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Biochim Biophys Acta Mol Cell Res ; 1868(1): 118878, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33011193


Ovarian cancer is the deadliest gynaecologic malignancy, and the five-year survival rate of patients is less than 35% worldwide. Cancer stem cells (CSCs) are a population of cells with stem-like characteristics that are thought to cause chemoresistance and recurrence. TRIM29 is aberrantly expressed in various cancers and associated with cancer development and progression. Previous studies showed that the upregulation of TRIM29 expression in pancreatic cancer is related to stem-like characteristics. However, the role of TRIM29 in ovarian cancer is poorly understood. In this study, we found that TRIM29 expression was increased at the translational level in both the cisplatin-resistant ovarian cancer cells and clinical tissues. Increased TRIM29 expression was associated with a poor prognosis of patients with ovarian cancer. In addition, TRIM29 could enhance the CSC-like characteristics of the cisplatin-resistant ovarian cancer cells. Recruitment of YTHDF1 to m6A-modified TRIM29 was involved in promoting TRIM29 translation in the cisplatin-resistant ovarian cancer cells. Knockdown of YTHDF1 suppressed the CSC-like characteristics of the cisplatin-resistant ovarian cancer cells, which could be rescued by ectopic expression of TRIM29. This study suggests TRIM29 may act as an oncogene to promote the CSC-like features of cisplatin-resistant ovarian cancer in an m6A-YTHDF1-dependent manner. Due to the roles of TRIM29 and YTHDF1 in the promotion of CSC-like features, they may become potential therapeutic targets to combat the recurrence of ovarian cancer.

Biochim Biophys Acta Mol Cell Res ; 1867(4): 118647, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31926942


Cisplatin-based chemotherapies have long been considered as a standard chemotherapy in ovarian cancer. However, cisplatin resistance restricts beneficial therapy for patients with ovarian cancer. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the post-translational modification of diverse proteins. In this work, we found that ISG15 was downregulated in cisplatin resistant tissues and cell lines of ovarian cancer. Functional studies demonstrated that overexpression of wild type (WT) ISG15, but not nonISGylatable (Mut) ISG15 increased cell responses to cisplatin in resistant ovarian cancer cells. Furthermore, we found that WT ISG15 decreased ABCC2 expression at the protein level. Importantly, overexpression of ABCC2 blocked sensitizing effect of ISG15 on cisplatin. In addition, we identified that hnRNPA2B1 was recruited to 5'UTR of ABCC2 mRNA and promoted its translation, which was blocked by ISG15. We further demonstrated that hnRNPA2B1 could be ISGylated, and ISGylation blocked its recruitment to ABCC2 mRNA, thereby suppressed translation of ABCC2. Altogether, our data support targeting ISG15 might be a potential therapeutic strategy for patients with cisplatin-resistant ovarian cancer.

Antineoplásicos/farmacologia , Cisplatino/farmacologia , Citocinas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Neoplasias Ovarianas/genética , Biossíntese de Proteínas , Ubiquitinas/metabolismo , Regiões 5' não Traduzidas , Adulto , Idoso , Linhagem Celular Tumoral , Citocinas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Neoplasias Ovarianas/metabolismo , RNA Mensageiro/metabolismo , Ubiquitinas/genética
Oncogene ; 39(3): 546-559, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31501523


TRIM family proteins are defined as E3 ubiquitin ligases because of their RING-finger domains. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the posttranslational modification of diverse proteins. Both TRIM29 and ISG15 play both pro-tumoral and anti-tumoral functions in cancer cells derived from different histology. In the current study, we demonstrated that correlation expression of TRIM29 and ISG15 in pancreatic ductal adenocarcinomas (PDACs). The current study demonstrated that TRIM29 knockdown destabilized ISG15 protein via promoting its processing by calpain 3 (CAPN3). Importantly, the current study found that TRIM29 knockdown suppressed cancer stem cell-like features of PDACs, which can be rescued by ISG15 independent of its conjugation function. In addition, the current study demonstrated that extracellular free ISG15 played an important role in maintenance of cancer stem cell-like features of PDACs. Thereby, the current study displayed a novel mechanism by which TRIM29 modulates ISG15 stability via CAPN3-mediated processing, and subsequently extracellular ISG15 maintains the cancer stem cell-like features of PDAC via autocrine mode of action.

Carcinoma Ductal Pancreático/patologia , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/patologia , Fatores de Transcrição/metabolismo , Ubiquitinas/metabolismo , Animais , Comunicação Autócrina , Calpaína/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Proteínas Musculares/metabolismo , Proteólise , Fatores de Transcrição/genética , Ensaios Antitumorais Modelo de Xenoenxerto
Am J Med Sci ; 349(6): 467-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25782333


BACKGROUND: Acute mountain sickness (AMS) is a common disabling condition observed in people ascending to high altitudes. However, a simple predictive test for AMS is not known. The aim of this study was to assess the relationship between baseline exhaled nitric oxide (FENO) and AMS occurrence. METHODS: Eighty healthy lowland Chinese adults were recruited for this study. FENO was measured at baseline, as well as 6 and 24 hours after arrival in Tibet. The standard Lake Louise Score (LLS) consensus symptoms questionnaire was used to assess the incidence and severity of AMS. RESULTS: Individuals with a high LLS (> 3) had higher FENO levels at baseline and after arrival in Tibet than people with a low LLS (≤ 3) (baseline: 22.9 ± 11.9 versus 16.7 ± 6.4; 6 hours: 26.2 ± 16.7 versus 17.9 ± 5.7; 24 hours: 24.9 ± 13.1 versus 16.3 ± 1.7; all P < 0.01). Evaluation of risk factors revealed that female gender, diabetes and not smoking were associated with a high AMS score (all P < 0.05), but that hypertension showed no association (P > 0.05). CONCLUSIONS: This prospective observational study suggests that baseline FENO levels may be positively correlated with AMS in healthy Chinese lowlanders.

Doença da Altitude/metabolismo , Óxido Nítrico/metabolismo , Doença Aguda , Adulto , Fatores Etários , Grupo com Ancestrais do Continente Asiático , Biomarcadores/metabolismo , Testes Respiratórios , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais
Zhonghua Xin Xue Guan Bing Za Zhi ; 34(9): 837-42, 2006 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-17217697


OBJECTIVE: To investigate the effect of telomerase reverse transcriptase (TERT) to the proliferation of 5-HT induced pulmonary artery smooth muscle cells (PASMCs). METHODS: The PASMCs proliferation experiment was performed to detect the effort on PASMCs of 5-HT or ASODN TERT (antisense oligoribonucleotides TERT designed according to the rat TERT mRNA sequence of gene bank). The immunohistochemistry staining experiment and the in situ hybridization experiment were to detect the TERT protein and mRNA expression with 5-HT or ASODN TERT. FITC marked ASODN TERT experiment was done to research the distribution of ASODN TERT in PASMCs. RESULTS: 5-HT promoted PASMCs proliferation in a dose-dependent manner (10(-9) - 10(-5) mol/L). 5-HT also significantly increased TERT expression at protein and mRNA levels as shown by immunohistochemistry staining and the in situ hybridization studies. This effect could be blocked by ASODN TERT in a time and dose-dependent manner. CONCLUSIONS: Our experiments show TERT is one of the key factors in the procession of 5-HT induced PASMCs proliferation. ASODN TERT might be a potential therapy agent for pulmonary hypertension.

Proliferação de Células , Músculo Liso Vascular/citologia , Serotonina/farmacologia , Telomerase/farmacologia , Animais , Células Cultivadas , Miócitos de Músculo Liso/citologia , Artéria Pulmonar/citologia , RNA Mensageiro/genética , Ratos