Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells

Fan, Qing; Yang, Liang; Zhang, Xiaodong; Ma, Yingbo; Li, Yan; Li, Dong; Zong, Zhi‐Hong; Hua, Xiangdong; Su, Dongming; Li, Hangyu; Liu, Jingang

doi:10.1186/s13046-018-0673-y

Cited by 169 publications

(121 citation statements)

References 34 publications

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“…The stage specificity of tumor metastasis may influence the cellular response to autophagy [ 13 ]. Moreover, the use of different model systems (mouse or different human cell lines) may explain the obvious variation in results [ 15 , 47 , 48 , 49 , 50 ]. Nevertheless, autophagy activation has been shown to impair the metastasis of tumor cells by reversing EMT [ 47 , 51 , 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Sinomenine Hydrochloride Inhibits the Metastasis of Human Glioblastoma Cells by Suppressing the Expression of Matrix Metalloproteinase-2/-9 and Reversing the Endogenous and Exogenous Epithelial-Mesenchymal Transition

Jiang

Jiao

Liu

et al. 2018

IJMS

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As shown in our previous study, sinomenine hydrochloride (SH), the major bioactive alkaloid isolated from Sinomenium acutum Rehd. et Wils. (Fam. Menispermaceae), initiates the autophagy-mediated death of human glioblastoma cells by generating reactive oxygen species and activating the autophagy-lysosome pathway. However, its effects on the migration and invasion of human glioblastoma cells have not yet been elucidated. Therefore, human glioblastoma U87 and SF767 cells were treated with SH (0.125 and 0.25 mM) for 24 h, and cell migration and invasion were assessed using scratch wound healing, migration and invasion assays. SH promoted G0/G1 phase arrest, inhibited the migration and invasion of the two cell lines, suppressed the activation of nuclear factor kappa B (NFκB) and the expression of matrix metalloproteinase (MMP)-2/-9, triggered endoplasmic reticulum (ER) stress, reversed the exogenous epithelial-mesenchymal transition (EMT) induced by the inflammatory microenvironment and the endogenous EMT. Additionally, NFκB p65 overexpression blocked the SH-mediated inhibitory effects on MMP-2/-9 expression and cell invasion. SH-induced autophagy was reduced in CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) or autophagy-related 5 (ATG5)-silenced human glioblastoma cells and cells treated with 4-phenylbutyric acid (4-PBA) or 3-methyladenine (3-MA), as shown by the decreased levels of the microtubule-associated protein light chain 3B (LC3B)-II and autophagic vacuoles (AVs) stained with monodansylcadaverine (MDC), respectively. Moreover, knockdown of CHOP or ATG5 and treatment with 4-PBA or 3-MA abolished the SH-mediated inhibition of mesenchymal markers (vimentin, Snail and Slug) expression and cell invasion, respectively. Importantly, SH also regulated the above related pathways in nude mice. Based on these findings, SH inhibited cell proliferation by inducing cell cycle arrest, and attenuated the metastasis of U87 and SF767 cells by suppressing MMP-2/-9 expression and reversing the endogenous and exogenous EMT in vitro and/or in vivo. Thus, SH might be a new potential anti-metastasis agent for the treatment of human glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Sinomenine Hydrochloride Inhibits the Metastasis of Human Glioblastoma Cells by Suppressing the Expression of Matrix Metalloproteinase-2/-9 and Reversing the Endogenous and Exogenous Epithelial-Mesenchymal Transition

Jiang

Jiao

Liu

et al. 2018

IJMS

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“…This suggests that activation of TGF-β/Smad3-dependent signaling plays a key role in regulating autophagy-induced EMT. Another study also highlighted the importance of the Wnt/β-catenin signaling pathway in regulating the role of autophagy in HCC metastasis[ 51 ]. They found that activation of autophagy can promote metastasis and glycolysis accompanied by MCT1 up-regulation in HCC cells, and autophagy induced MCT1 expression by activating Wnt/β-catenin signaling[ 51 ].…”

Section: Role Of Autophagy In Hccmentioning

confidence: 99%

“…Another study also highlighted the importance of the Wnt/β-catenin signaling pathway in regulating the role of autophagy in HCC metastasis[ 51 ]. They found that activation of autophagy can promote metastasis and glycolysis accompanied by MCT1 up-regulation in HCC cells, and autophagy induced MCT1 expression by activating Wnt/β-catenin signaling[ 51 ]. Thus, the study described the relationship between autophagy and glucose metabolism in HCC cell metastasis and may provide a potential therapeutic target for HCC treatment.…”

Section: Role Of Autophagy In Hccmentioning

confidence: 99%

Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma

Huang¹,

Wang²,

Wang³

2018

WJG

171

128

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Autophagy is a “self-degradative” process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients.

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“…Autophagy can sever as both tumor suppresser role and oncogenetic role in tumorigenesis, which may depend on the tumor microenvironments and tumor heterogeneity [6,35]. For example, Fan et al reported that autophagy can promote the metastasis and glycolysis of HCC cells through Wnt/β-catenin pathway [36]. Conversely, exenatide induced autophagy can inhibit the cell proliferation of HCC cells [37].…”

Section: Discussionmentioning

confidence: 99%

Development and validation of a survival model based on autophagy-associated genes for predicting prognosis of hepatocellular carcinoma

Yang

Niu

Zhao³

et al. 2020

Preprint

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Background: Hepatocellular carcinoma (HCC) is one of the devastating tumors with increasing incidence. Autophagy-associated genes (ARGs) are widely participated in the cellular processes of HCC. This study proposed to identify the novel prognostic gene signature based on ARGs in HCC. Methods: We downloaded the RNA sequencing data and clinical information of HCC and normal tissues from The Cancer Genome Atlas (TCGA) database. The differentially expressed ARGs were screened by the Wilcoxon signed-rank test. Functional enrichment analyses were conducted to explore the biological implications and mechanisms of ARGs in HCC. Cox regression analysis and Lasso regression analysis were performed to screen the ARGs which related to overall survival (OS). The OS-related ARGs were then used to establish a prognostic prediction model. Kaplan-Meier curves and receiver operating characteristic (ROC) curves were both applied to evaluate the accuracy of the model. GSE14520 dataset was downloaded as the testing cohort to validate the prognostic risk model in TCGA. A nomogram based on the clinical features and risk signature was established to predict the 3-year and 5-year survival rate of HCC patients. Results: Totally 27 differentially expressed ARGs were screened in this study. Then, 3 OS-related ARGs (SQSTM1, HSPB8, and BIRC5) were identified via the Cox regression and Lasso regression analyses. Based on these 3 ARGs, a prognostic prediction model was constructed. HCC patients in high-risk group presented poorer prognosis than those with low risk score in TCGA cohort (3-year OS, 53.7% vs 70.2%; 5-year OS, 42.0 % vs 55.2%; P=4.478e-04) and in the testing group (3-year OS, 57.7% vs 73.5%; 5-year OS, 43.2% vs 63.0%; P=1.274e-03). The risk score curve showed a well feasibility in predicting the patients’ survival both in TCGA and GEO cohort with the area under the ROC curve (AUC) of 0.756 and 0.672, respectively. Besides, the calibration curves and C-index indicated that the clinical nomogram performs well to predict the 3-year and 5-year survival rate in HCC patients. Conclusions: The survival model based on the ARGs may be a promising tool to predict the prognosis in HCC patients.

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Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells

Cited by 169 publications

References 34 publications

Sinomenine Hydrochloride Inhibits the Metastasis of Human Glioblastoma Cells by Suppressing the Expression of Matrix Metalloproteinase-2/-9 and Reversing the Endogenous and Exogenous Epithelial-Mesenchymal Transition

Sinomenine Hydrochloride Inhibits the Metastasis of Human Glioblastoma Cells by Suppressing the Expression of Matrix Metalloproteinase-2/-9 and Reversing the Endogenous and Exogenous Epithelial-Mesenchymal Transition

Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma

Development and validation of a survival model based on autophagy-associated genes for predicting prognosis of hepatocellular carcinoma

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