Lack of hepatic stimulator substance expression promotes hepatocellular carcinoma metastasis partly through ERK-activated epithelial–mesenchymal transition

Jia, Xiaowei; Liu, Dong; Sun, Guan; Wang, Xin; Gao, Jian; Li, Yipeng; Wu, Yuan; An, Wei

doi:10.1038/s41374-018-0039-2

Cited by 7 publications

(6 citation statements)

References 50 publications

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“… 27 , 28 An active ERK pathway promotes aggressiveness in HCC; however, inhibiting the ERK pathway can suppress HCC aggressiveness. 29 , 30 Our results indicated that clotrimazole inhibits the phosphorylation of ERK and p65. To further confirm that clotrimazole inhibits HCC metastasis by inhibiting ERK, the ERK activator honokiol was used to activate ERK in clotrimazole-treated HCC cells, in which ERK activity is repressed.…”

Section: Discussionmentioning

confidence: 58%

Clotrimazole Inhibits HCC Migration and Invasion by Modulating the ERK-p65 Signaling Pathway

Li¹,

Gao²,

Sun³

et al. 2022

DDDT

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Purpose Hepatocellular carcinoma (HCC), has a very high mortality rate and is the most common type of liver cancer. Clotrimazole, a traditional antifungal drug, has garnered considerable attention as a therapeutic strategy for HCC. However, its effects against the migration and invasion of HCC cells as well as the associated underlying mechanisms remain unclear. Therefore, in this study, we investigated its effects on HCC and attempted to elucidate the underlying molecular mechanisms. Methods CCK-8 was used to investigate the inhibitory effect of clotrimazole on the proliferation of different types of HCC cells, and wound healing and transwell assays were performed to investigate its inhibitory effect on the invasion and migration of the HCC cells. Further, western blotting was employed to detect changes in the expression levels of epithelial mesenchymal transition (EMT)-related proteins, extracellular-regulated protein kinases (ERK), p-ERK, p65, and p-p65. We also used ERK activators in combination with clotrimazole to treat the HCC cell lines. Results Clotrimazole inhibited the invasion and migration of HCC cells, and mechanistically, it exerted these anti-tumor effects via EMT by repressing ERK phosphorylation. Conclusion These findings suggest that clotrimazole inhibits HCC metastasis by repressing EMT in an ERK dephosphorylation-dependent manner.

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Section: Discussionmentioning

confidence: 58%

Clotrimazole Inhibits HCC Migration and Invasion by Modulating the ERK-p65 Signaling Pathway

Li¹,

Gao²,

Sun³

et al. 2022

DDDT

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“…Quiescent hepatic stellate cells (HSCs) and other normal fibroblasts suppress malignant cell growth via contact inhibition (18). While under liver injury, the inflammatory factors including sulfatase (SULF)-2, transforming growth factor (TGF)-b, CXCL6, and CXCR4 educate normal fibroblasts and other relevant cells toward CAFs (20)(21)(22) and increase the expression of CAF markers such as a-smooth muscle actin (SMA), FAP, vimentin, collagen, and fibroblast specific protein (FSP)-1 (23). The mechanisms for CAF activation are summarized in Figure 1.…”

Section: The Activation Of Cafs In the Premalignant Microenvironment Of Hccmentioning

confidence: 99%

“…The transformed HSECs display CAF features and express increased CAF biomarkers ( 35 ). HCC cells located around the blood sinusoid and undergoing EMT commonly express the CAF biomarkers α-SMA and FAP, indicating that both TGF-β and hypoxia-inducible factor (HIF)-1α enriched under hypoxic condition can induce CAF features in HCC cells ( 22 , 36 ).…”

Section: The Activation Of Cafs In the Premalignant Microenvironment Of Hccmentioning

confidence: 99%

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The Role of Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and the Value of Traditional Chinese Medicine Treatment

Jia¹,

Liang

Cheng³

et al. 2021

Front. Oncol.

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Invasion and metastasis are the main reasons for the high mortality of liver cancer, which involve the interaction of tumor stromal cells and malignant cells. Cancer-associated fibroblasts (CAFs) are one of the major constituents of tumor stromal cells affecting tumor growth, invasion, and metastasis. The heterogeneous properties and sources of CAFs make both tumor-supporting and tumor-suppression effects possible. The mechanisms for CAFs in supporting hepatocellular carcinoma (HCC) progression can be categorized into upregulated aggressiveness and stemness, transformed metabolism toward glycolysis and glutamine reductive carboxylation, polarized tumor immunity toward immune escape of HCC cells, and increased angiogenesis. The tumor-suppressive effect of fibroblasts highlights the functional heterogenicity of CAF populations and provides new insights into tumor–stromal interplay mechanisms. In this review, we introduced several key inflammatory signaling pathways in the transformation of CAFs from normal stromal cells and the heterogeneous biofunctions of activated CAFs. In view of the pleiotropic regulation properties of traditional Chinese medicine (TCM) and heterogeneous effects of CAFs, we also introduced the application and values of TCM in the treatment of HCC through targeting CAFs.

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“…Conversely, other reports suggest that ALR is highly expressed in HCC tissues [18,19]. An earlier meta-analysis demonstrated an inverse correlation of ALR protein expression with histological angioinvasion and tumor grade of HCC [20,21]. Moreover, Gandhi et al reported that mice with hepatocyte-speci c ALR deletion (ALR CKO ) exhibit severe hepatic steatosis shortly after birth progressing to HCC after 12 months, indicating a key role of ALR in the development of HCC from nonalcoholic steatohepatitis [16].…”

Section: Introductionmentioning

confidence: 96%

Imbalance in ALR ubiquitination accelerates the progression of nonalcoholic steatohepatitis to hepatocellular carcinoma

Zheng

Guo

et al. 2022

Oncogene

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Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Accumulating evidence indicates that non-alcoholic steatohepatitis (NASH) is a key predisposing factor for HCC occurrence. However, the precise mechanisms driving NASH transition to HCC remain largely obscure.Augmenter of liver regeneration (ALR) is a sulfhydryl oxidase and cytochrome c reductase that functions as an important regulator of mitochondrial dynamics. In this study, we focused on ALR ubiquitinationmediated degradation and its potential contribution to NASH-driven HCC progression at the mitochondrial level. Hepatic ALR expression in HCC patients was determined using immunohistochemical analysis.Mice with liver-speci c deletion of ALR (ALR CKO ) and ALR WT mice were fed a western diet (WD) and highsugar solution for induction of NASH. HCC in animals was induced via peritoneal administration of CCl 4 .ALR expression was markedly decreased in liver tissues of patients with NASH and HCC compared with non-NASH and non-tumor tissues. Similarly, in ALR WT mice, the ALR level in tumor tissue was reduced relative to that in para-tumor tissue. In the ALR CKO group, mice fed WD plus CCl 4 developed HCC starting at week 12 while ALR WT mice fed WD plus CCl 4 developed HCC at week 24. Analysis of protein posttranslational modi cations revealed ubiquitylation (Ub) and deubiquitination (DUb) of ALR by murine double minute 2 (MDM2) and ubiquitin-speci c protease 36 (USP36), respectively. Imbalance between Ub and DUb of ALR resulted in profound ALR degradation, which appeared to be reversibly associated with Edmondson-Steiner tumor grade. Rescue of ALR levels via gene transfection abolished tumor malignant features to a certain extent in vitro. Notably, ALR deletion substantially enhanced mitochondrial ssion by activating Drp1 phosphorylation, thus disrupting the balance of mitochondrial dynamics between ssion and fusion and severely impairing oxidative phosphorylation (OXPHOS) and ATP synthesis, instead enhancing anaerobic metabolism, which might be attributed to steatotic hepatocyte transition into the malignant HCC phenotype. Hepatic ALR depletion via dysregulation of ubiquitination is a critical aggravator of NASH-HCC progression and represents a promising therapeutic target for related liver diseases.

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Lack of hepatic stimulator substance expression promotes hepatocellular carcinoma metastasis partly through ERK-activated epithelial–mesenchymal transition

Cited by 7 publications

References 50 publications

Clotrimazole Inhibits HCC Migration and Invasion by Modulating the ERK-p65 Signaling Pathway

Clotrimazole Inhibits HCC Migration and Invasion by Modulating the ERK-p65 Signaling Pathway

The Role of Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and the Value of Traditional Chinese Medicine Treatment

Imbalance in ALR ubiquitination accelerates the progression of nonalcoholic steatohepatitis to hepatocellular carcinoma

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