Publications by authors named "Chu-Xia Deng"

200 Publications

SRC-3, a Steroid Receptor Coactivator: Implication in Cancer.

Int J Mol Sci 2021 Apr 30;22(9). Epub 2021 Apr 30.

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.

Steroid receptor coactivator-3 (SRC-3), also known as amplified in breast cancer 1 (AIB1), is a member of the SRC family. SRC-3 regulates not only the transcriptional activity of nuclear receptors but also many other transcription factors. Besides the essential role of SRC-3 in physiological functions, it also acts as an oncogene to promote multiple aspects of cancer. This review updates the important progress of SRC-3 in carcinogenesis and summarizes its mode of action, which provides clues for cancer therapy.
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http://dx.doi.org/10.3390/ijms22094760DOI Listing
April 2021

The continued global battle against SARS-CoV-2 and COVID-19.

Authors:
Chu-Xia Deng

Int J Biol Sci 2021 10;17(6):1440-1442. Epub 2021 Apr 10.

Editor in Chief, International Journal of Biological Sciences.

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http://dx.doi.org/10.7150/ijbs.60639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071758PMC
April 2021

Preclinical evaluation of radiation therapy of -associated mammary tumors using a mouse model.

Int J Biol Sci 2021 31;17(3):689-701. Epub 2021 Jan 31.

Research Institute, National Cancer Center, Goyang, 10408, Korea.

Although germline mutations in highly predispose women towards breast and ovarian cancer, few substantial improvements in preventing or treating such cancers have been made. Importantly, BRCA1 function is closely associated with DNA damage repair, which is required for genetic stability. Here, we examined the efficacy of radiotherapy, assessing the accumulation of genetic instabilities, in the treatment of -associated breast cancer using a -mutant mouse model. Treatment of -mutant tumor-engrafted mice with X-rays reduced tumor progression by 27.9% compared with untreated controls. A correlation analysis of irradiation responses and biomarker profiles in tumors at baseline identified differences between responders and non-responders at the protein level (pERα, pCHK2, p53, and EpCAM) and at the SOX2 target expression level. We further demonstrated that combined treatment of -mutant mammary tumors with irradiation and AZD2281, which inhibits PARP, significantly reduced tumor progression and extended survival. Our findings enhance the understanding of DNA damage and biomarker responses in -associated mammary tumors and provide preclinical evidence that radiotherapy with synthetic DNA damage is a potential strategy for the therapeutic management of -associated breast cancer.
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http://dx.doi.org/10.7150/ijbs.53667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975707PMC
January 2021

Oxygen-Enriched Metal-Phenolic X-Ray Nanoprocessor for Cancer Radio-Radiodynamic Therapy in Combination with Checkpoint Blockade Immunotherapy.

Adv Sci (Weinh) 2021 Feb 31;8(4):2003338. Epub 2020 Dec 31.

Cancer Center Faculty of Health Sciences University of Macau Macau SAR, 999078 China.

Radiotherapy (RT) based on DNA damage and reactive oxygen species (ROS) generation has been clinically validated in various types of cancer. However, high dose-dependent induced toxicity to tissues, non-selectivity, and radioresistance greatly limit the application of RT. Herein, an oxygen-enriched X-ray nanoprocessor Hb@Hf-Ce6 nanoparticle is developed for improving the therapeutic effect of RT-radiodynamic therapy (RDT), enhancing modulation of hypoxia tumor microenvironment (TME) and promoting antitumor immune response in combination with programmed cell death protein 1 (PD-1) immune checkpoint blockade. All functional molecules are integrated into the nanoparticle based on metal-phenolic coordination, wherein one high-Z radiosensitizer (hafnium, Hf) coordinated with chlorin e6 (Ce6) modified polyphenols and a promising oxygen carrier (hemoglobin, Hb) is encapsulated for modulation of oxygen balance in the hypoxia TME. Specifically, under single X-ray irradiation, radioluminescence excited by Hf can activate photosensitizer Ce6 for ROS generation by RDT. Therefore, this combinatory strategy induces comprehensive antitumor immune response for cancer eradication and metastasis inhibition. This work presents a multifunctional metal-phenolic nanoplatform for efficient X-ray mediated RT-RDT in combination with immunotherapy and may provide a new therapeutic option for cancer treatment.
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http://dx.doi.org/10.1002/advs.202003338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887592PMC
February 2021

Cisplatin prevents breast cancer metastasis through blocking early EMT and retards cancer growth together with paclitaxel.

Theranostics 2021 1;11(5):2442-2459. Epub 2021 Jan 1.

Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China.

Cancer growth is usually accompanied by metastasis which kills most cancer patients. Here we aim to study the effect of cisplatin at different doses on breast cancer growth and metastasis. We used cisplatin to treat breast cancer cells, then detected the migration of cells and the changes of epithelial-mesenchymal transition (EMT) markers by migration assay, Western blot, and immunofluorescent staining. Next, we analyzed the changes of RNA expression of genes by RNA-seq and confirmed the binding of activating transcription factor 3 (ATF3) to cytoskeleton related genes by ChIP-seq. Thereafter, we combined cisplatin and paclitaxel in a neoadjuvant setting to treat xenograft mouse models. Furthermore, we analyzed the association of disease prognosis with cytoskeletal genes and ATF3 by clinical data analysis. When administered at a higher dose (6 mg/kg), cisplatin inhibits both cancer growth and metastasis, yet with strong side effects, whereas a lower dose (2 mg/kg) cisplatin blocks cancer metastasis without obvious killing effects. Cisplatin inhibits cancer metastasis through blocking early steps of EMT. It antagonizes transforming growth factor beta (TGFβ) signaling through suppressing transcription of many genes involved in cytoskeleton reorganization and filopodia formation which occur early in EMT and are responsible for cancer metastasis. Mechanistically, TGFβ and fibronectin-1 (FN1) constitute a positive reciprocal regulation loop that is critical for activating TGFβ/SMAD3 signaling, which is repressed by cisplatin induced expression of ATF3. Furthermore, neoadjuvant administration of cisplatin at 2 mg/kg in conjunction with paclitaxel inhibits cancer growth and blocks metastasis without causing obvious side effects by inhibiting colonization of cancer cells in the target organs. Thus, cisplatin prevents breast cancer metastasis through blocking early EMT, and the combination of cisplatin and paclitaxel represents a promising therapy for killing breast cancer and blocking tumor metastasis.
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http://dx.doi.org/10.7150/thno.46460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797698PMC
January 2021

Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation.

Theranostics 2021 1;11(4):1672-1689. Epub 2021 Jan 1.

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating cancers without effective treatments. Amplified in breast cancer 1 (AIB1) is a member of the steroid receptor coactivator family that mediates the transcriptional activities of nuclear receptors. While AIB1 is associated with the initiation and progression of multiple cancers, the mechanism by which AIB1 contributes to PDAC progression remains unknown. In this study, we aimed to explore the role of AIB1 in the progression of PDAC and elucidate the underlying mechanisms. The clinical significance and mRNA level of AIB1 in PDAC were studied by database analysis. To demonstrate whether AIB1 mediates the malignant features of PDAC cells, namely, proliferation, migration, invasion, we performed real-time PCR and Western blot analysis, established xenograft models and used metastasis assay. With insights into the mechanism of AIB1, we performed RNA sequencing (Seq), ChIP-Seq, luciferase reporter assays and pull-down assays. Furthermore, we analyzed the relationship between AIB1 expression and its target expression in PDAC cells and patients and explored whether PDAC cells with high AIB1 levels are sensitive to inhibitors of its target. We found that AIB1 was significantly upregulated in PDAC and associated with its malignancy. Silencing AIB1 impaired hedgehog (Hh) activation by reducing the expression of smoothened (SMO), leading to cell cycle arrest and the inhibition of PDAC cell proliferation. In addition, AIB1, upregulation of integrin αv (ITGAV) expression, promoted extracellular matrix (ECM) signaling, which played an important role in PDAC progression. Further studies showed that AIB1 preferably bound to AP-1 related elements and served as a coactivator for enhancing the transcriptional activity of MafB, which promoted the expression of SMO and ITGAV. PDAC cells with high AIB1 levels were sensitive to Hh signaling inhibitors, suggesting that blocking Hh activation is an effective treatment against PDAC with high AIB1 expression. These findings reveal that AIB1 is a crucial oncogenic regulator associated with PDAC progression Hh and ECM signaling and suggest potential therapeutic targets for PDAC treatment.
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http://dx.doi.org/10.7150/thno.47390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778610PMC
January 2021

Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening.

Adv Sci (Weinh) 2020 Dec 11;7(23):2001914. Epub 2020 Oct 11.

Cancer Center Faculty of Health Sciences University of Macau Macau 999078 China.

Resistance to therapeutic drugs occurs in virtually all types of cancers, and the tolerance to one drug frequently becomes broad therapy resistance; however, the underlying mechanism remains elusive. Combining a whole whole-genome-wide RNA interference screening and an evolutionary drug pressure model with MDA-MB-231 cells, it is found that enhanced protein damage clearance and reduced mitochondrial respiratory activity are responsible for cisplatin resistance. Screening drug-resistant cancer cells and human patient-derived organoids for breast and colon cancers with many anticancer drugs indicates that activation of mitochondrion protein import surveillance system enhances proteasome activity and minimizes caspase activation, leading to broad drug resistance that can be overcome by co-treatment with a proteasome inhibitor, bortezomib. It is further demonstrated that cisplatin and bortezomib encapsulated into nanoparticle further enhance their therapeutic efficacy and alleviate side effects induced by drug combination treatment. These data demonstrate a feasibility for eliminating broad drug resistance by targeting its common mechanism to achieve effective therapy for multiple cancers.
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http://dx.doi.org/10.1002/advs.202001914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709997PMC
December 2020

Glucocorticoids save lives in COVID-19 patients.

Authors:
Chu-Xia Deng

Int J Biol Sci 2020 7;16(13):2477-2478. Epub 2020 Jul 7.

Editor in Chief, International Journal of Biological Sciences; Chair Professor, Faculty of Health Sciences, University of Macau, Macau SAR, China.

Recent studies showed that glucocorticoid drugs, which are easily available as pills on pharmacy shelves worldwide, could save lives of COVID-19 patients. With the swiftly increasing infections of the SARS-CoV-2 pandemic at a lethality rate of about 4.7% countless lives may be saved globally.
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http://dx.doi.org/10.7150/ijbs.49125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378644PMC
August 2020

Genomic characteristics and drug screening among organoids derived from non-small cell lung cancer patients.

Thorac Cancer 2020 08 7;11(8):2279-2290. Epub 2020 Jul 7.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.

Background: Patient-derived organoid (PDO) models are highly valuable and have potentially widespread clinical applications. However, limited information is available regarding organoid models of non-small cell lung cancer (NSCLC). This study aimed to characterize the consistency between primary tumors in NSCLC and PDOs and to explore the applications of PDOs as preclinical models to understand and predict treatment response during lung cancer.

Methods: Fresh tumor samples were harvested for organoid culture. Primary tumor samples and PDOs were analyzed via whole-exome sequencing. Paired samples were subjected to immunohistochemical analysis. There were 26 antineoplastic drugs tested in the PDOs. Cell viability was assessed using the Cell Titer Glo assay 7-10 days after drug treatment. A heatmap of log-transformed values of the half-maximal inhibitory concentrations was generated on the basis of drug responses of PDOs through nonlinear regression (curve fit). A total of 12 patients (stages I-III) were enrolled, and 7 paired surgical tumors and PDOs were analyzed.

Results: PDOs retained the histological and genetic characteristics of the primary tumors. The concordance between tumors and PDOs in mutations in the top 20 NSCLC-related genes was >80% in five patients. Sample purity was significantly and positively associated with variant allele frequency (Pearson r = 0.82, P = 0.0005) and chromosome stability. The in vitro response to drug screening with PDOs revealed high correlation with the mutation profiles in the primary tumors.

Conclusions: PDOs are highly credible models for detecting NSCLC and for prospective prediction of the treatment response for personalized precision medicine.

Key Points: Lung cancer organoid models could save precious time of drug testing on patients, and accurately select anticancer drugs according to the drug sensitivity results, so as to provide a powerful supplement and verification for the gene sequencing.
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http://dx.doi.org/10.1111/1759-7714.13542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396373PMC
August 2020

Function of DHX33 in promoting Warburg effect via regulation of glycolytic genes.

J Cell Physiol 2021 Feb 2;236(2):981-996. Epub 2020 Jul 2.

Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China.

Cancer cells metabolize glucose through glycolysis to promote cell proliferation even with abundant oxygen. Multiple glycolysis genes are deregulated during cancer development. Despite intensive effort, the cause of their deregulation remains incompletely understood. Here in this study, we discovered that DHX33 plays a critical role in Warburg effect of cancer cells. DHX33 deficient cells have markedly reduced glycolysis activity. Through RNA-seq analysis, we found multiple critical genes involved in Warburg effect were downregulated after DHX33 deficiency. These genes include lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase 1 (PDK1), pyruvate kinase muscle isoform 2 (PKM2), enolase 1 (ENO1), ENO2, hexokinase 1/2, among others. With LDHA, PDK1, and PKM2 as examples, we further revealed that DHX33 altered the epigenetic marks around the promoter of glycolytic genes. This is through DHX33 in complex with Gadd45a-a growth arrest and DNA damage protein. DHX33 is required for the loading of Gadd45a and DNA dioxygenase Tet1 at the promoter sites, which resulted in active DNA demethylation and enhanced histone H4 acetylation. We conclude that DHX33 changes local epigenetic marks in favor of the transcription of glycolysis genes to promote cancer cell proliferation. Our study highlights the significance of RNA helicase DHX33 in Warburg effect and cancer therapeutics.
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http://dx.doi.org/10.1002/jcp.29909DOI Listing
February 2021

MLL3/MLL4-Associated PAGR1 Regulates Adipogenesis by Controlling Induction of C/EBPβ and C/EBPδ.

Mol Cell Biol 2020 08 14;40(17). Epub 2020 Aug 14.

Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA

Transcription factors C/EBPβ and C/EBPδ are induced within hours after initiation of adipogenesis in culture. They directly promote the expression of master adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and are required for adipogenesis However, the mechanism that controls the induction of C/EBPβ and C/EBPδ remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPARγ and C/EBPα during adipogenesis. Here, we show MLL3/MLL4/PTIP-associated protein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBPβ and C/EBPδ in the early phase of adipogenesis. Deletion of in white and brown preadipocytes prevents the induction of C/EBPβ and C/EBPδ and leads to severe defects in adipogenesis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBPβ or PPARγ. Finally, the deletion of in Myf5 precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBPβ and C/EBPδ, PAGR1 plays a critical role in adipogenesis.
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http://dx.doi.org/10.1128/MCB.00209-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431048PMC
August 2020

NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation.

Nat Commun 2020 06 26;11(1):3256. Epub 2020 Jun 26.

Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China.

BRCA1 mutation carriers have a higher risk of developing triple-negative breast cancer (TNBC), which is a refractory disease due to its non-responsiveness to current clinical targeted therapies. Using the Sleeping Beauty transposon system in Brca1-deficient mice, we identified 169 putative cancer drivers, among which Notch1 is a top candidate for accelerating TNBC by promoting the epithelial-mesenchymal transition (EMT) and regulating the cell cycle. Activation of NOTCH1 suppresses mitotic catastrophe caused by BRCA1 deficiency by restoring S/G2 and G2/M cell cycle checkpoints, which may through activation of ATR-CHK1 signalling pathway. Consistently, analysis of human breast cancer tissue demonstrates NOTCH1 is highly expressed in TNBCs, and the activated form of NOTCH1 correlates positively with increased phosphorylation of ATR. Additionally, we demonstrate that inhibition of the NOTCH1-ATR-CHK1 cascade together with cisplatin synergistically kills TNBC by targeting the cell cycle checkpoint, DNA damage and EMT, providing a potent clinical option for this fatal disease.
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http://dx.doi.org/10.1038/s41467-020-16936-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320176PMC
June 2020

Retraction notice to "PP2ACα deficiency impairs early cortical development through inducing DNA damage in neuroprojenitor cells" [Int. J. Biochem. Cell Biol. 109C (2019) 40-58].

Int J Biochem Cell Biol 2020 08 10;125:105762. Epub 2020 Jun 10.

National Institute of Neurological Disorders and Stroke, National Institute of Heath, Bethesda, USA. Electronic address:

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http://dx.doi.org/10.1016/j.biocel.2020.105762DOI Listing
August 2020

Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells.

Acta Pharm Sin B 2020 Apr 5;10(4):615-627. Epub 2019 Sep 5.

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China.

Breast cancer susceptibility gene 1 () is a tumor suppressor gene, which is frequently mutated in breast and ovarian cancers. BRCA1 plays a key role in the homologous recombination directed DNA repair, allowing its deficiency to act as a therapeutic target of DNA damaging agents. In this study, we found that inhibition of the class I histone deacetylases (HDAC) exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells. Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein (TXNIP), causing reactive oxygen species (ROS)-mediated DNA damage. This effect induced preferential apoptosis in breast cancer cells where DNA repair system is compromised. Two animal experiments and gene expression-associated patients' survival analysis further confirmed synthetic lethality between BRCA1 and HDAC. Finally, the combination of inhibitors of HDAC and bromodomain and extra-terminal motif (BET), another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage, showed a strong anticancer effect in breast cancer cells. Together, this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries, HDAC and BET.
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http://dx.doi.org/10.1016/j.apsb.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161709PMC
April 2020

The global battle against SARS-CoV-2 and COVID-19.

Authors:
Chu-Xia Deng

Int J Biol Sci 2020 15;16(10):1676-1677. Epub 2020 Mar 15.

Editor in Chief, International Journal of Biological Sciences.

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http://dx.doi.org/10.7150/ijbs.45587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098033PMC
April 2020

Stagewise keratinocyte differentiation from human embryonic stem cells by defined signal transduction modulators.

Int J Biol Sci 2020 21;16(8):1450-1462. Epub 2020 Feb 21.

Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau.

Keratinocyte is the predominant cell type in the epidermis of skin, and it provides the protective barrier function for the body. Various signaling pathways have been implicated in keratinocyte differentiation in animal models; However, their temporal regulation and interactions are still to be explored in pluripotent stem cell models. In this report, we use human embryonic stem cells to demonstrate that epidermal ectoderm and subsequent keratinocyte cell fate can be determined step by step under the regulation of defined factors. The inhibition of TGFβ initiates ectodermal lineage differentiation, and the activation of BMP pathway drives epidermal expression. Meanwhile, the timely activation of WNT pathway suppresses extraembryonic lineage, and promotes epidermal cell fate. With further specification by NOTCH inhibition, more than 90% of cells become TP63-positive stage Ⅱ keratinocytes. Finally, stage Ⅲ keratinocytes are produced under defined hypo-calcium keratinocyte culture conditions, and are further matured in mouse xenograft model. This study not only establishes an platform to study keratinocyte cell fate determination, but also provides an efficient protocol to produce keratinocytes for disease models and clinical applications.
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http://dx.doi.org/10.7150/ijbs.44414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085224PMC
February 2020

BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis.

Adv Sci (Weinh) 2020 Mar 14;7(6):1903616. Epub 2020 Feb 14.

Cancer Center Faculty of Health Sciences University of Macau Macau Macau, SAR China.

The breast cancer susceptibility gene 1 () is a major tumor suppressor gene and is most frequently mutated in hereditary breast cancer. BRCA1 plays a critical role in many biological processes, especially maintaining genomic stability in the nucleus, yet its role in the cytoplasm remains elusive. Here, it is revealed that BRCA1 maintains a healthy mitochondrial network through regulating mitochondrial dynamics, including fission and fusion. BRCA1 deficiency causes dysfunctional mitochondrial dynamics through increased expression of mitofusin1/2. With mitochondrial stress, BRCA1 is recruited to the mitochondrial outer membrane, where it plays an essential role in maintaining a healthy mitochondrial network. Consequently, BRCA1 deficiency impairs stress-induced mitophagy through blocking ataxia-telangiectasia mutated (ATM)-AMP-activated protein kinase (AMPK)-Dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and triggers NLRP3 inflammasome activation, which creates a tumor-associated microenvironment, thereby facilitating tumor proliferation and metastasis. It is further shown that inflammasome inhibition can prevent tumor recurrence and metastasis. This study uncovers an important role of BRCA1 in regulating mitophagy and suggests a therapeutic approach for fighting this deadly disease.
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http://dx.doi.org/10.1002/advs.201903616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080549PMC
March 2020

Human Follicle-Stimulating Hormone ß Subunit Expression Depends on FOXL2 and SMAD4.

Endocrinology 2020 05;161(5)

Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.

Follicle-stimulating hormone (FSH), an essential regulator of mammalian fertility, is synthesized by pituitary gonadotrope cells in response to activins. In mice, activins signal via SMAD3, SMAD4, and FOXL2 to regulate transcription of the FSHβ subunit (Fshb) gene. Gonadotrope-specific deletion of Foxl2, alone or in combination with Smad4, renders mice FSH-deficient. Whether human FSHB expression is similarly regulated is not known. Here, we used a combination of transgenic and conditional knockout mouse strains to assess the roles of activins, FOXL2, and SMAD4 in regulation of the human FSHB gene. First, we cultured pituitaries from mice harboring a human FSHB transgene (hFSHB mice) and measured both murine Fshb and human FSHB messenger ribonucleic acid (mRNA) expression in response to exogenous activins or two antagonists of endogenous activin-like signaling (follistatin-288 and SB431542). Both murine Fshb and human FSHB expression were stimulated by activins and reduced by the inhibitors. Next, we analyzed human FSHB expression in hFSHB mice carrying floxed Foxl2 and Smad4 alleles. Cre-mediated ablation of FOXL2 and SMAD4 strongly reduced basal and activin-stimulated murine Fshb and human FSHB expression in cultured pituitaries. Finally, the hFSHB transgene was previously shown to rescue FSH production and fertility in Fshb knockout mice. However, gonadotrope-specific Foxl2/Smad4 knockout females carrying the hFSHB transgene have significantly reduced murine Fshb and human FSHB pituitary mRNA levels and are hypogonadal. Collectively, these data suggest that similar to Fshb regulation in mice, FOXL2 and SMAD4 play essential roles in human FSHB expression.
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http://dx.doi.org/10.1210/endocr/bqaa045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182064PMC
May 2020

The metabolic footprint during adipocyte commitment highlights ceramide modulation as an adequate approach for obesity treatment.

EBioMedicine 2020 Jan 2;51:102605. Epub 2020 Jan 2.

Faculty of Health Sciences, University of Macau, Macau SAR, China; Center for Cancer Research, Nation Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address:

Background: Metabolic modulation is capable of maintaining cell potency, regulating niche homeostasis, or determining cell fate. However, little is known regarding the metabolic landscape during early adipogenesis or whether metabolic modulation could be a potential approach for obesity treatment.

Methods: The metabolic footprint during adipocyte commitment was evaluated by metabolomics analysis in mouse embryonic fibroblasts (MEFs). The role of apoptosis induced by ceramide and how ceramide is regulated were evaluated by omics analysis in vitro, human database and the adipocyte-specific Sirt1 knockout mouse.

Findings: The metabolic footprint showed that a complicated diversity of metabolism was enriched as early as 3 h and tended to fluctuate throughout differentiation. Subsequently, the scale of these perturbed metabolic patterns was reduced to reach a balanced state. Of high relevance is the presence of apoptosis induced by ceramide accumulation, which is associated with metabolic dynamics. Interestingly, apoptotic cells were not merely a byproduct of adipogenesis but rather promoted the release of lipid components to facilitate adipogenesis. Mechanistically, ceramide accumulation stemming from hydrolysis and the de novo pathway during early adipogenesis is regulated by Sirt1 upon epigenetic alterations of constitutive Histone H3K4 methylation and H3K9 acetylation.

Interpretation: The metabolic footprint during adipocyte commitment highlights that apoptosis induced by ceramide is essential for adipogenesis, which is reversed by suppression of Sirt1. Therefore, Sirt1 may constitute a target to treat obesity or other ceramide-associated metabolic syndromes.

Funding: This project was supported by grants from the University of Macau (SRG2015-00008-FHS, MYRG2016-00054-FHS and MYRG2017-00096-FHS to RHW; CPG2019-00019-FHS to CXD) and from the National Natural Science Foundation of China (81672603 and 81401978) to QC.
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http://dx.doi.org/10.1016/j.ebiom.2019.102605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940659PMC
January 2020

Author Correction: Drug screening of cancer cell lines and human primary tumors using droplet microfluidics.

Sci Rep 2019 Dec 4;9(1):18660. Epub 2019 Dec 4.

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-55120-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890660PMC
December 2019

Targeting immune checkpoint B7-H3 antibody-chlorin e6 bioconjugates for spectroscopic photoacoustic imaging and photodynamic therapy.

Chem Commun (Camb) 2019 Nov;55(95):14255-14258

Cancer Centre, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR 999078, China.

In this study, we constructed bioconjugates of targeting immune checkpoint B7-H3 antibody and chlorin e6 to treat non-small cell lung cancer under the guidance of spectroscopic photoacoustic and fluorescence imaging. The B7-H3-Ce6 conjugates could display effective tumor diagnosis and therapy and provide a novel approach for immunotherapy.
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http://dx.doi.org/10.1039/c9cc06839bDOI Listing
November 2019

Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism.

Cell Metab 2019 08;30(2):385-401.e9

Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

The mechanisms by which steatosis of the liver progresses to non-alcoholic steatohepatitis and end-stage liver disease remain elusive. Metabolic derangements in hepatocytes controlled by SIRT1 play a role in the development of fatty liver in inbred animals. The ability to perform similar studies using human tissue has been limited by the genetic variability in man. We generated human induced pluripotent stem cells (iPSCs) with controllable expression of SIRT1. By differentiating edited iPSCs into hepatocytes and knocking down SIRT1, we found increased fatty acid biosynthesis that exacerbates fat accumulation. To model human fatty livers, we repopulated decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1 knockdown iPSC-derived hepatocytes and found that the human iPSC-derived liver tissue developed macrosteatosis, acquired proinflammatory phenotype, and shared a similar lipid and metabolic profiling to human fatty livers. Biofabrication of genetically edited human liver tissue may become an important tool for investigating human liver biology and disease.
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http://dx.doi.org/10.1016/j.cmet.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691905PMC
August 2019

SMAD signaling promotes melanoma metastasis independently of phenotype switching.

J Clin Invest 2019 04 30;129(7):2702-2716. Epub 2019 Apr 30.

Stem Cell Biology, Institute of Anatomy, University of Zurich, Zurich, Switzerland.

The development of metastatic melanoma is thought to require the dynamic shifting of neoplastic cells between proliferative and invasive phenotypes. Contrary to this conventional "phenotype switching" model, we now show that disease progression can involve malignant melanoma cells simultaneously displaying proliferative and invasive properties. Using a genetic mouse model of melanoma in combination with in vitro analyses of melanoma cell lines, we found that conditional deletion of the downstream signaling molecule Smad4, which abrogates all canonical TGF-β signaling, indeed inhibits both tumor growth and metastasis. Conditional deletion of the inhibitory signaling factor Smad7, however, generated cells that are both highly invasive and proliferative, indicating that invasiveness is compatible with a high proliferation rate. In fact, conditional Smad7 deletion led to sustained melanoma growth and at the same time promoted massive metastasis formation, a result consistent with data indicating that low SMAD7 levels in patient tumors are associated with a poor survival. Our findings reveal that modulation of SMAD7 levels can overcome the need for phenotype switching during tumor progression and may thus represent a novel therapeutic target in metastatic disease.
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http://dx.doi.org/10.1172/JCI94295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597210PMC
April 2019

SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions.

Autophagy 2019 08 4;15(8):1356-1375. Epub 2019 Mar 4.

a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.

SIRT3 (sirtuin 3), a mitochondrial protein deacetylase, maintains respiratory function, but its role in the regulation of innate immune defense is largely unknown. Herein, we show that SIRT3 coordinates mitochondrial function and macroautophagy/autophagy activation to promote anti-mycobacterial responses through PPARA (peroxisome proliferator activated receptor alpha). SIRT3 deficiency enhanced inflammatory responses and mitochondrial dysfunction, leading to defective host defense and pathological inflammation during mycobacterial infection. Antibody-mediated depletion of polymorphonuclear neutrophils significantly increased protection against mycobacterial infection in mice. In addition, mitochondrial oxidative stress promoted excessive inflammation induced by infection in macrophages. Notably, SIRT3 was essential for the enhancement of PPARA, a key regulator of mitochondrial homeostasis and autophagy activation in the context of infection. Importantly, overexpression of either PPARA or TFEB (transcription factor EB) in macrophages recovered antimicrobial activity through autophagy activation. Furthermore, pharmacological activation of SIRT3 enhanced antibacterial autophagy and functional mitochondrial pools during mycobacterial infection. Finally, the levels of and were downregulated and inversely correlated with (tumor necrosis factor) levels in peripheral blood mononuclear cells from tuberculosis patients. Collectively, these data demonstrate a previously unappreciated function of SIRT3 in orchestrating mitochondrial and autophagic functions to promote antimycobacterial responses. Ab: antibody; BCG: Bacillus Calmette-Guérin; Baf-A: bafilomycin A; BMDMs: bone marrow-derived macrophages; CFU: colony forming unit; CXCL5: C-X-C motif chemokine ligand 5; EGFP: enhanced green fluorescent protein; ERFP: enhanced red fluorescent protein; FOXO3: forkhead box O3; HC: healthy controls; H&E: haematoxylin and eosin; HKL: honokiol; IHC: immunohistochemistry; IL1B: interleukin 1 beta; IL6: interleukin 6; IL12B: interleukin 12B; MDMs: monocyte-derived macrophages; MMP: mitochondrial membrane potential; Mtb: ; PBMC: peripheral blood mononuclear cells; PBS: phosphate buffered saline; PMN: polymorphonuclear neutrophil; PPARA: peroxisome proliferator activated receptor alpha; ROS: reactive oxygen species; SIRT3: sirtuin 3; TB: tuberculosis; TEM: transmission electron microscopy; TFEB: transcription factor EB; TNF: tumor necrosis factor.
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http://dx.doi.org/10.1080/15548627.2019.1582743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628940PMC
August 2019

PP2ACα deficiency impairs early cortical development through inducing DNA damage in neuroprojenitor cells.

Int J Biochem Cell Biol 2019 04 30;109:40-58. Epub 2019 Jan 30.

National Institute of Neurological Disorders and Stroke, National Institute of Heath, Bethesda, USA. Electronic address:

The role of protein phosphatase 2ACα (PP2ACα) in brain development is poorly understood. To understand the function of PP2ACα in neurogenesis, we inactivated Pp2acα gene in the central nervous system (CNS) of mice by Cre/LoxP system and generated the PP2ACα deficient mice (designated as the Pp2acα mice). PP2ACα deletion results in DNA damage in neuroprogenitor cells (NPCs), which impairs memory formation and cortical neurogenesis. We first identify that PP2ACα can directly associate with Ataxia telangiectasia mutant kinase (ATM) and Ataxia telangiectasia/Rad3-related kinase (ATR) in neocortex and NPCs. Importantly, the P53 and hypermethylated in cancer 1 (HIC1) function complex, the newly found down-stream executor of the ATR/ATM cascade, will be translocated into nuclei and interact with homeodomain interacting protein kinase 2 (HIPK2) to respond to DNA damage. Notably, HICI plays a direct transcriptional regulatory role in HIPK2 gene expression. The interplay among P53, HIC1 and HIPK2 maintains DNA stability in neuroprogenitor cells. Taken together, our findings highlight a new role of PP2ACα in regulating early neurogenesis through maintaining DNA stability in neuroprogenitor cells. The P53/HIC/HIPK2 regulation loop, directly targeted by the ATR/ATM cascade, is involved in DNA repair in neuroprogenitor cells.
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http://dx.doi.org/10.1016/j.biocel.2019.01.021DOI Listing
April 2019

Current Progresses of Exosomes as Cancer Diagnostic and Prognostic Biomarkers.

Int J Biol Sci 2019 6;15(1):1-11. Epub 2019 Jan 6.

Faculty of Health Sciences, University of Macau, Macau SAR, China.

Cancer related exosomes are nano-size membrane vesicles that play important roles in tumor microenvironment. Emerging evidence indicates that exosomes can load unique cargoes, including proteins and nucleic acids that reflect the condition of tumor. Therefore, exosomes are being used as diagnostic and prognostic biomarkers for various cancers. In this review, we describe the current progresses of cancer related exosomes, including their biogenesis, molecular contents, biological functions, sources where they are derived from, and methods for their detection. We will also discuss the current exosomal biomarkers and the utilization of them for early diagnosis and prognostics in cancer.
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http://dx.doi.org/10.7150/ijbs.27796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329932PMC
January 2020

Effect of Stromal Cells in Tumor Microenvironment on Metastasis Initiation.

Int J Biol Sci 2018 13;14(14):2083-2093. Epub 2018 Nov 13.

Faculty of Health Sciences, University of Macau, Macau SAR, China.

The cellular environment where tumor cells reside is called the tumor microenvironment (TME), which consists of borders, blood vessels, lymph vessels, extracellular matrix (ECM), stromal cells, immune/inflammatory cells, secreted proteins, RNAs and small organelles. By dynamically interacting with tumor cells, stromal cells participate in all stages of tumor initiation, progression, metastasis, recurrence and drug response, and consequently, affect the fate of patients. During the processes of tumor evolution and metastasis initiation, stromal cells in TME also experience some changes and play roles in both the suppression and promotion of metastasis, while the overall function of stromal cells is beneficial for cancer cell survival and movement. In this review, we examine the effects of stromal cells in TME on metastasis initiation, including angiogenesis, epithelial-mesenchymal transition (EMT) and invasion. We also highlight functions of proteins, RNAs and small organelles secreted by stromal cells in their influences on multiple stages of tumor metastasis.
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http://dx.doi.org/10.7150/ijbs.25720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299363PMC
September 2019

Optimizing CRISPR/Cas9 technology for precise correction of the Fgfr3-G374R mutation in achondroplasia in mice.

J Biol Chem 2019 01 28;294(4):1142-1151. Epub 2018 Nov 28.

Cancer Center, Faculty of Health Sciences, Macau SAR; Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau SAR. Electronic address:

CRISPR/Cas9 is a powerful technology widely used for genome editing, with the potential to be used for correcting a wide variety of deleterious disease-causing mutations. However, the technique tends to generate more indels (insertions and deletions) than precise modifications at the target sites, which might not resolve the mutation and could instead exacerbate the initial genetic disruption. We sought to develop an improved protocol for CRISPR/Cas9 that would correct mutations without unintended consequences. As a case study, we focused on achondroplasia, a common genetic form of dwarfism defined by missense mutation in the gene that results in glycine to arginine substitution at position 374 in mice in fibroblast growth factor receptor 3 (Fgfr3-G374R), which corresponds to G380R in humans. First, we designed a GFP reporter system that can evaluate the cutting efficiency and specificity of single guide RNAs (sgRNAs). Using the sgRNA selected based on our GFP reporter system, we conducted targeted therapy of achondroplasia in mice. We found that we achieved higher frequency of precise correction of the Fgfr3-G374R mutation using Cas9 protein rather than Cas9 mRNA. We further demonstrated that targeting oligos of 100 and 200 nucleotides precisely corrected the mutation at equal efficiency. We showed that our strategy completely suppressed phenotypes of achondroplasia and whole genome sequencing detected no off-target effects. These data indicate that improved protocols can enable the precise CRISPR/Cas9-mediated correction of individual mutations with high fidelity.
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http://dx.doi.org/10.1074/jbc.RA118.006496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349110PMC
January 2019

BRCA1 represses DNA replication initiation through antagonizing estrogen signaling and maintains genome stability in parallel with WEE1-MCM2 signaling during pregnancy.

Hum Mol Genet 2019 03;28(5):842-857

Faculty of Health Sciences, University of Macau, Macau SAR, China.

The mammary gland undergoes fast cell proliferation during early pregnancy, yet the mechanism to ensure genome integrity during this highly proliferative stage is largely unknown. We show that pregnancy triggers replicative stresses leading to genetic instability in mice carrying a mammary specific disruption of breast cancer associated gene-1 (BRCA1). The fast cell proliferation was correlated with enhanced expression of most genes encoding replisomes, which are positively regulated by estrogen/ERα signaling but negatively regulated by BRCA1. Our further analysis revealed two parallel signaling pathways, which are mediated by ATR-CHK1 and WEE1-MCM2 and are responsible for regulating DNA replication checkpoint. Upon DNA damage, BRCA1 deficiency markedly enhances DNA replication initiation and preferably impairs DNA replication checkpoint mediated by ATR and CHK1. Meanwhile, DNA damage also activates WEE1-MCM2 signaling, which inhibits DNA replication initiation and enables BRCA1-deficient cells to avoid further genomic instability. Finally, we demonstrated that overriding this defense by WEE1 inhibition in combination with cisplatin, which causes DNA damage, serves as a promising therapeutic approach for killing BRCA1-deficient cancer cells.
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http://dx.doi.org/10.1093/hmg/ddy398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381318PMC
March 2019

Inhibition of AKT suppresses the initiation and progression of -associated mammary tumors.

Int J Biol Sci 2018 3;14(13):1769-1781. Epub 2018 Oct 3.

Research Institute, National Cancer Center, Goyang, 10408, Korea.

Despite the high incidence of -mutant breast cancer, few substantial improvements in preventing or treating such cancers have been made. Using a -mutant mouse model, we examined the contribution of AKT to the incidence and growth of -mutated mammary tumors. A haploinsufficiency of in -mutant mouse model significantly decreased mammary tumor formation from 54% in mice to 22% in mice. Notably, treatment of tumor-bearing -mutant mice with the AKT-inhibitor, MK-2206, yielded partial response or stable disease up to 91% of mice in maximum response. MK-2206 treatment also significantly reduced tumor volume and delayed recurrence in allograft and adjuvant studies, respectively. A correlation analysis of MK-2206 responses with gene expression profiles of tumors at baseline identified seven genes that were differentially expressed between tumors that did and did not respond to MK-2206 treatment. Our findings enhance our understanding of the involvement of AKT signaling in BRCA1-deficient mammary tumors and provide preclinical evidence that targeted AKT inhibition is a potential strategy for the prevention and therapeutic management of -associated breast cancer.
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http://dx.doi.org/10.7150/ijbs.29242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231214PMC
September 2019