scholarly journals SIX1 Down-Regulation Influence Drug Resistance, Epithelial-Mesenchymal Transcription Factors and Self-Renewal Capacity in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Pelin Balcik Ercin ◽  
Arzu Aysan ◽  
Nazli Salik ◽  
Esma Erciyas
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Expression Profile ◽  
Epithelial Mesenchymal Transition ◽  
Profile Analysis ◽  
Sorafenib Treatment ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Sine Oculis

Abstract Sine oculis homeoprotein 1 (SIX1) was discovered to exert an essential role in embryonic development and it was also identified to be re-activated in various types of mammalian cancer. Immunohistochemical and SIX1 gene expression analyses were performed to determine the prognostic role of SIX1 expression. SIX1 expression was suppressed by short hairpin RNA transduction in the SNU398 HCC cell line. The effects of SIX1 on proliferation, epithelial-mesenchymal transition, apoptosis, drug resistance, and sphere formation were assessed in SIX1 knock-down cells. The upregulated expression levels of SIX1 were revealed to be correlated with the stage of the disease in breast, colon and liver cancer, with liver cancer exhibiting the highest expression profile. SIX1 knockdown significantly affected the cell morphology, proliferation, downregulated the protein expression levels of ZEB1, ZEB2 and SNAI1 and upregulated the expression levels of TWIST1 in hepatocellular carcinoma cells. Furthermore, SIX1 knockdown cells were more sensitive to sorafenib treatment; however, the expression profile analysis of the drug resistance genes ABCB1, ABCC1 and ABCG2 did not explain this sensitivity. Finally, SIX1 knockdown cells were identified to have decreased CD90 levels and lost their sphere-forming ability, which is essential for cancer stem cell properties. Overall, these results indicated that SIX1 expression may be useful as a diagnostic marker for patients with HCC.

scholarly journals LncRNA DLX6-AS1 Contributes to Epithelial–Mesenchymal Transition and Cisplatin Resistance in Triple-negative Breast Cancer via Modulating Mir-199b-5p/Paxillin Axis

2020 ◽  
Vol 29 ◽  
pp. 096368972092998 ◽  
Author(s):  
Chuang Du ◽  
Yan Wang ◽  
Yingying Zhang ◽  
Jianhua Zhang ◽  
Linfeng Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Drug Resistance ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cisplatin Resistance ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Expression Levels

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer types with high recurrence, metastasis, and drug resistance. Recent studies report that long noncoding RNAs (lncRNAs)-mediated competing endogenous RNAs (ceRNA) play an important role in tumorigenesis and drug resistance of TNBC. Although elevated lncRNA DLX6 antisense RNA 1 (DLX6-AS1) has been observed to promote carcinogenesis in various cancers, the role in TNBC remained unclear. In this study, expression levels of DLX6-AS1 were increased in TNBC tissues and cell lines when compared with normal tissues or breast fibroblast cells which were determined by quantitative real-time PCR (RT-qPCR). Then, CCK-8 assay, cell colony formation assay and western blot were performed in CAL-51 cells transfected with siRNAs of DLX6-AS1 or MDA-MB-231 cells transfected with DLX6-AS1 over expression plasmids. Knock down of DLX6-AS1 inhibited cell proliferation, epithelial-mesenchymal transition (EMT), decreased expression levels of BCL2 apoptosis regulator (Bcl-2), Snail family transcriptional repressor 1 (Snail) as well as N-cadherin and decreased expression levels of cleaved caspase-3, γ-catenin as well as E-cadherin, while up regulation of DLX6-AS1 had the opposite effect. Besides, knockdown of DLX6-AS1 in CAL-51 cells or up regulation of DLX6-AS1 in MDA-MB-231 cells also decreased or increased cisplatin resistance of those cells analyzed by MTT assay. Moreover, by using dual luciferase reporter assay, RNA immunoprecipitation and RNA pull down assay, a ceRNA which was consisted by lncRNA DLX6-AS1, microRNA-199b-5p (miR-199b-5p) and paxillin (PXN) was identified. And DLX6-AS1 function through miR-199b-5p/PXN in TNBC cells. Finally, results of xenograft experiments using nude mice showed that DLX6-AS1 regulated cell proliferation, EMT and cisplatin resistance by miR-199b-5p/PXN axis in vivo. In brief, DLX6-AS1 promoted cell proliferation, EMT, and cisplatin resistance through miR-199b-5p/PXN signaling in TNBC in vitro and in vivo.

scholarly journals Pharmacoproteomics Identifies Kinase Pathways that Drive the Epithelial-Mesenchymal Transition and Drug Resistance in Hepatocellular Carcinoma

Cell Systems ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 196-207.e7
Author(s):  
Martin Golkowski ◽  
Ho-Tak Lau ◽  
Marina Chan ◽  
Heidi Kenerson ◽  
Venkata Narayana Vidadala ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals Silencing of the TROP2 gene suppresses proliferation and invasion of hepatocellular carcinoma HepG2 cells

2019 ◽  
Vol 47 (3) ◽  
pp. 1319-1329 ◽  
Author(s):  
Jian Zhang ◽  
Hai Ma ◽  
Liu Yang ◽  
Hongchun Yang ◽  
Zhenxing He
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Human Trophoblast ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Proliferation And Invasion

Objectives Overexpression of human trophoblast cell surface antigen 2 (Trop2) has been observed in many cancers; however, its roles in proliferation, apoptosis, migration, and invasion of hepatocellular carcinoma (HCC) remain unclear. Thus, this study aimed to characterize the function of Trop2 in HCC. Methods Trop2 protein expression was detected by immunohistochemistry in HCC tissues. Cell proliferation, apoptosis, and invasion were respectively measured by CCK-8, flow cytometry, Transwell, and wound healing assays. Expression levels of epithelial–mesenchymal transition-related proteins and Trop2 protein in HCC cell lines were detected by western blotting after silencing of the TROP2 gene. Results Trop2 protein was highly expressed in HCC tissues and HCC cell lines. Trop2 mRNA and protein expression levels decreased in HepG2 and HCCLM3 cells after transfection with Trop2 siRNA. Silencing of the TROP2 gene in HepG2 and HCCLM3 cells strongly inhibited cell proliferation and migration, while enhancing cell apoptosis. Investigation of the molecular mechanism revealed that silencing of the TROP2 gene suppressed epithelial–mesenchymal transition of HepG2 and HCCLM3 cells. Conclusions The results of the present study may improve understanding of the role of Trop2 in regulation of cell proliferation and invasion, and may aid in development of novel therapy for HCC.

scholarly journals The Effect of Alpha Mangostin on Epithelial-Mesenchymal Transition on Human Hepatocellular Carcinoma HepG2 Cells Surviving Sorafenib via TGF-β/Smad Pathways

2020 ◽  
Vol 10 (4) ◽  
pp. 648-655
Author(s):  
Syarinta Adenina ◽  
Melva Louisa ◽  
Vivian Soetikno ◽  
Wawaimuli Arozal ◽  
Septelia Inawati Wanandi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Viability ◽  
Hepg2 Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Sorafenib Treatment ◽  
Mesenchymal Transition ◽  
The Impact ◽  
Tgf Β1 ◽  
E Cadherin

Purpose : This study was intended to find out the impact of alpha mangostin administration on the epithelial-mesenchymal transition (EMT) markers and TGF-β/Smad pathways in hepatocellular carcinoma Hep-G2 cells surviving sorafenib. Methods: Hepatocellular carcinoma HepG2 cells were treated with sorafenib 10 μM. Cells surviving sorafenib treatment (HepG2surv) were then treated vehicle, sorafenib, alpha mangostin, or combination of sorafenib and alpha mangostin. Afterward, cells were observed for their morphology with an inverted microscope and counted for cell viability. The concentrations of transforming growth factor (TGF)-β1 in a culture medium were examined using ELISA. The mRNA expressions of TGF-β1, TGF-β1-receptor, Smad3, Smad7, E-cadherin, and vimentin were evaluated using quantitative reverse transcriptase–polymerase chain reaction. The protein level of E-cadherin was also determined using western blot analysis. Results: Treatment of alpha mangostin and sorafenib caused a significant decrease in the viability of sorafenib-surviving HepG2 cells versus control (both groups with P<0.05). Our study found that alpha mangostin treatment increased the expressions of vimentin (P<0.001 versus control). In contrast, alpha mangostin treatment tends to decrease the expressions of Smad7 and E-cadherin (both with P>0.05). In line with our findings, the expressions of TGF-β1 and Smad3 are significantly upregulated after alpha mangostin administration (both with P<0.05) versus control. Conclusion: Alpha mangostin reduced cell viability of sorafenib-surviving HepG2 cells; however, it also enhanced epithelial–mesenchymal transition markers by activating TGF-β/Smad pathways.

scholarly journals miR-650 Promotes the Metastasis and Epithelial–Mesenchymal Transition of Hepatocellular Carcinoma by Directly Inhibiting LATS2 Expression

2018 ◽  
Vol 51 (3) ◽  
pp. 1179-1192 ◽  
Author(s):  
Li Li Han ◽  
Xiao Ran Yin ◽  
Shu Qun Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Assay ◽  
Large Tumor ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Direct Target ◽  
Large Tumor Suppressor ◽  
Hcc Cells

Background/Aims: Previous studies have confirmed that microRNAs are involved in the metastasis and epithelial–mesenchymal transition (EMT) of malignancies. In this study, we examined whether miR-650 promotes the migration, invasion, and EMT of hepatocellular carcinoma (HCC) cells by targeting the large tumor suppressor kinase 2 gene (LATS2). Methods: qRT-PCR was used to detect expression of miR-650 in HCC tissues and paired normal tissues. MTT and Transwell assay were used to observe the effect of miR-650 on proliferation, migration and invasion of HCC cells. Western blot assay and Immunohistochemistry were performed to demonstrate association between miR-650 expression level and epithelial-mesenchymal transition (EMT) related protein. Mechanistically, Reporter luciferase assay was performed to reveal whether large tumor suppressor kinase 2 (LATS2) was a direct target of miR-650 in HCC cells. Results: We observed that miR-650 levels were largely up-regulated in HCC tissues, and that the increased expression was closely associated with the adverse clinical features of HCC patients. Additionally, the expression of LATS2, which was identified as a direct target of miR-650, can counteract the effects of miR-650 in HCC. Furthermore, we demonstrated that high miR-650 expression levels and low LATS2 expression levels in tumors may indicate a poor prognosis for HCC patients. Conclusion: In conclusion, the miR-650/LATS2 pathway may serve as a novel prognostic biomarker and an attractive therapeutic target for HCC patients.

scholarly journals ASIC1a Stimulates the Resistance of Human Hepatocellular Carcinoma by Promoting Epithelial-mesenchymal Transition via the AKT/GSK3β/Snail Signaling Pathway

2021 ◽  
Author(s):  
Yinci Zhang ◽  
Niandie Cao ◽  
Jiafeng Gao ◽  
Jiaojiao Liang ◽  
Yong Liang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Migration ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Cell Migration And Invasion ◽  
Gsk 3Β ◽  
Hcc Cells

Abstract Background: The main obstacle to the cure of hepatocellular carcinoma (HCC) is multidrug resistance. Acid sensing ion channel 1a (ASIC1a) acts as a critical roles in all stages of cancer progression, especially invasion and metastasis as well as in resistance to therapy. Epithelial to mesenchymal transition (EMT) is a phenomenon in which epithelial cells transform into mesenchymal cells after being stimulated by extracellular factors and is closely related to tumor infiltration and resistance. Methods: Western blotting assay, Immunofluorescence (IF) staining, Immunohistochemistry (IHC) staining, MTT and colony formation assay and scratch healing assay were used to detect the level of ASIC1a and the cell proliferation, migration and invasion capabilities in this research.Results: In this research, we found that the protein of ASIC1a is overexpressed in HCC cancer tissues. In addition, we identified that the levels of ASIC1a are highly expressed in resistant HCC cells. Compared with the parental cells, EMT occurred more frequently in drug-resistant cells. Functional studies demonstrated that inactivation of ASIC1a restrained cell migration and invasion and enhanced the chemosensitivity of cells through EMT. In HCC cells, the overexpression of ASIC1a stimulates the up-regulation of EMT characterization molecular level and proliferation, migration and invasion capabilities and further induces drug resistance, while knocking down ASIC1a with short hairpin RNA (shRNA) has the opposite effect. Further investigations found that ASIC1a increased cell migration and invasion through EMT by regulating α and β-catenin, vimentin and fibronectin expression via AKT/GSK-3β/Snail pathway. Conclusions: Our study demonstrated that ASIC1a acts an important assignment in drug resistance of HCC through EMT via AKT/GSK-3β/Snail pathway, thereby lending a latent therapeutic objective and new ideas regarding to HCC.

scholarly journals Suppression of Hepatocellular Carcinoma Progression through FOXM1 and EMT Inhibition via Hydroxygenkwanin-Induced miR-320a Expression

Biomolecules ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 20 ◽  
Author(s):  
Li-Fang Chou ◽  
Chi-Yuan Chen ◽  
Wan-Hua Yang ◽  
Chin-Chuan Chen ◽  
Junn-Liang Chang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cell Function ◽  
Epithelial Mesenchymal Transition ◽  
Xenograft Model ◽  
Loss Of Function ◽  
Chinese Medicinal Herb ◽  
Mesenchymal Transition ◽  
Mouse Xenograft Model

Daphne genkwa, a Chinese medicinal herb, is used frequently in Southeast Asian countries to treat diseases; the flavonoid hydroxygenkwanin (HGK) is extracted from its flower buds. The bioactivity of HGK, particularly as an anti-liver cancer agent, has not been explored. In this study, human hepatocellular carcinoma (HCC) cell lines and an animal xenograft model were employed to investigate both the activity of HGK against liver cancer and its cellular signaling mechanisms. HCC cells treated with HGK were subjected to cell function assays. Whole transcriptome sequencing was used to identify genes whose expression was influenced by HGK, and the flavonoid’s cancer suppression mechanisms were further investigated through gain- and loss-of-function assays. Finally, in vitro findings were tested in a mouse xenograft model. The data showed that HGK induced the expression of the microRNA miR-320a, which in turn inhibited the expression of the transcription factor ‘forkhead box protein M1’ (FOXM1) and downstream FOXM1-regulated proteins related to epithelial–mesenchymal transition, thereby leading to the suppression of liver cancer cell growth and invasion. Significant inhibition of tumor growth was also observed in HGK-treated mice. Hence, the present study demonstrated the activity of HGK against liver cancer and validated its potential use as a therapeutic agent.

scholarly journals The Delta Subunit of Rod-Specific Photoreceptor cGMP Phosphodiesterase (PDE6D) Contributes to Hepatocellular Carcinoma Progression

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 398 ◽  
Author(s):  
Peter Dietrich ◽  
Claus Hellerbrand ◽  
Anja Bosserhoff
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Erk Activation ◽  
Cgmp Phosphodiesterase ◽  
Tumor Stages ◽  
And Migration ◽  
Delta Subunit ◽  
Hcc Cells

Emerging evidence reveals crucial roles of wild type RAS in liver cancer. The delta subunit of rod-specific photoreceptor cGMP phosphodiesterase (PDE6D) regulates the trafficking of RAS proteins to the plasma membrane and thereby contributes to RAS activation. However, the expression and specific function of PDE6D in hepatocellular carcinoma (HCC) were completely unknown. In this study, PDE6D was newly found to be markedly upregulated in HCC tissues and cell lines. Overexpression of PDE6D in HCC correlated with enhanced tumor stages, tumor grading, and ERK activation. PDE6D depletion significantly reduced proliferation, clonogenicity, and migration of HCC cells. Moreover, PDE6D was induced by TGF-β1, the mediator of stemness, epithelial-mesenchymal transition (EMT), and chemoresistance. In non-resistant cells, overexpression of PDE6D conferred resistance to sorafenib-induced toxicity. Further, PDE6D was overexpressed in sorafenib resistance, and inhibition of PDE6D reduced proliferation and migration in sorafenib-resistant HCC cells. Together, PDE6D was found to be overexpressed in liver cancer and correlated with tumor stages, grading, and ERK activation. Moreover, PDE6D contributed to migration, proliferation, and sorafenib resistance in HCC cells, therefore representing a potential novel therapeutic target.

Secretory Clusterin: A Promising Target for Chemoresistance of Hepatocellular Carcinoma

2020 ◽  
Vol 20 (12) ◽  
pp. 1153-1165 ◽  
Author(s):  
Jie Zhang ◽  
Mengna Wu ◽  
Yuqing Xu ◽  
Qianqian Song ◽  
Wenjie Zheng
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Epithelial Mesenchymal Transition ◽  
Vital Role ◽  
Current Evidence ◽  
Drug Efflux ◽  
Mesenchymal Transition ◽  
Limited Efficacy ◽  
Promising Target ◽  
Chemotherapy Agents

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Chemoresistance remains the major factor for limited efficacy of the HCC treatment. Thus, exploring the mechanisms underlying drug resistance is of great importance. Secretory clusterin (sCLU), a stressactivated and ATP-independent molecular chaperone, is up-regulated in numerous tumors and correlated with malignant phenotypes. For HCC, the implication of sCLU was previously addressed in tumor growth, metastasis, as well as early diagnosis and poor prognosis. Notably, accumulating studies have emphasized its vital role in drug resistance of HCC. Depletion of sCLU synergistically could enhance the sensitivity of HCC cells to a variety of chemotherapy agents. Herein, we summarized the potential mechanisms accounting for the sCLU-induced chemoresistance, including promoting apoptosis evasion, facilitating epithelial-mesenchymal transition (EMT), maintaining the viability of cancer stem cell (CSC), enhancing drug efflux capacity, and regulating autophagic activities. The current evidence suggest that targeting sCLU might be a promising approach in overcoming chemoresistance of HCC.

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