Protopanaxadiol inhibits epithelial–mesenchymal transition of hepatocellular carcinoma by targeting STAT3 pathway

Receptor interacting serine/threonine kinase 4 (RIPK4) is a member of the threonine/serine protein kinase family; it plays related functions in a variety of tumours, but its biological function has not been fully revealed. It has been reported that it is differentially expressed in hepatocellular carcinoma (HCC). Our research aimed to reveal the role of RIPK4 in the progression of HCC and to reveal the biological behaviour of RIPK4 in HCC. We analysed the differences in RIPK4 expression in HCC by using a publicly available data set. By using PCR, Western blotting and immunohistochemical staining methods, we detected the expression level of RIPK4 in HCC patient specimens and studied the relationship between the expression of RIPK4 and the clinicopathological features of HCC patients. The prognostic data were combined to analyse the relationship between RIPK4 and HCC patient survival and tumour recurrence. We found that the expression level of RIPK4 in nontumour tissues was significantly higher than that in tumour tissues, and the level of RIPK4 was significantly positively correlated with postoperative survival and recurrence in HCC patients. Further, our study found that RIPK4 inhibits the progression of HCC by influencing the invasion and metastasis of HCC and that overexpression of RIPK4 reduces the invasion and metastasis of HCC by inhibiting epithelial-mesenchymal transition (EMT) and the STAT3 pathway. In in vivo experiments, overexpression of RIPK4 stably inhibited HCC metastasis. To summarize, our research revealed the relationship between RIPK4 and the prognosis of patients with HCC. We discovered that RIPK4 affects the invasion and metastasis of HCC through the EMT and STAT3 pathways. Targeted inhibition of the RIPK4 gene and the STAT3 pathway may be potential therapeutic strategies for inhibiting the postoperative recurrence and metastasis of HCC.

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Salvianolic acid B targets mortalin and inhibits the migration and invasion of hepatocellular carcinoma via the RECK/STAT3 pathway

Cancer Cell International ◽

10.1186/s12935-021-02367-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Mengying Teng ◽

Chunyan Hu ◽

Bingmo Yang ◽

Wei Xiao ◽

Qian Zhou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Migration ◽

Epithelial Mesenchymal Transition ◽

Matrix Metalloproteases ◽

Salvianolic Acid B ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Stat3 Pathway ◽

Cell Migration And Invasion ◽

Salvianolic Acid

Abstract Background Tumor migration and invasion is a complex and diverse process that involves the epithelial–mesenchymal transition (EMT) of tumor cells and degradation of the extracellular matrix by matrix metalloproteases (MMPs). Mortalin is an important oncogene. It has been reported to play an important role in tumor migration and invasion through various signaling pathways, but the underlying mechanism is not fully understood. Methods Here, we investigated the role of mortalin in the migration of the hepatocellular carcinoma (HCC) cell lines HepG2 and HCCLM3. Results The overexpression of mortalin in HepG2 cells decreased the protein level of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and activated the phosphorylation and acetylation of STAT3, thereby up-regulating matrix metalloproteinase 9 (MMP9) and promoting cell migration and invasion. In contrast, in HCCLM3 cells, mortalin knockdown increased the expression of RECK, inhibited the STAT3 pathway and the activity of MMP9, and inhibited cell migration and invasion. Furthermore, we found that salvianolic acid B, a caffeic acid phenethyl ester analog, specifically bound to mortalin and increased the degradation of mortalin proteasomes through ubiquitination, thereby up-regulating RECK, inhibiting STAT3, and finally inhibiting the migration and invasion of HCC cells. Conclusion Our work suggested that mortalin is a potential therapeutic target for hepatocellular carcinoma.

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TNF-α induces epithelial-mesenchymal transition through NF-κB in hepatocellular carcinoma

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2013.00271 ◽

2013 ◽

Vol 33 (3) ◽

pp. 271-276

Author(s):

Xing-rui KOU ◽

Ying-ying JING ◽

Guo-feng YU ◽

Meng-chao WU ◽

Li-xin WEI

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Tnf Α

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Intergrated Analysis of ELMO1, Serves As a Link between Tumor Mutation Burden and Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma

SSRN Electronic Journal ◽

10.2139/ssrn.3350534 ◽

2019 ◽

Author(s):

Hong Peng ◽

Yi Zhang ◽

Zhiwei Zhou ◽

Yu Guo ◽

Xiaohui Huang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Tumor Mutation Burden ◽

Mesenchymal Transition ◽

Mutation Burden

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Correction to: Forkhead box (FOX) G1 promotes hepatocellular carcinoma epithelial-Mesenchymal transition by activating Wnt signal through forming T-cell factor-4/Betacatenin/FOXG1 complex

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01900-2 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xingrong Zheng ◽

Jiaxin Lin ◽

Hewei Wu ◽

Zhishuo Mo ◽

Yunwen Lian ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cell ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

T Cell Factor ◽

Forkhead Box ◽

Wnt Signal

An amendment to this paper has been published and can be accessed via the original article.

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MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma

Cell Death and Disease ◽

10.1038/s41419-021-03973-5 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Peng Xia ◽

Hao Zhang ◽

Kequan Xu ◽

Xiang Jiang ◽

Meng Gao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

P53 Protein ◽

Rna Modifications ◽

M Cell ◽

Mesenchymal Transition ◽

Akt Phosphorylation ◽

Repeat Domain ◽

Cell Cycle Transition

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.

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FOXO1 inhibits the invasion and metastasis of hepatocellular carcinoma by reversing ZEB2-induced epithelial-mesenchymal transition

Oncotarget ◽

10.18632/oncotarget.13786 ◽

2016 ◽

Vol 8 (1) ◽

pp. 1703-1713 ◽

Cited By ~ 31

Author(s):

Tianxiu Dong ◽

Yu Zhang ◽

Yaodong Chen ◽

Pengfei Liu ◽

Tingting An ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Invasion And Metastasis ◽

Mesenchymal Transition

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Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma

Digestive Diseases ◽

10.1159/000439102 ◽

2015 ◽

Vol 33 (6) ◽

pp. 771-779 ◽

Cited By ~ 45

Author(s):

Naoshi Nishida ◽

Masayuki Kitano ◽

Toshiharu Sakurai ◽

Masatoshi Kudo

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factor ◽

Kinase Inhibitor ◽

Epithelial Mesenchymal Transition ◽

Growth Factor Receptor ◽

Stem Cell Markers ◽

Mesenchymal Transition ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Underlying Mechanisms

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC.

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