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1.
Commun Biol ; 5(1): 182, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35233061

RESUMO

Ovarian tumor (OTU) subfamily deubiquitinases are involved in various cellular processes, such as inflammation, ferroptosis and tumorigenesis; however, their pathological roles in prostate cancer (PCa) remain largely unexplored. In this study, we observed that several OTU members displayed genomic amplification in PCa, among which ovarian tumor deubiquitinase 6A (OTUD6A) amplified in the top around 15-20%. Further clinical investigation showed that the OTUD6A protein was highly expressed in prostate tumors, and increased OTUD6A expression correlated with a higher biochemical recurrence risk after prostatectomy. Biologically, wild-type but not a catalytically inactive mutant form of OTUD6A was required for PCa cell progression. In vivo experiments demonstrated that OTUD6A oligonucleotides markedly suppressed prostate tumorigenesis in PtenPC-/- mice and patient-derived xenograft (PDX) models. Mechanistically, the SWI/SNF ATPase subunit Brg1 and the nuclear receptor AR (androgen receptor) were identified as essential substrates for OTUD6A in PCa cells by a mass spectrometry (MS) screening approach. Furthermore, OTUD6A stabilized these two proteins by erasing the K27-linked polyubiquitination of Brg1 and K11-linked polyubiquitination of AR. OTUD6A amplification exhibited strong mutual exclusivity with mutations in the tumor suppressors FBXW7 and SPOP. Collectively, our results indicate the therapeutic potential of targeting OTUD6A as a deubiquitinase of Brg1 and AR for PCa treatment.


Assuntos
DNA Helicases , Proteínas Nucleares , Neoplasias Ovarianas , Neoplasias da Próstata , Receptores Androgênicos , Fatores de Transcrição , Animais , Transformação Celular Neoplásica , DNA Helicases/metabolismo , Enzimas Desubiquitinantes/metabolismo , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/patologia , Próstata/patologia , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitinação
2.
Small ; 18(12): e2105989, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35088522

RESUMO

Biomedical imaging technology (like digital subtraction angiography (DSA)) based on contrast agents has been widely employed in the diagnosis of vascular-related diseases. While the DSA achieves the high-resolution observation of specified vessels and their downstream perfusion at the cost of invasive, radioactive operation and hepatorenal toxicity. To address those problems, this study develops arterial labeling ultrasound (US) subtraction angiography (ALUSA) based on a new perfluorobutane (PFB) nanodroplets with a lower vaporization threshold through spontaneous nucleation. The nanodroplets can be selectively vaporized to microbubbles, indicating a highly echogenic signal at B-mode images only using a diagnostic transducer. By labeling a single blood vessel for nanodroplets vaporization and tracking its downstream blood perfusion in segmental renal arteries at a frame rate of 500 Hz. The results demonstrate the color-coded super-resolution ALUSA image, exhibiting the downstream arcuate and interlobular arteries of each segmental renal artery with a resolution of 36 µm in a rabbit kidney. Furthermore, ALUSA could offer the vascular structures, blood flow velocity, and direction of their primary supply vessels in the mouse breast tumor. ALUSA fills the gap of noninvasive labeling angiography in US and opens a broad vista in the diagnosis and treatment of tumor and vascular-related diseases.


Assuntos
Acústica , Microbolhas , Angiografia Digital , Animais , Artérias , Camundongos , Coelhos , Ultrassonografia/métodos
3.
Nutr Cancer ; : 1-13, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34907814

RESUMO

Targeting Bcr-Abl is the key to the treatment of chronic myeloid leukemia. Despite great progress in the treatment of patients with chronic CML, advanced CML patients are still unable to obtain effective and safe drugs. Momordica cochinchinensis seed is the dried ripe seed of Momordica cochinchinensis, which is a kind of fruit and consumed for dietary as well as medicinal uses. This study aimed to investigate the anticancer activity of Momordica cochinchinensis seed extract (MCSE) in CML cells. CML cells (KBM5 and KBM5-T315I) were treated with MCSE and analyzed for growth, apoptosis, and signal transduction. Nude mouse xenograft model was used to evaluate the antitumor activity of MCSE In Vivo. MCSE significantly reduced the cell viability of CML cells, triggered G0/G1 phase arrest in KBM5 cells and S phase arrest in KBM5-T315I cells. Concurrently, MCSE caused the activation of caspase-3, -8, -9, PARP and the degradation of Mcl-1, ultimately triggering endogenous and exogenous cell apoptosis. Meanwhile, MCSE downregulated Bcr-Abl levels and its downstream signaling pathways. Additionally, MCSE inhibited the growth of CML cells in nude mouse xenografts. Taken together, this study demonstrated the anticancer mechanism of MCSE, namely blocking Bcr-Abl and downregulating Mcl-1, and finally induced apoptosis of CML cells.

4.
ACS Nano ; 15(10): 16913-16923, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34647449

RESUMO

The advent of localization-based super-resolution ultrasound (SRUS) imaging creates a vista for precision vasculature and hemodynamic measurements in brain science, cardiovascular diseases, and cancer. As blinking fluorophores are crucial to super-resolution optical imaging, blinking acoustic contrast agents enabling ultrasound localization microscopy have been highly sought, but only with limited success. Here we report on the discovery and characterization of a type of blinking acoustic nanodroplets (BANDs) ideal for SRUS. BANDs of 200-500 nm diameters comprise a perfluorocarbon-filled core and a shell of DSPC, Pluronic F68, and DSPE-PEG2000. When driven by clinically safe acoustic pulses (MI < 1.9) provided by a diagnostic ultrasound transducer, BANDs underwent reversible vaporization and reliquefaction, manifesting as "blinks", at rates of up to 5 kHz. By sparse activation of perfluorohexane-filled BANDs-C6 at high concentrations, only 100 frames of ultrasound imaging were sufficient to reconstruct super-resolution images of a no-flow tube through either cumulative localization or temporal radiality autocorrelation. Furthermore, the use of high-density BANDs-C6-4 (1 × 108/mL) with a 1:9 admixture of perfluorohexane and perfluorobutane supported the fast SRUS imaging of muscle vasculature in live animals, at 64 µm resolution requiring only 100 frames per layer. We anticipate that the BANDs developed here will greatly boost the application of SRUS in both basic science and clinical settings.


Assuntos
Piscadela , Meios de Contraste , Acústica , Animais , Imagem Óptica , Ultrassonografia
5.
Phys Med Biol ; 66(21)2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34592723

RESUMO

Objective:Microvasculature is highly relevant to the occurrence and development of pathologies such as cancer and diabetes. Ultrasound localization microscopy (ULM) has bypassed the diffraction limit and demonstrated its great potential to provide new imaging modality and establish new diagnostic criteria in clinical application. However, sparse microbubble distribution can be a significant bottleneck for improving temporal resolution, even for further clinical translation. Other important challenges for ULM to tackle in clinic also include high microbubble concentration and low frame rate.Approach:As part of the efforts to facilitate clinical translation, this paper focused on the low frame rate and the high microbubble distribution issue and proposed a new super-resolution imaging strategy called entropy-based radiality super-resolution (ERSR). The feasibility of ERSR is validated with simulations, phantom experiment and contrast-enhanced ultrasound scan of rabbit sciatic nerve with clinical accessible ultrasound system.Main results:ERSR can achieve 10 times improvement in spatial resolution compared to conventional ultrasound imaging, higher temporal resolution (∼10 times higher) and contrast-to-noise ratio under high-density microbubbles, compared with ULM under low-density microbubbles.Significance:We conclude ERSR could be a valuable imaging tool with high spatio-temporal resolution for clinical diagnosis and assessment of diseases potentially.


Assuntos
Microbolhas , Microvasos , Animais , Meios de Contraste , Entropia , Microscopia/métodos , Microvasos/diagnóstico por imagem , Coelhos , Ultrassonografia/métodos
6.
Br J Cancer ; 124(2): 425-436, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32989225

RESUMO

BACKGROUND: A large proportion of gastric cancer patients are susceptible to chemoresistance, while the underlying mechanism remains obscure. Stress granules (SGs) play a self-defence role for tumour cells in inhibiting chemotherapy-induced apoptosis. As an SG assembly effector, G3BP1 (Ras-GTPase-activating protein SH3 domain-binding protein) has been reported to be overexpressed in gastric cancer; thus, here we aim to explore its potent roles in gastric cancer chemoresistance. METHODS: Kaplan-Meier analysis was used to compare survival rates in gastric cancer patients with different G3BP1 expression. The influence of G3BP1 on gastric cancer cell chemoresistance and apoptosis were evaluated by in vitro and in vivo approaches. The interaction between G3BP1 and YWHAZ was assessed by immunohistochemistry, immunoprecipitation and immunofluorescence. RESULTS: G3BP1 was associated with the poor outcome of gastric cancer patients who received adjuvant chemotherapy. G3BP1 knockdown significantly increased the sensitivity of gastric cancer cells to chemotherapy drugs. Mechanically, cell apoptosis and pro-apoptotic-associated molecules were significantly elevated upon G3BP1 depletion. Gene co-expression network analyses identified YWHAZ as the critical interlayer of G3BP1; as a result, G3BP1 interacted with YWHAZ to sequester Bax into the cytoplasm. Clinically, G3BP1highYWHAZhigh gastric cancer patients displayed the worst outcome compared with other patients after chemotherapy. CONCLUSIONS: The expression of G3BP1 and YWHAZ could predict the adjuvant chemotherapy benefit in gastric cancer patients.


Assuntos
Proteínas 14-3-3/metabolismo , Biomarcadores Tumorais/metabolismo , DNA Helicases/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Neoplasias Gástricas/patologia , Animais , Quimioterapia Adjuvante , Xenoenxertos , Humanos , Camundongos , Neoplasias Gástricas/tratamento farmacológico
7.
J Cancer ; 10(23): 5671-5680, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737104

RESUMO

Background: Targeting Bcr-Abl is the key for the treatment of CML. Although great progress has been achieved for the treatment of CML patients in chronic stage, effective drugs with good safety are not available for those in advanced stages of CML patients. In present study, a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was used to screen for microRNA that can target Bcr-Abl. Methods: RT-qPCR was used to determine Bcr-Abl and miR-4433 transcription level in CML cells. In CML cells, Proteins including PARP, caspase-3, acetyl-histone 3, histone 3 and Bcr-Abl, as well as Bcr-Abl downstream proteins were detected using western blot. Cell viability and apoptosis were monitored respectively by MTS assay and flow cytometry. The correlation between miR-4433 and Bcr-Abl was determined by luciferase reporter assay. The anti-tumor effect of miR-4433 to K562 cells was evaluated by nude mouse xenograft model in vivo. Results: SAHA up-regulated the acetylation level of histone 3, and effectively inhibited Bcr-Abl mRNA level and its downstream signal transduction pathway, while inhibiting the growth of CML cells and inducing apoptosis. Furthermore, bioinformatics tools predicted that miR-4433 is a putative microRNA targeting Bcr-Abl and that the expression level of miR-4433 was significantly increased after SAHA treatment in K562 cells. Luciferase activity analysis revealed that miR-4433 directly targets Bcr-Abl. Additionally, transient expression of miR-4433 abrogated Bcr-Abl activity and its downstream signaling pathways while inducing apoptosis in K562 cells. Moreover, stable expression of miR-4433 suppressed Bcr-Abl and its downstream signaling pathway, and inhibited the growth of K562 cells in vitro and the growth of K562-xenografts in nude mice. Conclusion: miR-4433 was identified as a microRNA targeting Bcr-Abl, which may be subject to epigenetic regulation of SAHA, a histone deacetylase inhibitor that has been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. The findings of this study provide a molecular basis from another angle for the use of SAHA in the treatment of CML.

8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(3): 266-270, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-31030721

RESUMO

Objective To analyze the relationship between the number of invasive T cells in in situ tumors and the clinical metastasis and prognosis in patients with non-small cell lung cancer (NSCLC). Methods A total of 140 lung cancer patients (including 43 cases with metastasis) were selected to observe the infiltration state of CD4+ T cells and CD8+ T cells in tumor tissues by immunohistochemical staining. The infiltration of CD4+ T cells and CD8+ T cells were compared between non-metastatic and metastatic patients. The effects of different infiltration levels of CD4+ T cells and CD8+ T cells on clinical prognosis were analyzed. Results The proportion of CD4+ T cells in the tumor tissues of the two groups was not significantly different. The number of CD8+ T cells in the metastatic group was significantly lower than that in the metastatic group, and the ratio of CD8/CD4 in the non-metastasis group was remarkably higher than that in the metastatic group. Patients with high CD8+ T cell infiltration level or high ratio of CD8/CD4 have a significantly better overall survival rate than the patients with low CD8+ T cell infiltration level or low ratio of CD8/CD4. Conclusion The number of CD8+ T cell infiltration and CD8/CD4 ratio in the tumor tissues of patients with metastatic NSCLC are significantly reduced, which is closely related to the poor prognosis of patients with NSCLC metastasis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Humanos , Linfócitos do Interstício Tumoral , Prognóstico
9.
Oncol Lett ; 17(3): 3017-3025, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30854080

RESUMO

Pristimerin is an active compound isolated from the traditional Chinese herbs Celastraceae and Hippocrateaceae. It has been reported to exert antitumor effects under experimental and clinical conditions; however, the antitumor effects and underlying mechanisms of pristimerin in oral cancer cells have not yet been identified. In the present study, the anticancer potential of pristimerin was investigated in two oral squamous cell carcinoma (OSCC) cell lines, CAL-27 and SCC-25. Results demonstrated that pristimerin was toxic against the two cell lines, and exhibited inhibitory effects against proliferation. Furthermore, pristimerin exhibited a more potent anti-proliferative activity in CAL-27 and SCC-25 cells than the common chemotherapy drugs cisplatin and 5-fluorouracil. In addition, cell cycle distribution analysis revealed that G0/G1 phase arrest was induced following pristimerin treatment in CAL-27 and SCC-25 cells, which was strongly associated with upregulation of p21 and p27, coupled with downregulation of cyclin D1 and cyclin E. Meanwhile, pristimerin induced significant apoptosis of CAL-27 and SCC-25 cells, alongside decreased levels of caspase-3 and specific cleavage of poly (ADP-ribose) polymerase. These effects were associated with inhibition of the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 and protein kinase B signaling pathways. With regards to these results, pristimerin may be considered a potent novel active substance for the treatment of OSCC.

10.
Am J Hum Genet ; 87(6): 905-14, 2010 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-21129721

RESUMO

CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development.


Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Anormalidades Múltiplas/genética , Alelos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Temperatura , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Éxons , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Homologia de Sequência de Aminoácidos , Adulto Jovem
11.
Am J Med Genet A ; 149A(11): 2469-78, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19842190

RESUMO

X-linked mental retardation (XLMR) affects 1-2/1,000 males and accounts for approximately 10% of all mental retardation (MR). We have ascertained a syndromic form of XLMR segregating within a five-generation family with seven affected males. Prominent characteristics include mild to severe MR, cortical malformation, microcephaly, seizures, thin build with distinct facial features including a long and thin face, epicanthic folds, almond-shaped eyes, upslanting palpebral fissures and micrognathia and behavioral problems. Carrier females have normal physical appearance and intelligence. This combination of features is unreported and distinct from Lujan-Fryns syndrome, Snyder-Robinson syndrome, and zinc finger DHHC domain-containing 9-associated MR. We propose the name of this new syndrome to be CK syndrome.


Assuntos
Constituição Corporal , Córtex Cerebral/anormalidades , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/genética , Microcefalia/complicações , Microcefalia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Facies , Evolução Fatal , Feminino , Mãos/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Gravidez , Radiografia
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