ABSTRACT
Hepatocellular carcinoma (HCC) is associated with a poor prognosis. Our previous study demonstrated that Pleomorphic adenoma gene like-2 (PLAGL2) was a potential therapeutic target in HCC. However, the mechanisms that lead to the upregulation of PLAGL2 in HCC remain unclear. The present study revealed that stress-induced epinephrine increased the expression of PLAGL2, thereby promoting the progression of HCC. Furthermore, PLAGL2 knockdown inhibited epinephrine-induced HCC development. Mechanistically, epinephrine upregulated ubiquitin-specific protease 10 (USP10) to stabilize PLAGL2 via the adrenergic ß-receptor-2-c-Myc (ADRB2-c-Myc) axis. Furthermore, PLAGL2 acted as a transcriptional regulator of USP10, forming a signaling loop. Taken together, these results reveal that stress-induced epinephrine activates the PLAGL2-USP10 signaling loop to enhance HCC progression. Furthermore, PLAGL2 plays a crucial role in psychological stress-mediated promotion of HCC progression.
Subject(s)
Carcinoma, Hepatocellular , DNA-Binding Proteins , Epinephrine , Gene Expression Regulation, Neoplastic , Liver Neoplasms , RNA-Binding Proteins , Signal Transduction , Transcription Factors , Ubiquitin Thiolesterase , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/genetics , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/etiology , Liver Neoplasms/genetics , Epinephrine/metabolism , Epinephrine/pharmacology , Signal Transduction/drug effects , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Animals , Ubiquitin Thiolesterase/metabolism , Ubiquitin Thiolesterase/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Gene Expression Regulation, Neoplastic/drug effects , Mice , Cell Line, Tumor , Disease Progression , Male , Stress, Physiological , Cell ProliferationABSTRACT
Chronic stress activates the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis to aggravates tumorigenesis and development. Although the importance of SNS and HPA in maintaining homeostasis has already attracted much attention, there is still a lot remained unknown about the molecular mechanisms by which chronic stress influence the occurrence and development of tumor. While some researches have already concluded the mechanisms underlying the effect of chronic stress on tumor, complicated processes of tumor progression resulted in effects of chronic stress on various stages of tumor remains elusive. In this reviews we concluded recent research progresses of chronic stress and its effects on premalignancy, tumorigenesis and tumor development, we comprehensively summarized the molecular mechanisms in between. And we highlight the available treatments and potential therapies for stressed patients with tumor.
Subject(s)
Hypothalamo-Hypophyseal System , Pituitary-Adrenal System , Carcinogenesis , Humans , Stress, Psychological/complications , Sympathetic Nervous SystemABSTRACT
Erlotinib, an EGFR tyrosine kinase inhibitor has been introduced into cancer chemotherapy. However, the therapeutic effects of erlotinib in hepatocellular carcinoma (HCC) remain vaguely understood. Our previous study found that a hypoxia-mediated PLAGL2-EGFR-HIF-1/2α signaling loop in HCC decreased response to erlotinib. The current study has demonstrated that the combination of erlotinib and 2ME2 exerted synergistic antitumor effects against HCC. Further investigation showed that erlotinib increased the expression level of EGFR, HIF-2α, and PLAGL2, which contributes to the insensitivity of hypoxic HCC cells to erlotinib. The simultaneous exposure to 2ME2 effectively inhibited the expression level of EGFR, HIF-2α, and PLAGL2 that was induced by erlotinib. This contributes to the synergistic effect of the two therapeutic agents. Furthermore, the combination of erlotinib and 2ME2 induced apoptosis and inhibited the stemness of hypoxic HCC cells. Our findings potentially explain the mechanism of HCC insensitivity to erlotinib and provide a new strategy of combining EGFR and HIF1/2α inhibitors for HCC treatment.
Subject(s)
2-Methoxyestradiol/therapeutic use , Antineoplastic Agents/therapeutic use , Basic Helix-Loop-Helix Transcription Factors/metabolism , Carcinoma, Hepatocellular/drug therapy , DNA-Binding Proteins/metabolism , Erlotinib Hydrochloride/therapeutic use , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Liver Neoplasms/drug therapy , RNA-Binding Proteins/metabolism , Signal Transduction/drug effects , Transcription Factors/metabolism , 2-Methoxyestradiol/administration & dosage , 2-Methoxyestradiol/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Drug Synergism , ErbB Receptors/metabolism , Erlotinib Hydrochloride/administration & dosage , Erlotinib Hydrochloride/pharmacology , Humans , Liver Neoplasms/metabolism , Male , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, Nude , Neoplasm TransplantationABSTRACT
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.
