation of cAMP/CREB-mediated transcription by a family of three CREB-regulated transcription coactivators (CRTC1-3). However, the significance and mechanism of CRTC activation in promoting the aggressive phenotype of LKB1-null cancer remain poorly characterized. Here, we observed overlapping CRTC expression patterns and mild growth phenotypes of individual CRTC-knockouts in lung cancer, suggesting functional redundancy of CRTC1-3. We consequently designed a dominant-negative mutant (dnCRTC) to block all three CRTCs to bind and co-activate CREB. Expression of dnCRTC efficiently inhibited the aberrantly activated cAMP/CREB-mediated oncogenic transcriptional program induced by LKB1-deficiency, and specifically blocked the growth of human and murine LKB1-inactivated lung cancer. Collectively, this study provides direct proof for an essential role of the CRTC-CREB activation in promoting the malignant phenotypes of LKB1-null lung cancer and proposes the CRTC-CREB interaction interface as a novel therapeutic target.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Neoplasias Pulmonares , Proteínas Serina-Treonina Quinasas/genética , Factores de Transcripción/genética , Células A549 , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Quinasas Activadas por AMP , Animales , Sistemas CRISPR-Cas , Línea Celular Tumoral , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Edición Génica , Xenoinjertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción/metabolismo , Transcriptoma/genéticaRESUMEN
Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and apoptosis during reactive oxygen species (ROS)-induced stress. We find that ROS significantly induces global mRNA N6-methyladenosine (m6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m6A levels that protect genomic integrity of cells in response to ROS.
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Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Daño del ADN , Reparación del ADN , Especies Reactivas de Oxígeno/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Desmetilación/efectos de los fármacos , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metilación/efectos de los fármacos , Ratones , Fosforilación , Procesamiento Proteico-Postraduccional , ARN Interferente Pequeño , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , RNA-Seq , Sumoilación/efectos de los fármacos , Espectrometría de Masas en Tándem , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismoRESUMEN
No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2-induced tumorigenesis. Cotargeting of aberrant p16-CDK4/6-RB signaling and CRTC1-MAML2 fusion-activated AREG/EGFR signaling with the respective CDK4/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4/6 inhibitors as a potential viable strategy for patients with MEC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Mucoepidermoide/genética , Neoplasias de las Glándulas Salivales/genética , Transactivadores/genética , Factores de Transcripción/genética , Animales , Carcinoma Mucoepidermoide/tratamiento farmacológico , Carcinoma Mucoepidermoide/patología , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Doxiciclina/farmacología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Transgénicos , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Fusión de Oncogenes , Proteínas de Fusión Oncogénica/genética , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Neoplasias de las Glándulas Salivales/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mucoepidermoid carcinoma (MEC) is the most common type of salivary gland cancers and patients with advanced, metastatic, and recurrent MECs have limited therapeutic options and poor treatment outcomes. MEC is commonly associated with a chromosomal translocation t(11;19) (q14-21;p12-13) that encodes the CRTC1-MAML2 oncogenic fusion. The CRTC1-MAML2 fusion is required for MEC growth in part through inducing autocrine AREG-EGFR signaling. Growing evidence suggests that MEC malignancy is maintained by cancer stem-like cells. In this study, we aimed to determine critical signaling for maintaining MEC stem-like cells and the effect of combined targeting of stem cell signaling and CRTC1-MAML2-induced EGFR signaling on blocking MEC growth. First, we evaluated the significance of Notch signaling in regulating MEC stem-like cells. Aberrantly activated Notch signaling was detected in human fusion-positive MEC cells. The inhibition of Notch signaling with genetic or pharmacological inhibitors reduced oncosphere formation and ALDH-bright population in vitro and blocked the growth of MEC xenografts in vivo. Next, we investigated the effect of co-targeting Notch signaling and EGFR signaling, and observed enhanced inhibition on MEC growth in vivo. Collectively, this study identified a critical role of Notch signaling in maintaining MEC stem-like cells and tumor growth, and revealed a novel approach of co-targeting Notch and EGFR signaling as a potential effective anti-MEC treatment.
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Carcinoma Mucoepidermoide/tratamiento farmacológico , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Transactivadores/genética , Factores de Transcripción/genética , Animales , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/patología , Proliferación Celular/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/farmacología , Xenoinjertos , Humanos , Ratones , Terapia Molecular Dirigida , Células Madre Neoplásicas/efectos de los fármacos , Proteínas de Fusión Oncogénica/genética , Receptores Notch/antagonistas & inhibidores , Receptores Notch/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Transducción de Señal/efectos de los fármacos , Translocación Genética/genéticaRESUMEN
BACKGROUND: Studies consistently demonstrate that older adults who are lonely have higher rates of depression and increased mortality risk. Pet ownership may be a solution for loneliness; however, challenges related to pet ownership exist for older adults. Therefore, researchers and practitioners are examining the use of animatronic pets to reduce loneliness. OBJECTIVE: To determine the feasibility of an animatronic pet program, and whether ownership of animatronic pets would decrease loneliness and improve well-being among lonely older adults. METHODS: Eligible individuals were identified as lonely through a prior survey. Participants were provided with the choice of an animatronic pet and completed T1/T2/T3 surveys. RESULTS: Attrition was high; 168 (63%) participants completed T1/T2 surveys, and 125 (48%) also completed a T3 survey. Post survey data indicated that loneliness decreased, while mental well-being, resilience, and purpose in life improved. Frequent interactions with the pets were associated with greater improvement in mental well-being and optimism. CONCLUSIONS: Animatronic pets appear to provide benefits for the well-being of lonely older adults. Future studies should employ randomized controlled designs examining the impact of animatronic pets.
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Soledad , Mascotas , Anciano , Animales , Humanos , Salud Mental , Propiedad , Encuestas y CuestionariosRESUMEN
BACKGROUND: Effective communications between health care providers and patients are critical for high-quality health care. OBJECTIVE: This study sampled adults age 65 years and older to explore (1) characteristics associated with limited health literacy (LHL) and (2) medical costs and gaps in care based on health literacy, hearing loss, and hearing aid use status. METHODS: The study included 19,223 adults age 65 years and older who completed a health survey that was linked to his or her medical claims that were generated after medical care provided in the year prior to survey completion. Health literacy, hearing loss, and hearing aid use were assessed through self-reports. Health literacy was coded as limited and adequate. Hearing loss and hearing aid use were coded into five categories: no hearing loss, unaided mild, aided mild, unaided severe, and aided severe hearing loss. KEY RESULTS: Seven percent reported LHL and 41% reported hearing loss. Hearing loss, especially unaided severe, was associated with LHL, as were memory loss, depression, loneliness, older age, and male gender. People with aided severe hearing loss and LHL had higher annual medical costs than those with adequate health literacy. Similarly, those with no hearing loss and LHL had higher annual medical costs than those with adequate health literacy. CONCLUSIONS: Unaided mild, aided severe, and unaided severe hearing loss were positively associated with LHL, although the association was reduced among hearing aid users. Specifically, aided mild or severe hearing loss had lower odds of LHL, compared to unaided mild or severe hearing loss, respectively. We also observed that people with both hearing loss and LHL were more likely to have higher medical costs. Continued focus on solutions to address both LHL and hearing loss remains warranted. [HLRP: Health Literacy Research and Practice. 2020;4(2):e129-e137.] PLAIN LANGUAGE SUMMARY: Health survey and medical claims data were used for this study. Hearing loss, especially unaided severe, was associated with limited health literacy, as were memory loss, depression, loneliness, older age, and male gender. Those with both limited health literacy and hearing loss had the highest medical costs. Health literacy and hearing loss can affect health care communications, warranting further study.
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Alfabetización en Salud/normas , Pérdida Auditiva/fisiopatología , Anciano , Anciano de 80 o más Años , Femenino , Alfabetización en Salud/estadística & datos numéricos , Audífonos , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/psicología , Humanos , Modelos Logísticos , Masculino , Encuestas y Cuestionarios , TexasRESUMEN
Chromatin topological organization is instrumental in gene transcription. Gene-enhancer interactions are accommodated in the same CTCF-mediated insulated neighborhoods. However, it remains poorly understood whether and how the 3D genome architecture is dynamically restructured by external signals. Here, we report that LATS kinases phosphorylated CTCF in the zinc finger (ZF) linkers and disabled its DNA-binding activity. Cellular stress induced LATS nuclear translocation and CTCF ZF linker phosphorylation, and altered the landscape of CTCF genomic binding partly by dissociating it selectively from a small subset of its genomic binding sites. These sites were highly enriched for the boundaries of chromatin domains containing LATS signaling target genes. The stress-induced CTCF phosphorylation and locus-specific dissociation from DNA were LATS-dependent. Loss of CTCF binding disrupted local chromatin domains and down-regulated genes located within them. The study suggests that external signals may rapidly modulate the 3D genome by affecting CTCF genomic binding through ZF linker phosphorylation.
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Factor de Unión a CCCTC/metabolismo , Proteínas Quinasas/metabolismo , Sitios de Unión , Factor de Unión a CCCTC/química , Cromatina/genética , Cromatina/metabolismo , Genómica/métodos , Humanos , Lipoproteínas/metabolismo , Modelos Biológicos , Fosforilación , Unión Proteica , Transducción de Señal , Estrés Fisiológico , Dedos de ZincRESUMEN
Liver regeneration after injury requires fine-tune regulation of connective tissue growth factor (Ctgf). It also involves dynamic expression of hepatocyte nuclear factor (Hnf)4α, Yes-associated protein (Yap), and transforming growth factor (Tgf)-ß. The upstream inducers of Ctgf, such as Yap, etc, are well-known. However, the negative regulator of Ctgf remains unclear. Here, we investigated the Hnf4α regulation of Ctgf post-various types of liver injury. Both wild-type animals and animals contained siRNA-mediated Hnf4α knockdown and Cre-mediated Ctgf conditional deletion were used. We observed that Ctgf induction was associated with Hnf4α decline, nuclear Yap accumulation, and Tgf-ß upregulation during early stage of liver regeneration. The Ctgf promoter contained an Hnf4α binding sequence that overlapped with the cis-regulatory element for Yap and Tgf-ß. Ctgf loss attenuated inflammation, hepatocyte proliferation, and collagen synthesis, whereas Hnf4α knockdown enhanced Ctgf induction and liver fibrogenesis. These findings provided a new mechanism about fine-tuned regulation of Ctgf through Hnf4α antagonism of Yap and Tgf-ß activities to balance regenerative and fibrotic signals.
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Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Factor Nuclear 4 del Hepatocito/metabolismo , Hepatocitos/metabolismo , Regeneración Hepática , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Colágeno/genética , Colágeno/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Células HEK293 , Células Hep G2 , Factor Nuclear 4 del Hepatocito/genética , Hepatocitos/fisiología , Humanos , Ratones , Unión Proteica , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia Arriba , Proteínas Señalizadoras YAPRESUMEN
Background: This study recruited older adults to explore physical and psychosocial conditions and other health outcomes associated with hearing loss (HL) and hearing aid use. Method: Survey data were used to categorize 20,244 participants into five groups: no HL, unaided mild HL, aided mild HL, unaided severe HL, and aided severe HL. Results: Individuals with unaided severe HL were more likely to report poor-fair self-rated health and were less likely to leave the home, or exercise 4 to 7 days per week, while there were no such associations for those with aided mild or severe HL. In addition, those with aided hearing were less likely to report depression, low social support, or mobility limitations. Discussion: In several instances, hearing aid use reduced associations between HL and negative psychosocial and physical characteristics, and health outcomes. More research using longitudinal study designs is needed to better understand the true implications of these findings.
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Depresión , Audífonos , Pérdida Auditiva , Funcionamiento Psicosocial , Anciano , Depresión/etiología , Depresión/prevención & control , Femenino , Estado Funcional , Audífonos/psicología , Audífonos/estadística & datos numéricos , Pérdida Auditiva/complicaciones , Pérdida Auditiva/psicología , Pérdida Auditiva/terapia , Humanos , Estudios Longitudinales , Masculino , Salud Mental , Evaluación de Resultado en la Atención de Salud , Encuestas y CuestionariosRESUMEN
OBJECTIVE: There are no effective systemic therapies for adenoid cystic cancer (ACC) and lack of tumor lines and mouse models have hindered drug development.We aim to develop MYB-activated models for testing new therapeutic agents. MATERIALS AND METHODS: We studied new ACC patient-derived xenograft (PDX) models and generated a matched cell line from one patient. In addition, we generated a genetically-engineered MYB-NFIB mouse model (GEMM) that was crossed with Ink4a+/-/Arf+/- mice to study tumor spectrum and obtain tumor lines. Using human and murine ACC-like tumor lines, we analyzed MYB expression by RNA-Seq and immunoblot and tested efficacy of new MYB inhibitors. RESULTS: We detected MYB-NFIB transcripts in both UFH1 and UFH2 PDX and observed tumor inhibition by MYB depletion using shRNA in vivo. We observed rapid loss of MYB expression when we cultured UFH1 in vitro, but were able to generate a UFH2 tumor cell line that retained MYB expression for 6â¯months. RNA-Seq expression detected an ACC-like mRNA signature in PDX samples and we confirmed an identical KMT2A/MLL variant in UFH2 PDX, matched cell line, and primary biopsy. Although the predominant phenotype of the MYB-NFIB GEMM was B-cell leukemia, we also generated a MYB-activated ACC-like mammary tumor cell line. We observed tumor inhibition using a novel MYB peptidomimetic in both human and murine tumor models. CONCLUSIONS: We generated and studied new murine and human MYB-activated tumor samples and detected growth inhibition with MYB peptidomimetics. These data provide tools to define treatment strategies for patients with advanced MYB-activated ACC.
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Antineoplásicos/farmacología , Carcinoma Adenoide Quístico/genética , Proteínas Proto-Oncogénicas c-myb/genética , Activación Transcripcional , Animales , Carcinoma Adenoide Quístico/tratamiento farmacológico , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , Línea Celular Tumoral , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Ratones , Ratones Transgénicos , Proteómica/métodos , Proteínas Proto-Oncogénicas c-myb/metabolismo , Análisis de Secuencia de ARN , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. METHODS: INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided. RESULTS: INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival. CONCLUSIONS: LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas Serina-Treonina Quinasas/genética , Transcriptoma/genética , Células A549 , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Comunicación Autocrina/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Ratones , Transducción de Señal/genética , Factores de Transcripción/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hearing loss is common among older adults. Thus, it was of interest to explore differences in health care utilization and costs associated with hearing loss and hearing aid use. Hearing loss and hearing aid use were assessed through self-reports and included 5 categories: no hearing loss, aided mild, unaided mild, aided severe, and unaided severe hearing loss. Health care utilization and costs were obtained from medical claims. Those with aided mild or severe hearing loss were significantly more likely to have an emergency department visit. Conversely, those with aided severe hearing loss were about 15% less likely to be hospitalized. Individuals with unaided severe hearing loss had the highest annual medical costs ($14349) compared with those with no hearing loss ($12118, P < .001). In this study, those with unaided severe hearing loss had the highest medical costs. Further studies should attempt to better understand the relationship between hearing loss, hearing aid use, and medical costs.
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Servicio de Urgencia en Hospital/estadística & datos numéricos , Gastos en Salud , Pérdida Auditiva , Aceptación de la Atención de Salud/estadística & datos numéricos , Autoinforme , Anciano , Anciano de 80 o más Años , Femenino , Audífonos , Hospitalización/estadística & datos numéricos , Humanos , Revisión de Utilización de Seguros , Masculino , Medicare , Estados UnidosRESUMEN
Accumulating evidence indicates that the Notch signaling pathway has crucial roles in the control of fate decision and differentiation in numerous cell types. However, the role of Notch signaling in regulating proliferation and differentiation of myeloid progenitor cells remains controversial. To elucidate this issue, we modulated Notch activity through transducing a constitutively activated form of Notch1 and/or a dominant-negative form of MAML1 (DNMAML1) into myeloid progenitor 32D cells and assessed their effects on cell proliferation and differentiation. We found that Notch1 activation enhances proliferation and delays granulocytic differentiation of 32D cells. The enhanced proliferation due to activated Notch1 signaling was associated with upregulation of c-Myc, followed by decreased expression of p21 and p27, and increased cdc2 kinase activity, through a mechanism that was not blocked by DNMAML1. Conversely, Notch1 activation significantly delayed granulocytic differentiation and maintained a part of myeloid progenitor cells in an immature stage, and this Notch1-mediated effect was dependent on MAML. The Notch1-induced effects on mye myeloid cell proliferation and differentiation were likely mediated by induction of c-Myc and repression of PU.1, respectively. Thus, Notch1 signaling plays an important part in modulating proliferation and differentiation in MAML-independent and -dependent manners and promoting expansion of myeloid progenitors.
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Proteína Quinasa CDC2/metabolismo , Diferenciación Celular , Proliferación Celular , Células Progenitoras Mieloides/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal , Proteína Quinasa CDC2/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Granulocitos/citología , Granulocitos/metabolismo , Células HL-60 , Humanos , Células Progenitoras Mieloides/citología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptor Notch1/genética , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Mucoepidermoid carcinoma (MEC) arises in many glandular tissues and contributes to the most common malignant salivary gland cancers. MEC is specifically associated with a unique t(11;19) translocation and the resulting CRTC1-MAML2 fusion is a major oncogenic driver for MEC initiation and maintenance. However, the molecular basis underlying the CRTC1-MAML2 oncogenic functions remains elusive. Through gene expression profiling analysis, we observed that LINC00473, a long non-coding RNA (lncRNA), was the top down-regulated target in CRTC1-MAML2-depleted human MEC cells. LncRNAs belong to a new class of non-coding RNAs with emerging roles in tumorigenesis and progression, but remain poorly characterized. In this study, we investigated the role of LINC00473 in mediating CRTC1-MAML2 oncogenic activity in human MEC. We found that LINC00473 transcription was significantly induced in human CRTC1-MAML2-positive MEC cell lines and primary MEC tumors, and was tightly correlated with the CRTC1-MAML2 RNA level. LINC00473 induction was dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Depletion of LINC00473 significantly reduced the proliferation and survival of human MEC cells in vitro and blocked the in vivo tumor growth in a human MEC xenograft model. RNA in situ hybridization analysis demonstrated a predominantly nuclear localization pattern for LINC00473 in human MEC cells. Furthermore, gene expression profiling revealed that LINC00473 depletion resulted in differential expression of genes important in cancer cell growth and survival. LINC00473 likely regulates gene expression in part through its ability to bind to a cAMP signaling pathway component NONO, enhancing the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Our overall results demonstrate that LINC00473 is a downstream target and an important mediator of the CRTC1-MAML2 oncoprotein. Therefore, LINC00473 acts as a promising biomarker and therapeutic target for human CRTC1-MAML2-positive MECs.
Asunto(s)
Carcinoma Mucoepidermoide/patología , Proliferación Celular/genética , Proteínas de Unión al ADN/fisiología , Proteínas Nucleares/fisiología , Proteínas de Fusión Oncogénica/fisiología , ARN Largo no Codificante/genética , Neoplasias de las Glándulas Salivales/patología , Factores de Transcripción/fisiología , Animales , Biomarcadores de Tumor/fisiología , Carcinoma Mucoepidermoide/genética , Supervivencia Celular/genética , Células Cultivadas , Proteínas de Unión al ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Proteínas Nucleares/genética , Neoplasias de las Glándulas Salivales/genética , Transactivadores , Factores de Transcripción/genéticaRESUMEN
Interventions to reduce caregiver burden are of great interest as the number of informal family caregivers continues to grow. The purpose of this study was to test the feasibility of an online mindfulness meditation intervention for community-dwelling older adult caregivers and to evaluate its impact on quality of life, caregiver burden, and psychological well-being. A total of 40 caregivers were recruited from 2 community center support groups to participate in an 8-week online mindfulness intervention. Pre and post surveys were administered. Retention rates were high with 55% completing the post surveys and attending at least 5 out of 8 sessions. Matched pairs t test indicated that the intervention reduced caregiver burden, perceived stress, anxiety, and loneliness and improved mental well-being. Online interventions offer flexibility for caregivers regardless of their responsibilities. Future research should expand this opportunity and explore the scalability of online mindfulness interventions.