RESUMO
BACE1 antisense RNA (BACE1-AS) is implicated in promoting cell proliferation in different types of tumors. However, the function and mechanism of BACE1-AS in hepatocellular carcinoma (HCC) are still unclear. In the present study, we found that the relative expression of BACE1-AS in HCC cell lines, HCC tissues, and serum samples of HCC patients was significantly increased, and its high expression was correlated with the poor prognosis of HCC patients. In addition, overexpression of BACE1 promoted HCC cell proliferation, cell cycle progression, migration, and invasion, but inhibited cell apoptosis, while knockdown of BACE1 exerted the opposite role. Furthermore, BACE1-AS sponged miR-214-3p and inhibited its expression, thus promoting Apelin (APLN) expression. Overexpression or knockdown of miR-214-3p could partially reverse the abnormal proliferation, cell cycle progression, migration, invasion, and apoptosis caused by overexpression or knockdown of BACE1. These findings suggest that the BACE1-AS/miR-214-3p/APLN axis is a novel signaling pathway that facilitates HCC.
Assuntos
Apelina/genética , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Apelina/metabolismo , Pareamento de Bases , Sequência de Bases , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , Invasividade Neoplásica , Prognóstico , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de SobrevidaRESUMO
Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide with high morbidity and high mortality rates. Previous studies have demonstrated that cytoskeleton regulator RNA (CYTOR) plays critical roles in the tumorigenesis of various types of cancer. The present study aimed to investigate the clinical significance, biological function and molecular mechanism of CYTOR in the progression of HCC. The expression level of CYTOR was determined by reverse transcription quantitative PCR in HCC tissues and cell lines. The biological function of CYTOR was investigated using CCK-8 assay, EdU immunofluorescence, western blotting and TUNEL assay in vitro. A xenograft tumor model and immunohistochemistry were used to validate the role of CYTOR in vivo. The downstream targets of CYTOR and micro-RNA (miR)-125b were confirmed by RNA immunoprecipitation assay and luciferase reporter assays. The results demonstrated that CYTOR was significantly increased in HCC tissues compared with non-tumor tissues and that CYTOR expression was associated with the poor prognosis of patients with HCC. Furthermore, CYTOR silencing could inhibit the proliferation and promote the apoptosis of HCC cells. CYTOR overexpression had the opposite effects. The results from in vivo xenograft demonstrated that CYTOR knockdown suppressed tumor growth. In addition, CYTOR could directly interact with and negatively regulate miR-125b. Furthermore, semaphorin 4C (SEMA4C) was the target of miR-125b and CYTOR regulated SEMA4C expression by modulating miR-125b. Taken together, the findings from the present study demonstrated that CYTOR could promote cell proliferation and tumor growth by sponging miR-125b and upregulating SEMA4C, which suggested that CYTOR may act as a potential therapeutic target in HCC.
RESUMO
BACKGROUND: The recurrence rate of hepatocellular carcinoma (HCC) after partial hepatectomy is still high. How to choose the most appropriate anti-tumor drug in the early postoperative period is crucial to improve the prognosis of patients. Recently, MiniPDX has been widely used as a new and reliable preclinical research model capable of predicting the sensitivities of anti-tumor drugs. METHODS: Twenty-eight patients with HCC were selected to use the MiniPDX model to screen the most sensitive anti-tumor drugs from five groups of drug regimens for preventive treatment after partial hepatectomy, and another 42 patients with HCC were selected to be treated with Sorafenib during the same period as the control group. The tumor-free survival rate and overall survival rate were analyzed and compared between these two groups. The relationship between drug sensitivity and biomarkers related to HCC was also analyzed. RESULTS: Kaplan-Meier survival curve analysis showed that the tumor-free survival (DFS) of patients in the MiniPDX group was significantly longer than that in the control group (median DFS: 25.8 months vs. 18.2 months, P = 0.022, HR 2.19, 95% CI 1.17-4.12). The overall survival (OS) of the patients in the MiniPDX group was also longer than that in the control group (median OS: 29.4 months vs. 23.8 months, P = 0.039, HR 2.37, 95% CI 1.12-5.00). The longest follow-up period was 36 months. The relationship analyzed between the efficacy of the five drugs (Regorafenib, Regorafenib, Lenvatinib, Gemcitabine, 5-FU + Oxaliplatin) and AFP, Ki-67, VEGFR, FGFR, P53, and Nrf2 showed different correlations. CONCLUSION: The use of the MiniPDX model to select drugs to guide anti-tumor treatment after partial hepatectomy could effectively prolong the survival of patients with HCC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Animais , Carcinoma Hepatocelular/patologia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Hepatectomia , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Taxa de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Non-coding RNA has been reported to be crucial regulator for cancer progression. This work was aimed to investigate the roles and associated mechanisms of non-coding RNA activated by DNA damage (NORAD) in hepatocellular carcinoma (HCC) progression. In this work, we explored the expression of NORAD, microRNA-144-3p (miR-144-3p), and septin 2 (SEPT2) in HCC tissues and cells. Effects of knockdown of ectopic of NORAD on HCC cell proliferation, colony formation, and apoptosis were explored. Rescue experiments were conducted to explore whether NORAD regulates HCC cell behaviors via the miR-144-3p/SEPT2 axis. Moreover, the effect of NORAD on HCC tumor progression in vivo was analyzed. We showed NORAD expression was elevated in both HCC tissues and cells. NORAD knockdown inhibits HCC cell growth but promotes apoptosis, while the overexpression of NORAD has opposite effects. Besides that, we found knockdown of NPRAD inhibits tumor growth. Moreover, we showed miR-144-3p expression was inversely correlated with NORAD and SEPT2, while NORAD and SEPT2 was positively correlated in HCC tissues. Functional assays showed NORAD functions as ceRNA through binding with miR-144-3p to regulate SEPT2 expression in HCC. Collectively, we showed NORAD serves as an oncogenic lncRNA to promote HCC progression via the miR-144-3p/SEPT2 axis.
