Insufficient radiofrequency ablation promotes hepatocellular carcinoma cell progression via autophagy and the CD133 feedback loop

Wang, Xiaofei; Deng, Qingsong; Feng, Kai; Chen, Shihan; Jiang, Jiayun; Xia, Feng; Ma, Kui; Bie, Ping

doi:10.3892/or.2018.6403

Cited by 19 publications

(25 citation statements)

References 33 publications

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“…Therefore, whether autophagy promotes cell survival or induces cell death depends on the cell type and environmental stress. Our team previously reported that IRFA promotes HCC cell progression via autophagy and the CD133 feedback loop [13]. In this study, we found that inhibition of heat stressinduced autophagy enhances heat-induced apoptosis both in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 54%

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Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma

Jiang

Chen

et al. 2019

International Journal of Hyperthermia

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Purpose: Radiofrequency ablation (RFA) is widely accepted as a curative treatment for small hepatocellular carcinoma (HCC). However, insufficient RFA (IRFA) can lead to rapid local recurrence. The underlying mechanisms remain poorly understood. This study aimed to elucidate the role and regulatory mechanisms of autophagy in the recurrence of HCC after IRFA. Materials and methods: SMMC7721 and Huh7 cells were exposed to sublethal heat stress to stimulate the transition zone of IRFA treatment. The levels of autophagy were measured by western blot, immunofluorescence and transmission electron microscopy. Functional assays, such as CCK-8, EdU incorporation and flow cytometry, were performed to determine the role of heat-induced autophagy. The involved signaling pathways were explored by western blot. Finally, the antitumor effects of chloroquine (CQ) on heat-treated HCC cells were evaluated via an in vivo xenograft tumor model. Results: Sublethal heat stress induced autophagy in a temperature-and time-dependent manner in HCC cells. Furthermore, the inhibition of autophagy by CQ or siRNA targeting the autophagy-related genes Beclin-1 and Atg5 enhanced heat-induced apoptosis. The combination of CQ and heat treatment significantly suppressed tumor growth both in vitro and in vivo. Mechanistically, we reported for the first time that the ATP-AMPK-mTOR signaling pathway was involved in heat-induced autophagy. Conclusions: Heat stress induced protective autophagy against heat-induced apoptosis in HCC via the ATP-AMPK-mTOR axis, suggesting that targeting autophagy may be a promising strategy for improving the efficacy of RFA treatment for HCC.

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Section: Discussionsupporting

confidence: 54%

“…Previous studies showed that sublethal heat stress induces autophagy in several human cancer cell lines, such as HeLa and A549 cells [12]. Recent studies reported that IRFA promotes the progression of residual HCC via autophagy [13,14]. These findings strongly support a correlation between autophagy and HCC progression after IRFA.…”

Section: Introductionsupporting

confidence: 53%

Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma

Jiang

Chen

et al. 2019

International Journal of Hyperthermia

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“…A combination of these treatments with an autophagy inhibitor (e.g. (hydroxy)chloroquine, 3-MA and Lys05) was associated with enhanced tumour cell necrosis and apoptosis, [148][149][150][151] suggesting that inhibiting autophagy to target residual tumour cells could be beneficial. Moreover, autophagy is implicated in tumour cells' resistance to systemic treatments.…”

Section: Targeting Autophagy In Hepatocellular Carcinoma: a Complex Amentioning

confidence: 99%

Autophagy in liver diseases: Time for translation?

Allaire

Rautou

Codogno

et al. 2019

Journal of Hepatology

309

222

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Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role in energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy. Indeed, enhancing autophagy may prevent the progression of a number of liver diseases, including storage disorders (alpha-1 antitrypsin deficiency, Wilson's disease), acute liver injury, non-alcoholic steatohepatitis and chronic alcohol-related liver disease. Nevertheless, in some situations such as fibrosis, targeting specific liver cells must be considered, as autophagy displays opposing functions depending on the cell type. In addition, an optimal therapeutic time-window should be identified, since autophagy might be beneficial in the initial stages of disease, but detrimental at more advanced stages, as in the case of hepatocellular carcinoma. Finally, identifying biomarkers of autophagy and methods to monitor autophagic flux in vivo are important steps for the future development of personalized autophagy-targeting strategies. In this review, we provide an update on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagy and discussing the potential to modulate autophagy as a therapeutic strategy in the context of liver diseases.

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“…The main mechanism is that the proliferation of cancer cells is accompanied by the increase of nutritional requirements, so that autophagy will be activated to provide tumor cells with nutrients and energy (28). Meanwhile, autophagy can enhance the chemoradiotherapy resistance of tumor cells (29). With our results, we guessed that autophagy may play a role in promoting the developing of LIHC, or the existence of LIHC may enhance the autophagy.…”

Section: Discussionmentioning

confidence: 78%

A novel prognostic index model constructed with five autophagy-related genes may be a potential prognostic biomarker and therapeutic target in liver hepatocellular carcinoma

Zhu¹,

Wang²,

Liu³

et al. 2020

Preprint

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Background Early diagnosis and effective treatment of liver hepatocellular carcinoma (LIHC) are keys to improving the prognosis of patients. Increasing evidences clarify that autophagy-related genes (ARGs) make great differences to the generation and progression of LIHC, and may serve as prognostic biomarkers for LIHC. Methods We randomly divided the LIHC patients in The Cancer Genome Atlas (TCGA) into the training and testing group. Next, use the training group to perform univariate Cox, LASSO and multivariate Cox analysis to construct our prognostic index (PI) model for LIHC; use the testing group and the whole TCGA set to make internal validations; use the International Cancer Genome Consortium to make external validations; and use the whole TCGA, GSE14520 and Oncomine to exam the expression patterns of the five ARGs. Then, we performed the ROC curve as well as univariate and multivariate analysis to evaluate the independent prognostic prediction power of the PI model, and made nomograms to estimate 1,3,5-year survival rate of LIHC patients. Besides, we conducted functional enrichment analyses of differentially expressed ARGs with GO, KEGG and GSEA, and made drug sensitivity analysis for the PI model via the GDSC database. Results A novel PI model which was composed of five key ARGs ( ATG9A , EIF2S1 , GRID1 , SAR1A and SQSTM1 ) succeeded to be constructed. All the internal and external validations testified that the PI model could well distinguish high-risk patients from low-risk ones, with AUC values > 0.60. Further comparison analysis showed that the PI model was no less than some common prognostic factors. People can estimate the 1,3,5-year survival rate of individual LIHC patient with the nomograms. Additionally, we obtained 62 differentially expressed ARGs and studied the potential mechanisms or pathways. Furthermore, we also found some potential targeted drugs associated to the five ARGs for LIHC patients. Conclusions The novel five-ARGs PI model has great potential to serve as a diagnostic or prognostic biomarker and therapeutic target in LIHC, which may guide future clinical applications to some extent and improve the outcome of LIHC patients.

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Insufficient radiofrequency ablation promotes hepatocellular carcinoma cell progression via autophagy and the CD133 feedback loop

Cited by 19 publications

References 33 publications

Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma

Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma

Autophagy in liver diseases: Time for translation?

A novel prognostic index model constructed with five autophagy-related genes may be a potential prognostic biomarker and therapeutic target in liver hepatocellular carcinoma

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