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1.
Am J Transl Res ; 13(2): 480-496, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33594305

RESUMO

The abnormal expression of ubiquitin-specific protease 11 (USP11) is thought to be related to tumor development and progression; however, few studies have reported the biological function and clinical importance of USP11 in colorectal cancer (CRC). Therefore, it is necessary to further explore the role of USP11 in CRC. Immunohistochemical staining was used to explore the association between prognosis and USP11 expression in CRC. Cholecystokinin octapeptide (CCK-8), colony formation, transwell, and animal assays were used to study the abilities of proliferation, migration, and invasion in CRC cells. Co-immunoprecipitation assays, Western blotting, ubiquitination assays, and rescue experiments were performed to elucidate the interaction between USP11 and insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3). We verified that USP11 was overexpressed in CRC tissues and was associated with the depth of tumor invasion and metastasis. USP11 knockdown or overexpression could weaken or reinforce the abilities of proliferation, migration, and invasion in CRC cells in vivo or in vitro. IGF2BP3 was protected by USP11 from degradation via deubiquitination. The rescue experiments revealed that IGF2BP3 overexpression could effectively reverse the decrease in cell proliferation, migration, and invasion caused by USP11 knockdown. Therefore, USP11 might be involved in CRC tumorigenesis and development through a USP11-IGF2BP3 axis pathway, and USP11 overexpression might be a novel indicator for poor prognosis and a potential therapeutic target in CRC patients.

2.
Hum Cell ; 34(2): 530-538, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33469898

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cause of malignancy-related deaths. Recently, RING-finger protein 5 (RNF5), an E3 ubiquitin ligase, was revealed to be associated with the development of several human cancers. However, the clinical implication and functional role of RNF5 in HCC are poorly understood. We analysed RNF5 expression in HCC samples and observed that both the mRNA and protein levels of RNF5 were significantly increased in HCC tissues. RNF5 upregulation was markedly associated with larger tumour size, more satellite foci, and higher alpha fetoprotein (AFP) level, indicating poor prognosis in patients with HCC. Knockdown and overexpression experiments demonstrated that RNF5 promoted the proliferation, migration, and invasion of HCC cells in vitro. Moreover, RNF5 facilitated HCC growth in vivo. Our findings indicated that RNF5 was an oncogene of HCC progression and could be used as a novel prognostic biomarker and therapeutic target for patients with HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA/fisiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Ubiquitina-Proteína Ligases/fisiologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Movimento Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Expressão Gênica/genética , Humanos , Neoplasias Hepáticas/diagnóstico , Terapia de Alvo Molecular , Invasividade Neoplásica/genética , Oncogenes , Prognóstico , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
3.
Onco Targets Ther ; 13: 5807-5817, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606791

RESUMO

PURPOSE: Accumulating studies have explored the potential diagnostic value of lncRNA MALAT1 in various cancers. However, there are still inconsistent results in diagnostic accuracy and reliability in individual studies. The aim of this pooled study was to summarize the overall diagnostic capacity of lncRNA MALAT1 in cancer detection and diagnosis. METHODS: Eligible studies satisfying the inclusion criteria were screened and selected from the online database. All statistical analyses were performed using Stata 14.0. RESULTS: A total of 17 eligible studies were included in this pooled analysis, with 1777 cases and 1478 controls. The overall results were shown as follows: sensitivity, 0.74 (95% CI=0.65-0.81), specificity, 0.79 (95% CI=0.73-0.84), positive likelihood ratio (PLR), 3.48 (95% CI=2.79-4.32), negative likelihood, 0.33 (95% CI=0.25-0.44), diagnostic score, 2.34 (95% CI=1.99-2.69), diagnostic odds ratio, 10.41 (95% CI=7.33-14.78) and area under the curve, 0.83 (95% CI=0.80-0.86). Deeks' funnel plot asymmetry test (p = 0.66) suggested no potential publication bias. CONCLUSION: All these results indicate that lncRNA MALAT1 achieves a relatively moderate accuracy in cancer detection and diagnosis, and could serve as a diagnostic biomarker for cancers.

4.
Am J Cancer Res ; 10(5): 1416-1428, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32509388

RESUMO

Growing evidence indicates that deubiquitinase ubiquitin-specific protease 11 (USP11) plays an important role in cellular function by regulating the stability of its substrates. USP11 is dysregulated in many types of cancer and involved in tumor development and progression. We previously showed that USP11 was upregulated in hepatocellular carcinoma (HCC) and promoted HCC cell invasion and metastasis potency. However, the mechanism underlying the role of USP11 in HCC cell metastasis and its function in cell proliferation remain unknown. Here, CCK-8, soft agar assays and nude mouse models showed that USP11 was essential for HCC cells survival and proliferation in vitro and in vivo. Results form mass spectrometry, co-immunoprecipitation, and ubiquitination assays demonstrated that USP11 interacted with nuclear factor 90 (NF90) and promoted its deubiquitination, thereby stabilizing it in HCC cells. Moreover, the effect of USP11 on promoting HCC cells proliferation and metastasis was dependent on NF90, and USP11 expression was positively correlated with NF90 expression in human HCC tissues, as demonstrated via immunohistochemistry. Collectively, the present findings indicated that USP11 binded to and deubiquitinated NF90, thereby stabilizing the protein expression level and promoting HCC cell proliferation and metastasis. NF90 was identified as an important downstream target of USP11. Dysregulated signaling of this novel USP11/NF90 axis might promote HCC proliferation and metastasis, and the axis could be a potential therapeutic target in HCC.

5.
Mol Oncol ; 13(9): 1993-2009, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31294922

RESUMO

The cross-talk between hepatic stellate cells (HSCs) and hepatic carcinoma cells contributes to hepatocellular carcinoma (HCC) progression, but the underlying mechanism is largely unknown. We report here that activated HSCs induce upregulation of nicotinamide N-methyltransferase (NNMT), which is known to regulate multiple metabolic pathways in hepatoma cells of the liver. High levels of NNMT in HCC tissues were positively correlated with vascular invasion, increased serum HBV-DNA levels, and distant metastasis. In addition, functional assays showed that NNMT promoted HCC cell invasion and metastasis by altering the histone H3 methylation on 27 methylation pattern and transcriptionally activating cluster of differentiation 44 (CD44). NNMT-mediated N6-methyladenosine modification of CD44 mRNA resulted in the formation of a CD44v3 splice variant, while its product 1-methyl-nicotinamide stabilized CD44 protein by preventing ubiquitin-mediated degradation. Finally, NNMT was also shown to be a target of statins that inhibited metastasis of hepatoma cells. Taken together, our study shows for the first time that the NNMT/CD44v3 axis regulates HCC metastasis and presents NNMT as a promising prognostic biomarker and therapeutic target for HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Receptores de Hialuronatos/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/metabolismo , Nicotinamida N-Metiltransferase/biossíntese , Animais , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Regulação Enzimológica da Expressão Gênica , Células Hep G2 , Células Estreladas do Fígado/patologia , Humanos , Receptores de Hialuronatos/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Proteínas de Neoplasias/genética , Nicotinamida N-Metiltransferase/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
6.
Hum Pathol ; 84: 213-220, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30339968

RESUMO

DHX15 is an outstanding member of the DEAH-box RNA helicase family. A few studies suggest that DHX15 contributes to carcinogenesis in several tumor cell lines. However, whether DHX15 acts as an oncogene or tumor suppressor and its association with hepatocellular carcinoma (HCC) prognosis are still poorly understood. To address this question, we used immunohistochemistry to evaluate DHX15 expression patterns and their association with clinicopathological factors and the prognosis of patients with HCC. Our results showed that DHX15 expression was significantly higher in cancerous tissues than that in nontumor tissues (P < .0001). DHX15 expression in HCC patients was associated with differentiation status (P = .018), tumor number (P = .048), intrahepatic or extrahepatic metastasis (P = .001), serum α-fetoprotein (P = .006), hepatitis B virus level (P = .018), and recurrence (P < .001). In addition, the survival analysis revealed that the DHX15-high group had significantly decreased overall survival time (P = .004) and lower 1-year survival rates (P = .002) compared with the DHX15-low group. Furthermore, multivariate analysis identified DHX15 expression as an independent factor associated with poor prognosis in HCC (P = .036). In summary, these findings demonstrate, for the first time, that DHX15 is significantly upregulated in HCC and its high expression was correlated with poor prognosis, suggesting its pivotal role in the progression of HCC. The present results suggest that DHX15 may serve as a potential prognostic biomarker for HCC patients.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , RNA Helicases/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Regulação para Cima , Adulto Jovem
7.
Am J Cancer Res ; 8(10): 2076-2087, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30416857

RESUMO

YEATS domain containing 4 (YEATS4) is usually amplified and functions as an oncogene in several malignancies, such as colorectum, ovarian, breast and lung. However, the biological role of YEATS4 in hepatocellular carcinoma (HCC) has not yet been discussed. Herein, we found that YEATS4 was significantly upregulated in HCC compared to para-cancerous tissues, and was associated with poor prognosis, large tumor size, poor differentiation and distant metastasis. In addition, YEATS4 promoted HCC cell proliferation and colony formation by binding to and increasing the transcriptional activity of the TCEA1 promoter. Concurrently, upregulation of TCEA1 increased the stability of the DDX3 protein, a member of the DEAD box RNA helicase family, and augmented the proliferative and colony forming ability of HCC cells. Furthermore, YEATS4 accelerated tumor growth in vivo in a xenograft HCC model. Taken together, our study provides evidence for the first time on the potential role of the YEATS4/TCEA1/DDX3 axis in regulating HCC progression, and presents YEATS4 as a promising therapeutic target and prognosis maker for HCC.

8.
Biosci Rep ; 38(3)2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29776974

RESUMO

Hepatocellular carcinoma (HCC) accounts for a large proportion of cancer-associated mortality worldwide. The functional impact of long noncoding RNAs (lncRNAs) in human cancer is not fully understood. Here, we identified a novel oncogenic lncRNA termed as lncPARP1, which was significantly up-regulated in HCC. Increase in lncPARP1 expression was associated with age, α-fetoprotein (AFP) levels, tumor size, recurrence, and poor prognosis of HCC patients. Loss-of-function approaches showed that knockdown of lncPARP1 inhibited proliferation, migration, and invasion, while induced apoptosis in HCC cells. Moreover, mechanistic investigation demonstrated that PARP1 was an underlying target of lncPARP1 in HCC. In summary, we provide the first evidence that lncPARP1 exerts an oncogene to promote HCC development and progression, at least in part, by affecting poly (ADP-ribose) (PAR) polymerase 1 (PARP1) expression.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Poli(ADP-Ribose) Polimerase-1/genética , RNA Longo não Codificante/genética , Idoso , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Poli(ADP-Ribose) Polimerase-1/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida
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