LIMK1 nuclear translocation promotes hepatocellular carcinoma progression by increasing p-ERK nuclear shuttling and by activating c-Myc signalling upon EGF stimulation

Oncogene ◽  
2021 ◽  
Author(s):  
Zhihua Pan ◽  
Chaoqun Liu ◽  
Yunfei Zhi ◽  
Zhiyue Xie ◽  
Ling Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nuclear Translocation ◽  
Nuclear Shuttling

scholarly journals YAP inactivation in estrogen receptor alpha-positive hepatocellular carcinoma with less aggressive behavior

2021 ◽  
Author(s):  
Youngsic Jeon ◽  
Jeong Eun Yoo ◽  
Hyungjin Rhee ◽  
Young-Joo Kim ◽  
Gwang Il Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Nuclear Translocation ◽  
Disease Free Survival ◽  
Cancer Cell Growth ◽  
Receptor Alpha ◽  
Downstream Signaling ◽  
Favorable Prognosis ◽  
Serum Alpha Fetoprotein

AbstractThe expression of estrogen receptor alpha (ERα, encoded by ESR1) has been shown to be associated with the prognostic outcomes of patients in various cancers; however, its prognostic and mechanistic significance in hepatocellular carcinoma (HCC) remain unclear. Here, we evaluated the expression of ERα and its association with clinicopathological features in 339 HCC patients. ERα was expressed in 9.4% (32/339) of HCCs and was related to better overall survival (OS; hazard ratio [HR] = 0.11, p = 0.009, 95% C.I. = 0.016–0.82) and disease-free survival (DFS, HR = 0.4, p = 0.013, 95% C.I. = 0.18–0.85). ERα expression was also associated with features related to more favorable prognosis, such as older age, lower serum alpha-fetoprotein level, and less microvascular invasion (p < 0.05). In addition, to obtain mechanistic insights into the role of ERα in HCC progression, we performed integrative transcriptome data analyses, which revealed that yes-associated protein (YAP) pathway was significantly suppressed in ESR1-expressing HCCs. By performing cell culture experiments, we validated that ERα expression enhanced YAP phosphorylation, attenuating its nuclear translocation, which in turn suppressed the downstream signaling pathways and cancer cell growth. In conclusion, we suggest that ERα expression is an indicator of more favorable prognosis in HCC and that this effect is mediated by inactivation of YAP signaling. Our results provide new clinical and pathobiological insights into ERα and YAP signaling in HCC.

Peritumoral ductular reaction is related to nuclear translocation of β-catenin in hepatocellular carcinoma

2015 ◽  
Vol 76 ◽  
pp. 11-16 ◽  
Author(s):  
Xiaobo Cai ◽  
Feng Li ◽  
QingQing Zhang ◽  
Mingyi Xu ◽  
Ying Qu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nuclear Translocation ◽  
Ductular Reaction

scholarly journals Terminalia catappaExerts Antimetastatic Effects on Hepatocellular Carcinoma through Transcriptional Inhibition of Matrix Metalloproteinase-9 by Modulating NF-κB and AP-1 Activity

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Chao-Bin Yeh ◽  
Ming-Ju Hsieh ◽  
Yih-Shou Hsieh ◽  
Ming-Hsien Chien ◽  
Pen-Yuan Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Matrix Metalloproteinase ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Matrix Metalloproteinase 9 ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Mrna Levels ◽  
Inhibitory Effects ◽  
Huh7 Cells ◽  
Metalloproteinase 9

High mortality and morbidity rates for hepatocellular carcinoma (HCC) in Taiwan primarily result from uncontrolled tumor metastasis. Previous studies have identified thatTerminalia catappaleaf extracts (TCE) exert hepatoprotective, antioxidative, antiinflammatory, anticancer, and antimetastatic activities. However, the effects of TCE on HCC and the underlying molecular mechanisms of its activities have yet to be fully elucidated. The present study's findings demonstrate that TCE concentration dependently inhibits human HCC migration/invasion. Zymographic and western blot analyses revealed that TCE inhibited the activities and expression of matrix metalloproteinase-9 (MMP-9). Assessment of mRNA levels, using reverse transcriptase polymerase chain reaction (PCR) and real-time PCR, and promoter assays confirmed the inhibitory effects of TCE on MMP-9 expression in HCC cells. The inhibitory effects of TCE on MMP-9 proceeded by upregulating tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as suppressing nuclear translocation and DNA binding activity of nuclear factor-kappa B (NF-κB) and activating protein-1 (AP-1) on the MMP-9 promoter in Huh7 cells. In conclusion, TCE inhibits MMP-9 expression and HCC cell metastasis and, thus, has potential use as a chemopreventive agent. Its inhibitory effects are associated with downregulation of the binding activities of the transcription factors NF-κB and AP-1.

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

2020 ◽  
Author(s):  
Tong-tong Li ◽  
Jie Mou ◽  
Yao-jie Pan ◽  
Fu-chun Huo ◽  
Wen-qi Du ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Kinase Inhibitor ◽  
Flow Cytometric Analysis ◽  
Luciferase Reporter ◽  
Advanced Hepatocellular Carcinoma ◽  
Cell Viability Assay ◽  
Resistant Cells

Abstract Background: Kinase inhibitor sorafenib is the first-line targeted drug for advanced hepatocellular carcinoma (HCC) patients. However, the appearance of anti-cancer agents’ resistance has limited its therapeutic effect. Methods: In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in HCC sorafenib-resistant cells and their parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assay, plate colony formation assay and flow cytometric analysis. The potential mechanisms of PAK5 were evaluated via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib chemoresistant characteristics were investigated by a xenotransplantation model. Results: We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in HCC sorafenib resistance cell lines. Mechanical studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 elevated the phosphorylation and nuclear translocation of β-catenin that enhanced the transcriptional activity of multidrug resistance protein ABCB1. Conclusions: PAK5 contributed to the sorafenib chemoresistant characteristics of HCC by activity β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated HCC sorafenib resistance, which provided a potential therapeutic target for advanced HCC patients.

scholarly journals HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma

Theranostics ◽  
2019 ◽  
Vol 9 (25) ◽  
pp. 7583-7598 ◽  
Author(s):  
Xian Lin ◽  
Shi Zuo ◽  
Rongcheng Luo ◽  
Yonghao Li ◽  
Guifang Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nuclear Translocation

scholarly journals MEIS2C and MEIS2D promote tumor progression via Wnt/β-catenin and hippo/YAP signaling in hepatocellular carcinoma

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Lei Guan ◽  
Ting Li ◽  
Nanping Ai ◽  
Wei Wang ◽  
Bing He ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chromatin Immunoprecipitation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Therapeutic Strategies ◽  
Regulatory Mechanisms ◽  
Migration And Invasion ◽  
Gene Regulatory

Abstract Background MEIS2 has been identified as one of the key transcription factors in the gene regulatory network in the development and pathogenesis of human cancers. Our study aims to identify the regulatory mechanisms of MEIS2 in hepatocellular carcinoma (HCC), which could be targeted to develop new therapeutic strategies. Methods The variation of MEIS2 levels were assayed in a cohort of HCC patients. The proliferation, clone-formation, migration, and invasion abilities of HCC cells were measured to analyze the effects of MEIS2C and MEIS2D (MEIS2C/D) knockdown with small hairpin RNAs in vitro and in vivo. Chromatin immunoprecipitation (ChIP) was performed to identify MEIS2 binding site. Immunoprecipitation and immunofluorescence assays were employed to detect proteins regulated by MEIS2. Results The expression of MEIS2C/D was increased in the HCC specimens when compared with the adjacent noncancerous liver (ANL) tissues. Moreover, MEIS2C/D expression negatively correlated with the prognosis of HCC patients. On the other hand, knockdown of MEIS2C/D could inhibit proliferation and diminish migration and invasion of hepatoma cells in vitro and in vivo. Mechanistically, MESI2C activated Wnt/β-catenin pathway in cooperation with Parafibromin (CDC73), while MEIS2D suppressed Hippo pathway by promoting YAP nuclear translocation via miR-1307-3p/LATS1 axis. Notably, CDC73 could directly either interact with MEIS2C/β-catenin or MEIS2D/YAP complex, depending on its tyrosine-phosphorylation status. Conclusions Our studies indicate that MEISC/D promote HCC development via Wnt/β-catenin and Hippo/YAP signaling pathways, highlighting the complex molecular network of MEIS2C/D in HCC pathogenesis. These results suggest that MEISC/D may serve as a potential novel therapeutic target for HCC.

EGF promotes DKK1 transcription in hepatocellular carcinoma by enhancing the phosphorylation and acetylation of histone H3

2020 ◽  
Vol 13 (657) ◽  
pp. eabb5727
Author(s):  
Jie Niu ◽  
Wei Li ◽  
Chao Liang ◽  
Xiao Wang ◽  
Xin Yao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nuclear Translocation ◽  
Histone H3 ◽  
Growth Factor Receptor ◽  
Transcript Level ◽  
Metastatic Progression ◽  
Chemically Induced ◽  
Epidermal Growth ◽  
Dual Inhibition ◽  
Dickkopf 1

The protein Dickkopf-1 (DKK1) is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC) and promotes metastatic progression through the induction of β-catenin, a Wnt signaling effector. We investigated how DKK1 expression is induced in HCC and found that activation of the epidermal growth factor receptor (EGFR) promoted parallel MEK-ERK and PI3K-Akt pathway signaling that converged to epigenetically stimulate DKK1 transcription. In HCC cell lines stimulated with EGF, EGFR-activated ERK phosphorylated the kinase PKM2 at Ser37, which promoted its nuclear translocation. Also in these cells, EGFR-activated Akt phosphorylated the acetyltransferase p300 at Ser1834. Subsequently, PKM2 and p300 mediated the phosphorylation and acetylation, respectively, of histone H3 at the DKK1 promoter, which synergistically enhanced DKK1 transcription. The mechanism was supported with mutational analyses in cells and in a chemically induced HCC model in rats. The findings suggest that dual inhibition of the MEK and PI3K pathways might suppress the expression of DKK1 and, consequently, tumor metastasis in patients with HCC.

HEG1 indicates poor prognosis and promotes hepatocellular carcinoma invasion, metastasis, and EMT by activating Wnt/β-catenin signaling

2019 ◽  
Vol 133 (14) ◽  
pp. 1645-1662 ◽  
Author(s):  
Yan-rong Zhao ◽  
Ji-long Wang ◽  
Cong Xu ◽  
Yi-ming Li ◽  
Bo Sun ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Heart Development ◽  
Poor Prognosis ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Disease Free Survival ◽  
Intrahepatic Metastasis ◽  
Mesenchymal Transition

Abstract Heart development protein with EGF-like domains 1 (HEG1) plays critical roles in embryo development and angiogenesis, which are closely related to tumor progression. However, the role of HEG1 in hepatocellular carcinoma (HCC) remains unknown. In the present study, we explored the clinical significance, biological function and regulatory mechanisms of HEG1 in HCC and found that HEG1 is significantly up-regulated in HCC cell lines and primary tumor samples. Additionally, high HEG1 expression is correlated with aggressive clinicopathological features. Patients with high HEG1 expression had shorter overall survival (OS) and disease-free survival (DFS) than those with low HEG1 expression, which indicated that HEG1 is an independent factor for poor prognosis. Lentivirus-mediated HEG1 overexpression significantly promotes HCC cell migration, invasion and epithelial–mesenchymal transition (EMT) in vitro and promotes intrahepatic metastasis, lung metastasis and EMT in vivo. Opposing results are observed when HEG1 is silenced. Mechanistically, HEG1 promotes β-catenin expression and maintains its stability, leading to intracellular β-catenin accumulation, β-catenin nuclear translocation and Wnt signaling activation. Loss- and gain-of-function assays further confirmed that β-catenin is essential for HEG1-mediated promotion of HCC invasion, metastasis and EMT. In conclusion, HEG1 indicates poor prognosis; plays important roles in HCC invasion, metastasis and EMT by activating Wnt/β-catenin signaling; and can serve as a potentially valuable prognostic biomarker and therapeutic target for HCC.

scholarly journals MiR-141 Activates Nrf2-Dependent Antioxidant Pathway via Down-Regulating the Expression of Keap1 Conferring the Resistance of Hepatocellular Carcinoma Cells to 5-Fluorouracil

2015 ◽  
Vol 35 (6) ◽  
pp. 2333-2348 ◽  
Author(s):  
Liang Shi ◽  
Lili Wu ◽  
Zhanguo Chen ◽  
Jianrong Yang ◽  
Xiaofei Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Therapy ◽  
Nuclear Translocation ◽  
Therapy Resistance ◽  
Parental Cell ◽  
Significant Inhibition ◽  
Carcinoma Cells ◽  
Pcr Analysis ◽  
Hepatocellular Carcinoma Cells

Background: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. A major cause for the failure of cancer therapy is the development of chemoresistance. Although progress has been made in the study of the mechanisms underlying cancer cells resistance, little is known about the role of microRNAs (miRNAs) in cancer therapy resistance. Methods and Results: Fifteen miRNAs, including 6 up-regulated miRNAs (> 2.0-fold) and 9 down-regulated miRNAs (< 0.5-fold) were differentially expressed in 5-fluorouracil-resistant and their parental cell-lines (HepG2, HepG2/5-FU) by miRNA microarrays. Microarray results were confirmed by validating quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Up-regulation of miR-141 expression resulted in a significant inhibition of 5-FU-mediated cytotoxicity and apoptosis in various hepatocellular carcinoma cells-lines. Mechanically, miR-141 promoted Kelch-like ECH-associated protein 1 (Keap1) mRNA degradation by directly targeting the Keap1 3'untranslated region (3'UTR). Treatment with miR-141 mimics in parental HepG2 cells, restored miR-141 expression and reduced Keap1 levels, thereby resulting in erythroid transcription factor NFE2-L2 (Nrf2) nuclear translocation, activation of Nrf2-dependent HO-1 gene transcription, and subsequent enhancement in 5-FU resistance. Conversely, restoring the expression of Keap1 partly recovered 5-FU sensitivity by counteracting miR-141-mediated 5-FU resistance. Conclusion: Our study showed that miR-141 plays a key role in 5-FU resistance by down-regulating Keap1 expression, thereby reactivating the Nrf2-dependent antioxidant pathway, which may serve as a potential target for overcoming 5-FU resistance in hepatocellular carcinoma cells.

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