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1.
Nat Commun ; 12(1): 5262, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489456

RESUMO

TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer with no standard treatment for advanced disease. We describe comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion and several somatic copy number alterations, including the loss of 22q, are associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibit low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis reveals five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which show association with fusion patterns and prognosis. In line with the aggressive nature, the high angiogenesis/stroma/proliferation cluster exclusively consists of tumors with ASPSCR1-TFE3 fusion. Here, we describe the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Adolescente , Adulto , Idoso , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Fusão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Análise de Sequência de RNA , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Sequenciamento Completo do Exoma , Adulto Jovem
2.
Cell Mol Life Sci ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34557935

RESUMO

The atrioventricular canal (AVC) is the site where key structures responsible for functional division between heart regions are established, most importantly, the atrioventricular (AV) conduction system and cardiac valves. To elucidate the mechanism underlying AVC development and function, we utilized transgenic zebrafish line sqet31Et expressing EGFP in the AVC to isolate this cell population and profile its transcriptome at 48 and 72 hpf. The zebrafish AVC transcriptome exhibits hallmarks of mammalian AV node, including the expression of genes implicated in its development and those encoding connexins forming low conductance gap junctions. Transcriptome analysis uncovered protein-coding and noncoding transcripts enriched in AVC, which have not been previously associated with this structure, as well as dynamic expression of epithelial-to-mesenchymal transition markers and components of TGF-ß, Notch, and Wnt signaling pathways likely reflecting ongoing AVC and valve development. Using transgenic line Tg(myl7:mermaid) encoding voltage-sensitive fluorescent protein, we show that abolishing the pacemaker-containing sinoatrial ring (SAR) through Isl1 loss of function resulted in spontaneous activation in the AVC region, suggesting that it possesses inherent automaticity although insufficient to replace the SAR. The SAR and AVC transcriptomes express partially overlapping species of ion channels and gap junction proteins, reflecting their distinct roles. Besides identifying conserved aspects between zebrafish and mammalian conduction systems, our results established molecular hallmarks of the developing AVC which underlies its role in structural and electrophysiological separation between heart chambers. This data constitutes a valuable resource for studying AVC development and function, and identification of novel candidate genes implicated in these processes.

3.
J Mol Cell Cardiol ; 162: 62-71, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34509499

RESUMO

Direct conversion of cardiac fibroblast into induced cardiomyocytes (iCMs) by forced expression of cardiac transcription factors, such as Mef2c, Gata4, and Tbx5 (MGT), holds great promise for regenerative medicine. The process of cardiac reprogramming consists of waves of transcriptome remodelling events. However, how this transcriptome remodelling is driven by the upstream chromatin landscape alteration is still unclear. In this study, we performed single-cell ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) on early reprogramming iCMs given the known epigenetic changes as early as day 3. This approach unveiled networks of transcription factors (TFs) involved in the early shift of chromatin accessibility during cardiac reprogramming. Combining our analysis with functional assays, we identified Smad3 to be a bimodal TF in cardiac reprogramming, a barrier in the initiation of reprogramming and a facilitator during the intermediate stage of reprogramming. Moreover, integrative analysis of scATAC-seq with scRNA-seq data led to the identification of active TFs important for iCM conversion. Finally, we discovered a global rewiring of cis-regulatory interactions of cardiac genes along the reprogramming trajectory. Collectively, our scATAC-seq study and the integrative analysis with scRNA-seq data provided valuable resources to understand the epigenomic heterogeneity and its alteration in relation to transcription changes during early stage of cardiac reprogramming.

4.
EMBO Rep ; : e52901, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523214

RESUMO

Cardiac regeneration occurs primarily through proliferation of existing cardiomyocytes, but also involves complex interactions between distinct cardiac cell types including non-cardiomyocytes (non-CMs). However, the subpopulations, distinguishing molecular features, cellular functions, and intercellular interactions of non-CMs in heart regeneration remain largely unexplored. Using the LIGER algorithm, we assemble an atlas of cell states from 61,977 individual non-CM scRNA-seq profiles isolated at multiple time points during regeneration. This analysis reveals extensive non-CM cell diversity, including multiple macrophage (MC), fibroblast (FB), and endothelial cell (EC) subpopulations with unique spatiotemporal distributions, and suggests an important role for MC in inducing the activated FB and EC subpopulations. Indeed, pharmacological perturbation of MC function compromises the induction of the unique FB and EC subpopulations. Furthermore, we developed computational algorithm Topologizer to map the topological relationships and dynamic transitions between functional states. We uncover dynamic transitions between MC functional states and identify factors involved in mRNA processing and transcriptional regulation associated with the transition. Together, our single-cell transcriptomic analysis of non-CMs during cardiac regeneration provides a blueprint for interrogating the molecular and cellular basis of this process.

5.
EMBO Rep ; : e52707, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34472665

RESUMO

Genome-wide association studies (GWAS) have identified multiple gastric cancer risk loci and several protein-coding susceptibility genes. However, the role of long-noncoding RNAs (lncRNAs) transcribed from these risk loci in gastric cancer development and progression remains to be explored. Here, we functionally characterize a lncRNA, lncPSCA, as a novel tumor suppressor whose expression is fine-regulated by a gastric cancer risk-associated genetic variant. The rs2978980 T > G change in an intronic enhancer of lncPSCA interrupts binding of transcription factor RORA, which down-regulates lncPSCA expression in an allele-specific manner. LncPSCA interacts with DDX5 and promotes DDX5 degradation through ubiquitination. Increased expression of lncPSCA results in low levels of DDX5, less RNA polymerase II (Pol II) binding with DDX5 in the nucleus, thus activating transcription of multiple p53 signaling genes by Pol II. These findings highlight the importance of functionally annotating lncRNAs in GWAS risk loci and the great potential of modulating lncRNAs as innovative cancer therapy.

6.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445647

RESUMO

Unveiling the molecular features in the heart is essential for the study of heart diseases. Non-cardiomyocytes (nonCMs) play critical roles in providing structural and mechanical support to the working myocardium. There is an increasing amount of single-cell RNA-sequencing (scRNA-seq) data characterizing the transcriptomic profiles of nonCM cells. However, no tool allows researchers to easily access the information. Thus, in this study, we develop an open-access web portal, ExpressHeart, to visualize scRNA-seq data of nonCMs from five laboratories encompassing three species. ExpressHeart enables comprehensive visualization of major cell types and subtypes in each study; visualizes gene expression in each cell type/subtype in various ways; and facilitates identifying cell-type-specific and species-specific marker genes. ExpressHeart also provides an interface to directly combine information across datasets, for example, generating lists of high confidence DEGs by taking the intersection across different datasets. Moreover, ExpressHeart performs comparisons across datasets. We show that some homolog genes (e.g., Mmp14 in mice and mmp14b in zebrafish) are expressed in different cell types between mice and zebrafish, suggesting different functions across species. We expect ExpressHeart to serve as a valuable portal for investigators, shedding light on the roles of genes on heart development in nonCM cells.


Assuntos
Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Ventrículos do Coração/metabolismo , Internet , Macrófagos/metabolismo , Pericitos/metabolismo , Transcriptoma , Algoritmos , Animais , Perfilação da Expressão Gênica , Humanos , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Software , Peixe-Zebra
7.
Dig Dis Sci ; 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34417924

RESUMO

BACKGROUND: Long noncoding RNA colon cancer-associated transcript 1 (LncRNA CCAT1) is highly expressed in gastric cancer tissues and plays a role in autophagy. However, the underlying mechanism still needs to be further clarified. OBJECTIVE: To study the role of LncRNA CCAT1 in regulating autophagy of gastric cancer cells, analyze its downstream targets, and elucidate the mechanism. METHODS: qPCR detected the expression of LncRNA CCAT1 in gastric cancer cells. The proliferation, migration, and invasion ability of LncRNA CCAT1 and the expression level of autophagy-related proteins in gastric cancer cells were detected. Bioinformatics method predicted the downstream targets of LncRNA CCAT1, and they were verified by dual-luciferase assay. The relationship between LncRNA CCAT1, miR-140, and ATG5 was verified by co-transfection, and the expression levels of ATG5 and ATG5-ATG12 complex proteins were detected. Finally, the role of LncRNA CCAT1 in vivo was confirmed by gastric cancer transplantation model. RESULTS: LncRNA CCAT1 was highly expressed in gastric cancer cells. LncRNA CCAT1 can promote the proliferation, migration, invasion, and autophagy activity of gastric cancer cells. LncRNA CCAT1 can bind to miR-140-3p and regulate its expression, while miR-140-3p further regulates the expression of ATG5. Overexpression of LncRNA CCAT1 can promote tumor growth in nude mice. After LncRNA CCAT1 silencing, the positive expression rate of ATG5 in nude mice was low. CONCLUSION: LncRNA CCAT1 may inhibit the expression of miR-140-3p by sponge adsorption, thus weakening its inhibitory effect on ATG5. Eventually, gastric cancer cells were more prone to autophagy under the pressure of stress.

8.
Angew Chem Int Ed Engl ; 60(38): 20717-20722, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34288325

RESUMO

The safety and electrochemical performance of rechargeable lithium-metal batteries (LMBs) are primarily influenced by the additives in the organic liquid electrolytes. However, multi-functional additives are still rarely reported. Herein, we proposed heptafluorobutyric anhydride (HFA) as a qua-functional additive to optimize the composition and structure of the solid electrolyte interphase (SEI) at the electrode/electrolyte interface. The reduction/oxidation decomposition of the fluorine-rich HFA facilitate uniform inorganic-rich SEI and compact cathode electrolyte interphase (CEI) formation, which enables stable lithium plating during charge and suppresses the dissolution of transition-metal ions. Moreover, HFA optimizes the Li-ion solvation for stable Li plating/stripping and serves as the surfactant to enhance the wettability of the separator by the electrolyte to increase Li-ion flux. The symmetric Li∥Li cell with 1.0 wt % HFA electrolyte had an excellent cycling performance over 340 h at 1.0 mA cm-2 with a capacity of 0.5 mAh cm-2 while the Li∥NCM622 cell maintained high capacity retention after 250 cycles and outstanding rate performance even at 15 C.

9.
Semin Cell Dev Biol ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34304993

RESUMO

The adult human heart has limited regenerative capacity. As such, the massive cardiomyocyte loss due to myocardial infarction leads to scar formation and adverse cardiac remodeling, which ultimately results in chronic heart failure. Direct cardiac reprogramming that converts cardiac fibroblast into functional cardiomyocyte-like cells (also called iCMs) holds great promise for heart regeneration. Cardiac reprogramming has been achieved both in vitro and in vivo by using a variety of cocktails that comprise transcription factors, microRNAs, or small molecules. During the past several years, great progress has been made in improving reprogramming efficiency and understanding the underlying molecular mechanisms. Here, we summarize the direct cardiac reprogramming methods, review the current advances in understanding the molecular mechanisms of cardiac reprogramming, and highlight the novel insights gained from single-cell omics studies. Finally, we discuss the remaining challenges and future directions for the field.

10.
Semin Cell Dev Biol ; 118: 144-149, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33994094

RESUMO

Heart malformation is the leading cause of human birth defects, and many of the congenital heart diseases (CHDs) originate from genetic defects that impact cardiac development and maturation. During development, the vertebrate heart undergoes a series of complex morphogenetic processes that increase its ability to pump blood. One of these processes leads to the formation of the sheet-like muscular projections called trabeculae. Trabeculae increase cardiac output and permit nutrition and oxygen uptake in the embryonic myocardium prior to coronary vascularization without increasing heart size. Cardiac trabeculation is also crucial for the development of the intraventricular fast conduction system. Alterations in cardiac trabecular development can manifest as a variety of congenital defects such as left ventricular noncompaction. In this review, we discuss the latest advances in understanding the molecular and cellular mechanisms underlying cardiac trabecular development.

11.
Org Biomol Chem ; 19(22): 4887-4890, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34021299

RESUMO

Facile construction of 1,3-dienes building upon cross-electrophile coupling of two open-chain vinyl halides is disclosed in this work, showing moderate chemoselectivities between the terminal bromoalkenes and internal vinyl bromides. The present method is mild and tolerates a range of functional groups and can be applied to the total synthesis of a tobacco fragrance solanone.

12.
Oncogene ; 40(21): 3734-3747, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33941854

RESUMO

Esophageal cancer is a complex malignancy and the sixth leading cause of cancer death worldwide. In Eastern Asia including China, about 90% of all incident cases have esophageal squamous cell carcinoma (ESCC). Mounting evidence elucidates that aberrant expression of various non-coding RNAs (ncRNAs) contributes to ESCC progression, but it remains unclear how small nucleolar RNAs (snoRNAs) are involved in ESCC development. We systemically screened clinically relevant snoRNAs in ESCC via integrative analyses of The Cancer Genome Atlas (TCGA) data and validation in ESCC tissues. We found that snoRNA SNORD12B was one of the most evidently upregulated snoRNAs in ESCC specimens and its high expression was significantly associated with poor prognosis of patients. SNORD12B profoundly promoted proliferation, migration, invasion, and metastasis of ESCC cells in vitro and in vivo, indicating its oncogene nature. In particular, SNORD12B could interact with PP-1α, one of the three catalytic subunits of serine/threonine protein phosphatase 1, which is a major phosphatase that directly dephosphorylates AKT to suppress its activation. Interestingly, high levels of SNORD12B in ESCC cells could break interactions between 14-3-3ζ and PP-1α, abolish the retention of PP-1α in the cytosol by 14-3-3ζ and relocate PP-1α from the cytosol to the nucleus. This led to sequestered PP-1α in the nucleus, enhanced phosphorylation of AKT in the cytosol, activated AKT-mTOR-4EBP1 signaling, and, thus, ESCC progression. These insights would improve our understanding of how snoRNAs contribute to tumorigenesis and highlight the potential of snoRNAs as future therapeutic targets against cancers.

13.
Brief Bioinform ; 22(5)2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33839756

RESUMO

Batch effect correction is an essential step in the integrative analysis of multiple single-cell RNA-sequencing (scRNA-seq) data. One state-of-the-art strategy for batch effect correction is via unsupervised or supervised detection of mutual nearest neighbors (MNNs). However, both types of methods only detect MNNs across batches of uncorrected data, where the large batch effects may affect the MNN search. To address this issue, we presented a batch effect correction approach via iterative supervised MNN (iSMNN) refinement across data after correction. Our benchmarking on both simulation and real datasets showed the advantages of the iterative refinement of MNNs on the performance of correction. Compared to popular alternative methods, our iSMNN is able to better mix the cells of the same cell type across batches. In addition, iSMNN can also facilitate the identification of differentially expressed genes (DEGs) that are relevant to the biological function of certain cell types. These results indicated that iSMNN will be a valuable method for integrating multiple scRNA-seq datasets that can facilitate biological and medical studies at single-cell level.

14.
Cardiovasc Res ; 2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33839759

RESUMO

AIMS: The precise cellular identity and molecular features of non-myocytes (nonCM) in a mammalian heart at a single cell level remain elusive. Depiction of epigenetic landscape with transcriptomic signatures using the latest single-cell multi-omics has the potential to unravel the molecular programs underlying the cellular diversity of cardiac non-myocytes. Here, we characterized the molecular and cellular features of cardiac nonCM populations in the adult murine heart at the single cell level. METHODS AND RESULTS: Through single-cell dual omics analysis, we mapped the epigenetic landscapes, characterized the transcriptomic profiles and delineated the molecular signatures of cardiac nonCMs in the adult murine heart. Distinct cis-regulatory elements and trans-acting factors for the individual major nonCM cell types (endothelial cells, fibroblast, pericytes and immune cells) were identified. In particular, unbiased sub-clustering and functional annotation of cardiac fibroblasts (FB) revealed extensive FB heterogeneity and identified FB subtypes with functional states related to cellular response to stimuli, cytoskeleton organization and immune regulation, respectively. We further explored the function of marker genes Hsd11b1 and Gfpt2 that label major FB sub-populations and determined the distribution of Hsd11b1+ and Gfp2+ FBs in murine healthy and diseased hearts. CONCLUSIONS: In summary, we characterized the nonCM cellular identity at the transcriptome and epigenome levels using single-cell omics approaches and discovered previously unrecognized cardiac fibroblast subpopulations with unique functional states. TRANSLATIONAL PERSPECTIVE: Our research identified discrete cell types of nonCM in the heart and differentially expressed genes with regulatory factors. Unveiling the heterogeneity of nonCMs and molecular signatures of each cell type or subtypes allows for study, precise capture and manipulation of specific cell type(s) in heart and will provide insights into the development of therapeutics for cardiovascular diseases.

15.
Arch Toxicol ; 95(5): 1621-1629, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33713148

RESUMO

Transarterial chemoembolization (TACE) has significantly improved overall survival (OS) of unresectable hepatocellular carcinoma (HCC) patients. Unfortunately, a portion of patients show no therapeutic responses to TACE. N6-methyladenosine (m6A) as well as its epigenetic writers, erasers, and readers play a crucial role in HCC development. However, it is still largely unclear how functional small nucleotide polymorphisms (SNPs) in m6A-regulating genes contribute to prognosis of TACE-treated HCC patients. In this study, potential functional SNPs were systematically evaluated to identify their roles in the prognosis of HCC patients after TACE in a Chinese Han population. Employing multiple databases, we successfully annotated 55 candidate SNPs. After genotyping these SNPs in our TACE cohort, we identified three genetic variants in YTHDC2 (rs6594732, rs10071816, and rs2303718) and one SNP in FTO (rs7202116) having statistically significant associations with the OS of HCC patients treated with TACE. For example, multivariate Cox proportional hazards model indicated that the rs7202116 GG genotype carriers had markedly shorter OS and an 87% increased death risk compared with the AA carriers after TACE therapy (P = 0.002). When investigating functional relevance of these SNPs, we observed an allelic regulation of rs7202116 on FTO expression in HCC tissue samples, with higher tumor suppressor FTO expression among the A allele carriers. Our findings reported the first evidence supporting the prognostic value of m6A reader YTHDC2 and m6A eraser FTO SNPs in TACE-treated HCC patients. Importantly, our data implicated that m6A-regulating genes may be targets to improve therapeutic strategy for unresectable HCC patients.

16.
J Colloid Interface Sci ; 593: 408-416, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33744548

RESUMO

Potassium-ion batteries (PIBs) is one of the most promising alternatives for Lithium-ion batteries (LIBs) due to the low-cost and abundant potassium reserves. However, the electrochemical performances of PIBs were seriously hindered by the larger radius of potassium ions, resulting in a slow kinetic during the electrochemical reaction, especially in the PIB anodes. In the study, we propose FeS nanodots embedded S-doped porous carbon (FeS@SPC) synthesized by a simple self-template method for the storage of potassium-ions. The FeS nanodots with an average diameter of 5 nm are uniformly distributed in S-doped porous carbon nanosheets. When the FeS@SPC was used as the anode in PIBs, the unique structure of FeS@SPC can relieve the agglomeration and volume expansion of FeS effectively during the charge-discharge process. Even after 3000 cycles, the FeS nanodots are still uniformly embedded in porous carbon without agglomeration. Ascribed to the merits, the FeS@SPC exhibits a reversible capacity of 309 mAh g-1 at 0.1 A g-1 after 100 cycles and 232 mAh g-1 at 1 A g-1 after 3000 cycles. The excellent electrochemical performance of FeS@SPC is attributed to the synergistic effects of FeS nanodots and S-doped porous carbon, which facilitated the diffusion of electrolyte and accelerated the migration of potassium ions. Moreover, theoretical calculation results also suggest that the van der waals heterostructure of FeS@SPC displays higher adsorption energy for potassium ions than that of S-doped graphene, indicating the suitability of FeS@SPC for K storage.

17.
Nat Rev Mol Cell Biol ; 22(6): 410-424, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33619373

RESUMO

The reprogramming of somatic cells with defined factors, which converts cells from one lineage into cells of another, has greatly reshaped our traditional views on cell identity and cell fate determination. Direct reprogramming (also known as transdifferentiation) refers to cell fate conversion without transitioning through an intermediary pluripotent state. Given that the number of cell types that can be generated by direct reprogramming is rapidly increasing, it has become a promising strategy to produce functional cells for therapeutic purposes. This Review discusses the evolution of direct reprogramming from a transcription factor-based method to a small-molecule-driven approach, the recent progress in enhancing reprogrammed cell maturation, and the challenges associated with in vivo direct reprogramming for translational applications. It also describes our current understanding of the molecular mechanisms underlying direct reprogramming, including the role of transcription factors, epigenetic modifications, non-coding RNAs, and the function of metabolic reprogramming, and highlights novel insights gained from single-cell omics studies.


Assuntos
Diferenciação Celular/fisiologia , Reprogramação Celular/fisiologia , Epigênese Genética/genética , Animais , Diferenciação Celular/genética , Transdiferenciação Celular/genética , Transdiferenciação Celular/fisiologia , Reprogramação Celular/genética , Humanos
18.
J Mol Cell Biol ; 13(1): 41-58, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33582796

RESUMO

Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). However, the signaling mechanisms by which injury induces CM renewal remain incompletely understood. Here, we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors, including Dickkopf 1 (Dkk1), Dkk3, secreted Frizzled-related protein 1 (sFrp1), and sFrp2, in cardiac tissue adjacent to injury sites. Experimental blocking of Wnt activity via Dkk1 overexpression enhances CM proliferation and heart regeneration, whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation. Although Wnt signaling is dampened upon injury, the cytoplasmic ß-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges. Our analyses indicated that p21-activated kinase 2 (Pak2) is induced at regenerating CMs, where it phosphorylates cytoplasmic ß-catenin at Ser 675 and increases its stability at disassembled sarcomeres. Myocardial-specific induction of the phospho-mimetic ß-catenin (S675E) enhances CM dedifferentiation and sarcomere disassembly in response to injury. Conversely, inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylated ß-catenin (pS675-ß-catenin) and attenuates CM sarcomere disorganization and dedifferentiation. Taken together, these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-ß-catenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.

19.
Clin Cancer Res ; 27(6): 1734-1743, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33414138

RESUMO

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC. EXPERIMENTAL DESIGN: Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded. RESULTS: We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade-based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03). CONCLUSIONS: These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.

20.
J Cancer ; 12(4): 1231-1239, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33442421

RESUMO

Gastric cardia adenocarcinoma (GCA) is one of two main gastric cancer subtypes and has its own epidemiological, pathogenic and clinical characteristics. Genetic polymorphisms locating in a microRNA (miRNA) gene enhancer could transcriptionally regulates miRNA expression via impacting binding of transcriptional factors. It is still unclear how miR-1262 and a potential regulatory rs12740674 polymorphism mapping to a strong enhancer region of miR-1262 contribute to GCA development. We genotyped miR-1262 rs12740674 in two independent case-control sets consisting of 1,024 GCA patients and 1,118 controls, and found that the rs12740674 CT or TT genotype carriers had a 0.69-fold decreased risk to develop GCA compared to the CC genotype carriers (95% confidence interval=0.57-0.84, P=2.1×10-4). In the genotype-phenotype correlation analyses of 21 pairs of GCA-normal tissues, the rs12740674 CT or TT genotype was associated with significantly increased levels of miR-1262. Cell proliferation, wound healing and transwell assays elucidated that miR-1262 is a novel GCA tumor suppressor. Consistently, a significantly down-regulated level of miR-1262 exists in GCA specimens compared to normal tissues. Furthermore, multiple lines of evidences indicated that oncogene ULK1 is the target gene of miR-1262 in GCA. Our findings demonstrate miR-1262 transcriptionally modulated by an enhancer genetic variant suppresses GCA via targeting oncogene ULK1. Our data highlight miR-1262 as a promising diagnostic marker and therapeutic target for GCA.

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