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1.
Cancer Cell ; 2024 May 30.
Article in English | MEDLINE | ID: mdl-38848721

ABSTRACT

Cancer engineering is an interdisciplinary approach that promises to confront the complexities of cancer and accelerate transformative discoveries by integrating innovative fields across engineering and the physical sciences with a focus on cancer. We offer a conceptual framework for the hallmarks of cancer engineering, integrating 12 fields: system dynamics; imaging, radiation, and spectroscopy; robotics and controls; solid mechanics; fluid mechanics; chemistry and nanomaterials; mathematics and simulation; cellular and protein engineering; kinetics and thermodynamics; materials science; manufacturing and biofabrication; and microsystems.

4.
Cancer Res Commun ; 4(2): 264-278, 2024 02 01.
Article in English | MEDLINE | ID: mdl-38165157

ABSTRACT

The p53 family member TP63 encodes two sets of N-terminal isoforms, TAp63 and ΔNp63 isoforms. They each regulate diverse biological functions in epidermal morphogenesis and in cancer. In the skin, where their activities have been extensively characterized, TAp63 prevents premature aging by regulating the quiescence and genomic stability of stem cells required for wound healing and hair regeneration, while ΔNp63 controls maintenance and terminal differentiation of epidermal basal cells. This functional diversity is surprising given that these isoforms share a high degree of similarity, including an identical sequence for a DNA-binding domain. To understand the mechanisms of the transcriptional programs regulated by each p63 isoform and leading to diverse biological functions, we performed genome-wide analyses using p63 isoform-specific chromatin immunoprecipitation, RNA sequencing, and metabolomics of TAp63-/- and ΔNp63-/- mouse epidermal cells. Our data indicate that TAp63 and ΔNp63 physically and functionally interact with distinct transcription factors for the downstream regulation of their target genes, thus ultimately leading to the regulation of unique transcriptional programs and biological processes. Our findings unveil novel transcriptomes regulated by the p63 isoforms to control diverse biological functions, including the cooperation between TAp63 and NRF2 in the modulation of metabolic pathways and response to oxidative stress providing a mechanistic explanation for the TAp63 knock out phenotypes. SIGNIFICANCE: The p63 isoforms, TAp63 and ΔNp63, control epithelial morphogenesis and tumorigenesis through the interaction with distinct transcription factors and the subsequent regulation of unique transcriptional programs.


Subject(s)
NF-E2-Related Factor 2 , Neoplasms , Mice , Animals , NF-E2-Related Factor 2/genetics , Genome-Wide Association Study , Neoplasms/genetics , Protein Isoforms/genetics , Epidermis/metabolism
5.
NPJ Precis Oncol ; 7(1): 68, 2023 Jul 18.
Article in English | MEDLINE | ID: mdl-37464050

ABSTRACT

Preclinical genetically engineered mouse models (GEMMs) of lung adenocarcinoma are invaluable for investigating molecular drivers of tumor formation, progression, and therapeutic resistance. However, histological analysis of these GEMMs requires significant time and training to ensure accuracy and consistency. To achieve a more objective and standardized analysis, we used machine learning to create GLASS-AI, a histological image analysis tool that the broader cancer research community can utilize to grade, segment, and analyze tumors in preclinical models of lung adenocarcinoma. GLASS-AI demonstrates strong agreement with expert human raters while uncovering a significant degree of unreported intratumor heterogeneity. Integrating immunohistochemical staining with high-resolution grade analysis by GLASS-AI identified dysregulation of Mapk/Erk signaling in high-grade lung adenocarcinomas and locally advanced tumor regions. Our work demonstrates the benefit of employing GLASS-AI in preclinical lung adenocarcinoma models and the power of integrating machine learning and molecular biology techniques for studying the molecular pathways that underlie cancer progression.

6.
Rev. cuba. med. mil ; 52(2)jun. 2023.
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1559824

ABSTRACT

Introducción: Es importante conocer el desarrollo psicomotor de los niños con parálisis cerebral de acuerdo con sus características sociodemográficas y clínicas para realizar un mejor tratamiento en este tipo de pacientes. Objetivo: Describir el desarrollo psicomotor según las características sociodemográficas y clínicas de niños hasta 36 meses con parálisis cerebral. Métodos: Estudio observacional, descriptivo, de corte transversal con datos retrospectivos. Se revisaron 177 historias clínicas de pacientes con diagnóstico de parálisis cerebral de 0 a 36 meses, atendidos del 1 de enero de 2015 al 31 de diciembre de 2016 en un instituto nacional de rehabilitación de Lima, Perú. Resultados: La edad promedio fue 25,1 ± 7,16 meses, el 58,19 % fue del sexo masculino, el grupo etario de 25-36 meses representó el 67,89 %, predominó la parálisis cerebral espástica cuadripléjica con 28,25 %, el 14,12 % tenía alteración en la audición y el 19,21 % convulsiones. El promedio de porcentajes de desarrollo psicomotor global fue de 62,66 %; los menores promedios fueron para el comportamiento motor grueso (57,15 %), el grupo etario de 0 a 12 meses (51,49 %), las niñas (57,72 %), la parálisis cerebral espástica cuadriplejia (42,55 %), niños con alteración auditiva y visual (36,92 %), con convulsiones (46,17 %) y prematuros (58,26 %). Conclusiones: Los niños hasta 36 meses con parálisis cerebral tienen un retraso global del desarrollo psicomotor de aproximadamente el 35 %, con mayor afectación los de menor edad, las niñas, los que tienen parálisis cerebral espástica cuadripléjica, alteración auditiva y visual, convulsiones y son prematuros.


Introduction: It is important to know the psychomotor development of children with cerebral palsy according to their sociodemographic and clinical characteristics to carry out a better approach in this type of patients. Objective: To describe the psychomotor development according to sociodemographic and clinical characteristics of children up to 36 months with cerebral palsy. Methods: Observational, descriptive, cross-sectional study with retrospective data. 177 medical records of patients with a diagnosis of cerebral palsy from 0 to 36 months were reviewed, treated from January 1, 2015 to December 31, 2016 at a national rehabilitation institute in Lima, Peru. Results: The average age was 25.1 ± 7.16 months, the 58.19% were male, the age group of 25-36 months represented 67.89%, quadriplegic spastic cerebral palsy predominated with 28.25%, 14.12% had alteration in hearing and 19.21% seizures. The average percentage of global psychomotor development was 62.66%; the lowest averages were for gross motor behavior (57.15%), the age group from 0 to 12 months (51.49%), girls (57.72%), spastic cerebral palsy quadriplegia (42.55%), children with hearing and visual impairment (36.92%), with seizures (46.17%) and premature (58.26%). Conclusions: Children up to 36 months with cerebral palsy have a global delay in psychomotor development of approximately 35%, with greater affectation in younger children, girls, those with spastic quadriplegic cerebral palsy, hearing and visual disorders, seizures and are premature.

7.
Cancer Res ; 83(9): 1426-1442, 2023 05 02.
Article in English | MEDLINE | ID: mdl-36862034

ABSTRACT

Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and redox metabolism. The intracellular cysteine pool can be sustained by cystine uptake or de novo synthesis from serine and homocysteine. Demand for cysteine is increased during tumorigenesis for generating glutathione to deal with oxidative stress. While cultured cells have been shown to be highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized. We comprehensively interrogated cysteine metabolism in normal murine tissues and cancers that arise from them using stable isotope 13C1-serine and 13C6-cystine tracing. De novo cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue, while cysteine synthesis was either inactive or downregulated during tumorigenesis. In contrast, cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and tumors. However, differences in glutathione labeling from cysteine were evident across tumor types. Thus, cystine is a major contributor to the cysteine pool in tumors, and glutathione metabolism is differentially active across tumor types. SIGNIFICANCE: Stable isotope 13C1-serine and 13C6-cystine tracing characterizes cysteine metabolism in normal murine tissues and its rewiring in tumors using genetically engineered mouse models of liver, pancreas, and lung cancers.


Subject(s)
Cysteine , Neoplasms , Mice , Animals , Cysteine/metabolism , Cystine/metabolism , Glutathione/metabolism , Carcinogenesis , Serine , Mammals/metabolism
8.
J Natl Cancer Inst ; 114(12): 1619-1627, 2022 12 08.
Article in English | MEDLINE | ID: mdl-36053203

ABSTRACT

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as considering signal-seeking trial designs. A fourth breakout group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other breakout groups prior to the meeting to aid in study development. A total of 4 concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the Clinical Trials Planning Meeting with the goal of developing clinical trials for patients with TP53-mutant HNSCC that can be conducted within the National Clinical Trials Network.


Subject(s)
Head and Neck Neoplasms , Papillomavirus Infections , Humans , Squamous Cell Carcinoma of Head and Neck/genetics , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/therapy , Tumor Suppressor Protein p53/genetics , Papillomavirus Infections/complications , Papillomavirus Infections/genetics , Genes, p53 , Mutation
9.
Cancers (Basel) ; 14(17)2022 Sep 02.
Article in English | MEDLINE | ID: mdl-36077845

ABSTRACT

Despite aggressive combination chemotherapy and surgery, outcomes for patients with osteosarcoma have remained stagnant for more than 25 years, and numerous clinical trials have identified no new therapies. p53 deletion or mutation is found in more than 80% of osteosarcoma tumors. In p53-deficient cancers with structurally altered p63 and p73, interfering with tumor cell metabolism using Pramlintide (an FDA-approved drug for type 2 diabetes) results in tumor regression. Pramlintide response is mediated through upregulation of islet amyloid polypeptide (IAPP). Here, we showed that osteosarcoma cells have altered p63, p73, and p53, and decreased IAPP expression but have the two main IAPP receptors, CalcR and RAMP3, which inhibit glycolysis and induce apoptosis. We showed that in osteosarcoma cells with high- or mid-range glycolytic activity, Pramlintide decreased cell glycolysis, resulting in decreased proliferation and increased apoptosis in vitro. In contrast, Pramlintide had no effect in osteosarcoma cells with low glycolytic activity. Using a subcutaneous osteosarcoma mouse model, we showed that intratumoral injection of Pramlintide-induced tumor regression. Tumor sections showed increased apoptosis and a decrease in Ki-67 and HIF-1α. These data suggest that in osteosarcoma cells with altered p53, p63, and p73 and a high glycolytic function, Pramlintide therapy can modulate metabolic programming and inhibit tumor growth.

10.
Cell Death Dis ; 13(4): 397, 2022 04 22.
Article in English | MEDLINE | ID: mdl-35459267

ABSTRACT

As a key component of the RNA-induced silencing complex (RISC), Argonaute2 (Ago2) exhibits a dual function regulatory role in tumor progression. However, the mechanistic basis of differential regulation remains elusive. p63 is a homolog of the tumor suppressor p53. p63 isoforms play a critical role in tumorigenesis and metastasis. Herein, we show that p63 isoforms physically interact with and stabilize Ago2. Expression of p63 isoforms increases the levels of Ago2 protein, while depletion of p63 isoforms by shRNA decreases Ago2 protein levels. p63 strongly guides Ago2 dual functions in vitro and in vivo. Ectopic expression of the miR-144/451 cluster increases p63 protein levels; TAp63 transactivates the miR-144/451 cluster, forming a positive feedback loop. Notably, miR-144 activates p63 by directly targeting Itch, an E3 ligase of p63. Ectopic expression of miR-144 induces apoptosis in H1299 cells. miR-144 enhances TAp63 tumor suppressor function and inhibits cell invasion. Our findings uncover a novel function of p63 linking the miRNA-144 cluster and the Ago2 pathway. FACTS AND QUESTIONS: Identification of Ago2 as a p63 target. Ago2 exhibits a dual function regulatory role in tumor progression; however, the molecular mechanism of Ago2 regulation remains unknown. p63 strongly guides Ago2 dual functions in vitro and in vivo. Unraveling a novel function of p63 links the miRNA-144 cluster and the Ago2 pathway.


Subject(s)
MicroRNAs , Neoplasms , Argonaute Proteins , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasms/metabolism , Protein Isoforms/metabolism , RNA-Induced Silencing Complex/metabolism , Transcription Factors , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases/metabolism
12.
Nat Commun ; 13(1): 614, 2022 02 01.
Article in English | MEDLINE | ID: mdl-35105868

ABSTRACT

Distinct lung stem cells give rise to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). ΔNp63, the p53 family member and p63 isoform, guides the maturation of these stem cells through the regulation of their self-renewal and terminal differentiation; however, the underlying mechanistic role regulated by ∆Np63 in lung cancer development has remained elusive. By utilizing a ΔNp63-specific conditional knockout mouse model and xenograft models of LUAD and LUSC, we found that ∆Np63 promotes non-small cell lung cancer by maintaining the lung stem cells necessary for lung cancer cell initiation and progression in quiescence. ChIP-seq analysis of lung basal cells, alveolar type 2 (AT2) cells, and LUAD reveals robust ∆Np63 regulation of a common landscape of enhancers of cell identity genes. Importantly, one of these genes, BCL9L, is among the enhancer associated genes regulated by ∆Np63 in Kras-driven LUAD and mediates the oncogenic effects of ∆Np63 in both LUAD and LUSC. Accordingly, high BCL9L levels correlate with poor prognosis in LUAD patients. Taken together, our findings provide a unifying oncogenic role for ∆Np63 in both LUAD and LUSC through the regulation of a common landscape of enhancer associated genes.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Animals , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Proliferation , Epithelium , Female , Humans , Lung/pathology , Lung Neoplasms/pathology , Male , Mice , Mice, Knockout
13.
J Invest Dermatol ; 142(7): 1956-1965.e2, 2022 07.
Article in English | MEDLINE | ID: mdl-34890627

ABSTRACT

Cutaneous squamous cell carcinoma (cSCC) comprises 15‒20% of all skin cancers and has a well-defined progression sequence from precancerous actinic keratosis to invasive cSCC. To identify targets for chemoprevention, we previously reported a cross-species analysis to identify the transcriptional drivers of cSCC development and identified miR-181a as a potential oncomiR. We show that the upregulation of miR-181a promotes multiple protumorigenic properties by targeting an understudied component of TGFß signaling, TGFßR3. miR-181a and TGFßR3 are upregulated and downregulated, respectively, in cSCC. miR-181a overexpression (OE) and TGFßR3 knockdown (KD) significantly suppresses UV-induced apoptosis in HaCaT cells and in primary normal human epidermal keratinocytes. In addition, OE of miR-181a or KD of TGFßR3 by short hairpin RNA enhances anchorage-independent survival. miR-181a OE or TGFßR3 KD enhances cellular migration and invasion and upregulation of epithelial‒mesenchymal transition markers. Luciferase reporter assays demonstrate that miR-181a directly targets the 3'-untranslated region of TGFßR3. miR-181a upregulates phosphorylated SMAD3 levels after TGFß2 administration and results in elevated SNAIL and SLUG expression. Finally, we confirm in vivo that miR-181a inhibition compromises tumor growth. Importantly, these phenotypes can be reversed with TGFßR3 OE or KD in the context of miR-181a OE or KD, respectively, further highlighting the physiologic relevance of this regulation in cSCC.


Subject(s)
Carcinoma, Squamous Cell , MicroRNAs , Proteoglycans , Receptors, Transforming Growth Factor beta , Skin Neoplasms , 3' Untranslated Regions/genetics , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/genetics , Proteoglycans/genetics , Receptors, Transforming Growth Factor beta/genetics , Skin Neoplasms/pathology
14.
Front Artif Intell ; 4: 754641, 2021.
Article in English | MEDLINE | ID: mdl-34568816

ABSTRACT

The tumor immune microenvironment (TIME) encompasses many heterogeneous cell types that engage in extensive crosstalk among the cancer, immune, and stromal components. The spatial organization of these different cell types in TIME could be used as biomarkers for predicting drug responses, prognosis and metastasis. Recently, deep learning approaches have been widely used for digital histopathology images for cancer diagnoses and prognoses. Furthermore, some recent approaches have attempted to integrate spatial and molecular omics data to better characterize the TIME. In this review we focus on machine learning-based digital histopathology image analysis methods for characterizing tumor ecosystem. In this review, we will consider three different scales of histopathological analyses that machine learning can operate within: whole slide image (WSI)-level, region of interest (ROI)-level, and cell-level. We will systematically review the various machine learning methods in these three scales with a focus on cell-level analysis. We will provide a perspective of workflow on generating cell-level training data sets using immunohistochemistry markers to "weakly-label" the cell types. We will describe some common steps in the workflow of preparing the data, as well as some limitations of this approach. Finally, we will discuss future opportunities of integrating molecular omics data with digital histopathology images for characterizing tumor ecosystem.

15.
Cancer Res ; 81(17): 4394-4396, 2021 09 01.
Article in English | MEDLINE | ID: mdl-34470782

ABSTRACT

In 1990, Baker and colleagues reported their seminal findings in Cancer Research focusing on the transition from adenoma to carcinoma of the colon. By sequencing the TP53 locus in 58 colorectal tumors (25 adenomas and 33 carcinomas) and measuring its allelic deletions, they discovered that this transition requires the loss of one TP53 allele and the mutation of the other one. Here, we discuss how this landmark discovery shed a new light on p53 mutations, prompting the generation of novel mouse models that definitively proved the mutant p53 gain-of-function hypothesis suggested by these results. Finally, we evaluate the implications that the Vogelstein model of cancer progression had on numerous aspects of cancer biology and cancer care, including the characterization of tumor evolution and the response to therapy, and how it ultimately contributed to the wider adoption of early detection screenings and personalized medicine.See related article by Baker and colleagues, Cancer Res 1990;50:7717-22.


Subject(s)
Adenoma , Colorectal Neoplasms , Animals , Gain of Function Mutation , Mice , Mutation , Precision Medicine , Tumor Suppressor Protein p53/genetics
16.
Cancer ; 127(23): 4413-4420, 2021 12 01.
Article in English | MEDLINE | ID: mdl-34358340

ABSTRACT

BACKGROUND: The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival. METHODS: The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation. RESULTS: A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group (P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3-4), those who underwent END did not have improved survival rates. CONCLUSIONS: Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Skin Neoplasms , Carcinoma, Squamous Cell/pathology , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/surgery , Humans , Lymphatic Metastasis , Neck Dissection/methods , Neoplasm Staging , Retrospective Studies , Skin Neoplasms/pathology , Skin Neoplasms/surgery
17.
Sci Rep ; 11(1): 12673, 2021 06 16.
Article in English | MEDLINE | ID: mdl-34135394

ABSTRACT

A subset of hepatocellular carcinoma (HCC) overexpresses the chromosome 19 miRNA cluster (C19MC) and is associated with an undifferentiated phenotype marked by overexpression of cancer testis antigens (CTAs) including anti-apoptotic melanoma-A antigens (MAGEAs). However, the regulation of C19MC miRNA and MAGEA expression in HCCs are not understood. Here we show that, C19MC overexpression is tightly linked to a sub-set of HCCs with transcription-incompetent p53. Using next-generation and Sanger sequencing we found that, p53 in Hep3B cells is impaired by TP53-FXR2 fusion, and that overexpression of the C19MC miRNA-520G in Hep3B cells promotes the expression of MAGEA-3, 6 and 12 mRNAs. Furthermore, overexpression of p53-R175H and p53-R273H mutants promote miR-520G and MAGEA RNA expression and cellular transformation. Moreover, IFN-γ co-operates with miR-520G to promote MAGEA expression. On the other hand, metals such as nickel and zinc promote miR-526B but not miR-520G, to result in the suppression of MAGEA mRNA expression, and evoke cell death through mitochondrial membrane depolarization. Therefore our study demonstrates that a MAGEA-promoting network involving miR-520G, p53-defects and IFN-γ that govern cellular transformation and cell survival pathways, but MAGEA expression and survival are counteracted by nickel and zinc combination.


Subject(s)
Antigens, Neoplasm , Carcinoma, Hepatocellular , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic , Antigens, Neoplasm/genetics , Antigens, Neoplasm/metabolism , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Chromosomes, Human, Pair 19 , Humans , Interferon-gamma/metabolism , Liver Neoplasms/etiology , Liver Neoplasms/pathology , Male , MicroRNAs/metabolism , Mutation , Oncogene Fusion , Peptide Fragments/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Testis/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
18.
Bioinformatics ; 37(20): 3681-3683, 2021 Oct 25.
Article in English | MEDLINE | ID: mdl-33901274

ABSTRACT

SUMMARY: The heterogeneous cell types of the tumor-immune microenvironment (TIME) play key roles in determining cancer progression, metastasis and response to treatment. We report the development of TIMEx, a novel TIME deconvolution method emphasizing on estimating infiltrating immune cells for bulk transcriptomics using pan-cancer single-cell RNA-seq signatures. We also implemented a comprehensive, user-friendly web-portal for users to evaluate TIMEx and other deconvolution methods with bulk transcriptomic profiles. AVAILABILITY AND IMPLEMENTATION: TIMEx web-portal is freely accessible at http://timex.moffitt.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

19.
Nucleic Acids Res ; 49(5): 2740-2758, 2021 03 18.
Article in English | MEDLINE | ID: mdl-33619536

ABSTRACT

The major clinical problem in human cancer is metastasis. Metastases are the cause of 90% of human cancer deaths. TAp63 is a critical suppressor of tumorigenesis and metastasis. ΔNp63 acts as a dominant-negative inhibitor to block the function of p53 and TAp63. Although several ubiquitin E3 ligases have been reported to regulate p63 stability, the mechanism of p63 regulation remains partially understood. Herein, we show that CHIP, an E3 ligase with a U-box domain, physically interacts with p63 and promotes p63 degradation. Notably, Hsp70 depletion by siRNA stabilizes TAp63 in H1299 cells and destabilizes ΔNp63 in SCC9 cells. Loss of Hsp70 results in a reduction in the TAp63-CHIP interaction in H1299 cells and an increase in the interaction between ΔNp63 and CHIP in SCC9 cells. Our results reveal that Hsp70 acts as a molecular switch to control CHIP-mediated ubiquitination and degradation of p63 isoforms. Furthermore, regulation of p63 by the Hsp70-CHIP axis contributes to the migration and invasion of tumor cells. Hence, our findings demonstrate that Hsp70 is a crucial regulator of CHIP-mediated ubiquitination and degradation of p63 isoforms and identify a new pathway for maintaining TAp63 or ΔNp63 stability in cancers.


Subject(s)
HSP70 Heat-Shock Proteins/metabolism , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Animals , Apoptosis , Cell Line, Tumor , Cell Movement , Cells, Cultured , HSP70 Heat-Shock Proteins/physiology , Humans , Mice , Neoplasm Invasiveness , Neoplasms/metabolism , Neoplasms/mortality , Trans-Activators/metabolism , Transcriptional Activation
20.
ACS Omega ; 5(45): 29073-29080, 2020 Nov 17.
Article in English | MEDLINE | ID: mdl-33225138

ABSTRACT

In Chile, one of the ways in which small-scale mining industries sustain themselves is through the sale of copper ores to the state company ENAMI, which monetizes this product depending on the copper's mineral grade. To sell this mineral, small mining companies must transport the product to ENAMI, which means a high monetary cost, added to the fact that there are large amounts of waste minerals that cannot be sold because of their low grade. The present work aims that small miners can process these copper ores in situ to commercialize a more valuable product, such as copper salts. Considering the high solar radiation and the scarce superficial water resources found in the north side of the country, a possible process alternative is the leaching of the ores using acid seawater solutions followed by crystallization by solar evaporation. As a necessary tool for this process design, the present work has developed a model able to predict the copper sulfate pentahydrate crystallization from multicomponent solutions, preventing the co-precipitation of undesired compounds (such as iron salts, sodium chloride, and sodium sulphate among others) that contaminate the final product. The Pitzer thermodynamic model was successfully applied to predict the crystallization process of copper sulfate pentahydrate from synthetic leaching solutions. These results were validated through experimental tests.

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