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Horm Cancer ; 10(4-6): 177-189, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31713780


In hepatocellular carcinoma (HCC), the hypoxic tumor microenvironment can drive enhance tumor malignancy and recurrence. The microRNA (miRNA) miR-196-5p has been shown to modulate the progression of several cancer types, but its roles in HCC remain uncertain. In the present report we observed significant miR-196-5p downregulation in HCC tissues and cells, and we found that the expression of this miRNA significantly impaired the proliferation and metastatic potential of HCC in vitro and in vivo. We identified high-mobility group AT-hook 2 (HMGA2) as a miR-196-5p target gene that was associated with the ability of miR-196-5p to modulate the progression of HCC. Expression of miR-196-5p and HMGA2 were correlated with the clinical characteristics and poor outcomes in patients with HCC. Finally, we found that hypoxic conditions were linked with reduced miR-196-5p expression in the context of HCC. Together these results highlight the role for miR-196-5p as an inhibitor of the proliferation and metastasis of HCC via the targeting of HMGA2, with this novel hypoxia/miR-196-5p/HMGA2 pathway serving as a potential target for future therapeutic intervention.

Mol Carcinog ; 58(10): 1897-1907, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313392


The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss-of-function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase-2, -7, and -9 which required PI3K-AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K-AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K-AKT signaling pathway.

Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Neoplasias Hepáticas/genética , Tropomodulina/genética , Animais , Carcinoma Hepatocelular/patologia , Progressão da Doença , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/genética , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética
Hepatology ; 63(3): 850-63, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26663434


UNLABELLED: Systemic analyses using large-scale genomic profiles have successfully identified cancer-driving somatic copy number variations (SCNVs) loci. However, functions of vast focal SCNVs in "protein-coding gene desert" regions are largely unknown. The integrative analysis of long noncoding RNA (lncRNA) expression profiles with SCNVs in hepatocellular carcinoma (HCC) led us to identify the recurrent deletion of lncRNA-PRAL (p53 regulation-associated lncRNA) on chromosome 17p13.1, whose genomic alterations were significantly associated with reduced survival of HCC patients. We found that lncRNA-PRAL could inhibit HCC growth and induce apoptosis in vivo and in vitro through p53. Subsequent investigations indicated that the three stem-loop motifs at the 5' end of lncRNA-PRAL facilitated the combination of HSP90 and p53 and thus competitively inhibited MDM2-dependent p53 ubiquitination, resulting in enhanced p53 stability. Additionally, in vivo lncRNA-PRAL delivery efficiently reduced intrinsic tumors, indicating its potential therapeutic application. CONCLUSIONS: lncRNA-PRAL, one of the key cancer-driving SCNVs, is a crucial stimulus for HCC growth and may serve as a potential target for antitumor therapy.

Carcinoma Hepatocelular/genética , Variações do Número de Cópias de DNA , Neoplasias Hepáticas/genética , RNA Longo não Codificante/genética , Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Animais , Sequência de Bases , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , China/epidemiologia , Pontos de Quebra do Cromossomo , Feminino , Genes p53 , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Sequências Repetidas Invertidas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Dados de Sequência Molecular , Prognóstico