RESUMO
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, hence a major public health threat. Pleomorphic adenoma gene like-2 (PLAGL2) has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood. APPROACH AND RESULTS: In this study, we demonstrated that PLAGL2 was up-regulated in HCC compared with that of adjacent nontumorous tissues and also correlated with overall survival times. We further showed that PLAGL2 promoted HCC cell proliferation, migration, and invasion both in vitro and in vivo. PLAGL2 expression was positively correlated with epidermal growth factor receptor (EGFR) expression. Mechanistically, this study demonstrated that PLAGL2 functions as a transcriptional regulator of EGFR and promotes HCC cell proliferation, migration, and invasion through the EGFR-AKT pathway. Moreover, hypoxia was found to significantly induce high expression of PLAGL2, which promoted hypoxia inducible factor 1/2 alpha subunit (HIF1/2A) expression through EGFR. Therefore, this study demonstrated that a PLAGL2-EGFR-HIF1/2A signaling loop promotes HCC progression. More importantly, PLAGL2 expression reduced hepatoma cells' response to the anti-EGFR drug erlotinib. PLAGL2 knockdown enhanced the response to erlotinib. CONCLUSIONS: This study reveals the pivotal role of PLAGL2 in HCC cell proliferation, metastasis, and erlotinib insensitivity. This suggests that PLAGL2 can be a potential therapeutic target of HCC.
Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Ligação a DNA/metabolismo , Cloridrato de Erlotinib/farmacologia , Neoplasias Hepáticas/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Idoso , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/uso terapêutico , Retroalimentação Fisiológica , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Estimativa de Kaplan-Meier , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Proteínas de Ligação a RNA/genética , RNA-Seq , Transdução de Sinais/genética , Fatores de Transcrição/genética , Hipóxia Tumoral , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The current treatment of HCC mainly includes surgery, chemotherapy, and liver transplantation. HCC differentiation therapy aims to restore tumor cells' normal liver characteristics and unlock their phenotypic plasticity. Understanding the molecular and signaling pathways that control HCC differentiation can help identify new targets for inducing differentiation and provide ideas for drug design. Downregulation of liver enriched transcription factors, imbalanced signal pathway, and dysregulated microRNA play essential roles in regulating the differentiation state of HCC. Restoring normal expression levels of these molecules could induce the tumor cells to differentiate into hepatocyte-like cells (HLCs) and suppress the malignant tumor phenotype. The strategies for inducing HLCs from induced pluripotent stem cells, fibroblasts, and other somatic cells provide a reference for the induced differentiation of liver cancer. The differentiation therapy is expected to be a promising and effective treatment for HCC.