Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Liu, Zhikui; Tu, Kangsheng; Wang, Yufeng; Yao, Bowen; Li, Qing; Wang, Liang; Dou, Changwei; Liu, Qingguang; Zheng, Xin

doi:10.1159/000485821

Cited by 78 publications

(65 citation statements)

References 44 publications

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“…In summary, HCC tissue sections were incubated with GPR39 (1:300, Abcam, USA) overnight at 4°C and then flushed with PBS and re‐incubated with biotinylated secondary antibodies (Goldenbridge, Zhongshan, China) according to the SP‐IHC assay instructions. The experiment was performed according to our previously reported protocol …”

Section: Methodsmentioning

confidence: 99%

microRNA‐1914, which is regulated by lncRNA DUXAP10, inhibits cell proliferation by targeting the GPR39‐mediated PI3K/AKT/mTOR pathway in HCC

Sun

Wang

Chen

et al. 2019

J Cellular Molecular Medi

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Increasing studies have confirmed that abnormally expressed microRNAs (miRNAs) take part in the carcinogenesis as well as the aggravation of hepatocellular carcinoma (HCC). However, little information is currently available about miR‐1914 in HCC. Here, we first confirmed that miR‐1914 inhibition in HCC cell lines and tumour specimens correlates with tumour size and histological grade. In a series of functional experiments, miR‐1914 inhibited tumour proliferation and colony formation, resulting in cell cycle arrest and increased apoptosis. Moreover, miR‐1914 mediated its functional effects by directly targeting GPR39 in HCC cells, leading to PI3K/AKT/mTOR repression. Restoring GPR39 expression incompletely counteracted the physiological roles of miR‐1914 in HCC cells. In addition, down‐regulation of AKT phosphorylation inhibited the effects of miR‐1914 in HCC. Furthermore, the overexpression of lncRNA DUXAP10 negatively correlated with the expression of miR‐1914 in HCC; thus, lncRNA DUXAP10 regulated miR‐1914 expression and modulated the GPR39/PI3K/AKT‐mediated cellular behaviours. In summary, the present study demonstrated for the first time that lncRNA DUXAP10–regulated miR‐1914 plays a functional role in inhibiting HCC progression by targeting GPR39‐mediated PI3K/AKT/mTOR pathway, and this miRNA represents a novel therapeutic target for patients with HCC.

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Section: Methodsmentioning

confidence: 99%

microRNA‐1914, which is regulated by lncRNA DUXAP10, inhibits cell proliferation by targeting the GPR39‐mediated PI3K/AKT/mTOR pathway in HCC

Sun

Wang

Chen

et al. 2019

J Cellular Molecular Medi

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“…In hepatocellular carcinoma (HCC) patients, SMO mutation at the C-terminal lysine (K575M) involves the binding between PTCH and SMO to alleviate SMO from PTCH suppression to activate the downstream signaling [57]. Liu et al found that hypoxia-inducing oxidative stress, epithelial-mesenchymal transition (EMT), and activation of the non-canonical SHH signaling pathway aggravates the invasiveness of HCC cells [58]. Chen et al found that the SHH pathway induces the migration and the invasion of HCC cells via activation of focal adhesion kinase (FAK)/P13K/AKT signaling-mediated matrix metalloproteinase-2, as well as matrix metalloproteinase-9 production [59].…”

Section: Shh In Liver Injury and Hepatocarcinogenesismentioning

confidence: 99%

Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments

Jeng

Chang

Lin

2020

IJMS

147

126

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During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.

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“…For example, the paradoxical trend towards increase in glycogen content after IH, despite inhibition of AKT/GSK-3β, may implicate hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1 [33]. Third, in addition to JNK, changes in other stress/hypoxia-inducible pathways including Sestrins, oxidative stress, as well as microRNA profiles should be considered in interpreting the metabolic consequences of IH in liver cells [34][35][36].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner

Gu¹,

Yi²,

Feng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Obstructive sleep apnea is associated with diabetes and insulin resistance, but the underlying mechanisms remain unclear. The purpose of the current study was to determine the molecular effects of intermittent hypoxia (IH) on hepatic insulin signaling and glucose homeostasis, and whether c-Jun NH₂-terminal-kinase (JNK) contributed to metabolic responses to IH in liver cells. Methods: The human HepG₂ cells and rat FAO cells were exposed to 10, 30, 120, 240 or 360 cycles of IH (1% O₂ for 60 s followed by 21% O₂ for 60s, 7.5 cycles per hour) or normoxia as a control. In a subgroup, we exposed cells to 360 cycles of IH with the JNK inhibitor SP600125. After IH exposure, cell glycogen content and glucose output were measured using colorimetric assay kits. Canonical insulin signaling and gluconeogenic genes were measured by western blot and quantitative polymerase chain reaction. Results: IH decreased insulin-stimulated protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β) phosphorylation in a time-dependent manner, while inhibiting forkhead box protein O1 (FOXO1) expression and phosphoenolpyruvate carboxykinase (PEPCK) transcription independent of insulin signaling. JNK inhibitor SP600125 partially restored AKT/ GSK-3β phosphorylation and glycogen synthesis, but did not affect other IH-induced glucose metabolic changes. Conclusion: IH in vitro impaired insulin signal transduction in liver cells as assessed by inhibited AKT/GSK-3β phosphorylation via JNK activation. IH inhibited FOXO1 and gluconeogenesis in an insulin-independent manner.

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Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Cited by 78 publications

References 44 publications

microRNA‐1914, which is regulated by lncRNA DUXAP10, inhibits cell proliferation by targeting the GPR39‐mediated PI3K/AKT/mTOR pathway in HCC

microRNA‐1914, which is regulated by lncRNA DUXAP10, inhibits cell proliferation by targeting the GPR39‐mediated PI3K/AKT/mTOR pathway in HCC

Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments

Intermittent Hypoxia Disrupts Glucose Homeostasis in Liver Cells in an Insulin-Dependent and Independent Manner

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