scholarly journals LINC02027 / MiR-625-3p /PDLIM5 Axis Inhibits The Proliferation, Migration And Invasion And Promotes Apoptosis of HCC By Inhibiting RAS-MAPK Pathway

2021 ◽  
Author(s):  
Jinyi Wang ◽  
Yong Zhu ◽  
Xiaoming Ai ◽  
Hong Wan ◽  
Wenbo Jia ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Cell Function ◽  
Mapk Pathway ◽  
Underlying Mechanism ◽  
Primary Objective ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Hcc Cells

Abstract Background and Aims: Long non-coding RNAs have been shown to promote or inhibit various cancers, acting as competing endogenous RNAs for specific microRNAs. The primary objective of this research was to investigate the underlying mechanism by which the LINC02027/miR-625-3p/PDLIM5 axis affects proliferation, migration, invasion and apoptosis in hepatocellular carcinoma (HCC). Methods: The level of LINC02027 in HCC tissues and cells and its regulatory effect on the development of HCC were detected. According to the results of database prediction and qRT-PCR, the downstream microRNA and target gene were searched. Finally, HCC cells were transfected with lentivirus and used for cell function assays (in vitro) and subcutaneous tumorigenesis assay in nude mice (in vivo).Results: Downregulation of LINC02027 was detected in HCC tissues and cell lines. The knockdown or overexpression of LINC02027 increased or reduced the proliferation migration and invasion of HCC cells, and the apoptotic ability of HCC cells decreased or increased, respectively. Mechanistically, INC02027 inhibited epithelial-to-mesenchymal transition (EMT). As a ceRNA, LINC02027 inhibited the malignant ability of HCC by competitively binding to miR-625-3p to regulate the expression of PDLIM5 and the activity of RAS-MAPK pathway.Conclusion: LINC02027/miR-625-3p/PDLIM5 axis inhibits the EMT and promotes apoptosis of HCC by regulating RAS-MAPK pathway.

scholarly journals TDO2 Promotes the EMT of Hepatocellular Carcinoma Through Kyn-AhR Pathway

2021 ◽  
Vol 10 ◽  
Author(s):  
Lei Li ◽  
Tao Wang ◽  
Shanbao Li ◽  
Zhengqian Chen ◽  
Junyi Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Aryl Hydrocarbon Receptor ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Aryl Hydrocarbon ◽  
Hcc Cells

Tryptophan 2,3-dioxygenase (TDO2), an enzyme involved in tryptophan (Trp) metabolism has been linked with some malignant traits of various cancers. Kyn, the main product of Trp metabolism pathway catalyzed by TDO2 and indoleamine 2,3-dioxygenase (IDO) in tumor cells, was also demonstrated to activate aryl hydrocarbon receptor (AhR), which may regulate cancer growth and invasion in some malignancies. However, whether TDO2 participates in the metastasis and invasion of HCC has not been explored before. The underlying mechanism played by TDO2 in this process still requires further investigation. Here, we demonstrated that overexpression of TDO2 correlates with advanced stage or malignant traits in HCC patients. Knockdown or inhibition of TDO2 suppressed the migration and invasion of HCC cells in vitro and in vivo. Epithelial to mesenchymal transition (EMT) is an essential program happened in the initial phase of cancer metastasis. We found that in HCC cells, TDO2 promoted the EMT process evidenced by altered levels of biomarkers for EMT. Mechanically, TDO2 regulated the Kyn production in HCC cell via activated aryl hydrocarbon receptor (AhR). Together, these results indicate that TDO2 promotes the EMT of hepatocellular carcinoma through activating Kyn-AhR pathway, thereby participating in the metastasis and invasion of HCC.

scholarly journals Armadillo Repeat-Containing Protein 8 (ARMC8) Silencing Inhibits Proliferation and Invasion in Osteosarcoma Cells

2016 ◽  
Vol 24 (5) ◽  
pp. 381-389 ◽  
Author(s):  
Feng Jiang ◽  
Yan Shi ◽  
Hong Lu ◽  
Guojun Li
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Mesenchymal Transition ◽  
Armadillo Repeat ◽  
Proliferation And Invasion

Armadillo repeat-containing protein 8 (ARMC8) plays an important role in regulating cell migration, proliferation, tissue maintenance, signal transduction, and tumorigenesis. However, the expression pattern and role of ARMC8 in osteosarcoma are still unclear. In this study, our aims were to examine the effects of ARMC8 on osteosarcoma and to explore its underlying mechanism. Our results demonstrated that ARMC8 was overexpressed in osteosarcoma cell lines. Knockdown of ARMC8 significantly inhibited osteosarcoma cell proliferation in vitro and markedly inhibited xenograft tumor growth in vivo. ARMC8 silencing also suppressed the epithelial‐mesenchymal transition (EMT) phenotype, as well as inhibited the migration and invasion of osteosarcoma cells. Furthermore, knockdown of ARMC8 obviously inhibited the expression of β-catenin, c-Myc, and cyclin D1 in MG-63 cells. In conclusion, this report demonstrates that ARMC8 silencing inhibits proliferation and invasion of osteosarcoma cells. Therefore, ARMC8 may play an important role in the development and progression of human osteosarcoma and may represent a novel therapeutic target in the treatment of osteosarcoma.

scholarly journals LncRNA ZFPM2-AS1 Promotes Metastasis and Epithelial-mesenchymal Transition of Hepatocellular Carcinoma via Targeting miR-3612/ADAM15 Axis

2020 ◽  
Author(s):  
Nan Yang ◽  
Tianxiang Chen ◽  
Bowen Yao ◽  
Liang Wang ◽  
Runkun Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Biological Effects ◽  
Luciferase Reporter Assay ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Reporter Assay ◽  
Mesenchymal Transition ◽  
Hcc Cells

Abstract Background: Long non-coding RNAs (lncRNAs) have obtained growing attention due to their potential effects as novel regulators in various tumors. This study aimed to investigate the expression and roles of lncRNA ZFPM2-AS1 in the progression of hepatocellular carcinoma (HCC). Methods: Transwell was used to determine migration and invasion of HCC cells in vitro. The lung metastasis mouse model was established to detect tumor metastasis of HCC in vivo. The direct binding of miR-3612 to 3'UTR of DAM15 was confirmed by luciferase reporter assay. The expression of ZFPM2-AS1 and miR-3612 in HCC specimens and cell lines were detected by real-time PCR. The correlation among ZFPM2-AS1 and miR-3612 were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay.Results: In present study, we found that ZFPM2-AS1 was up-regulated in HCC tissues and cells and its upregulation was associated with TNM stage, vascular invasion, and poor prognosis of HCC patients. Functionally, gain- and loss-of-function experiments indicated that ZFPM2-AS1 promoted cell migration, invasion and EMT progress in vitro and in vivo. ZFPM2-AS1 could function as a competing endogenous RNA (ceRNA) by sponging miR-3612 in HCC cells. Mechanically, miR-3612 inhibited HCC metastasis and alternation of miR-3612 reversed the promotive effects of ZFPM2-AS1 on HCC cells. In addition, we confirmed that ADAM15 was a direct target of miR-3612 in HCC and mediated the biological effects of miR-3612 and ZFPM2-AS1 in HCC. Curcumin, an active derivative from turmeric, exerts its anticancer effects through ZFPM2-AS1/miR-3612/ADAM15 pathway. Our data identified ZFPM2-AS1 as a novel oncogenic lncRNA and correlated malignant clinical outcomes in HCC patients. Conclusions: ZFPM2-AS1 performed as oncogenic role via targeting miR-3612 and subsequently promoted ADAM15 expression in HCC. Our results revealed that ZFPM2-AS1 could be a potential prognostic biomarker and therapeutic target for HCC.

scholarly journals CircMTO1 suppresses hepatocellular carcinoma progression via the miR-541-5p/ZIC1 axis by regulating Wnt/β-catenin signaling pathway and epithelial-to-mesenchymal transition

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Dandan Li ◽  
Jiawei Zhang ◽  
Jing Yang ◽  
Jie Wang ◽  
Runling Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Epithelial To Mesenchymal Transition ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
Mesenchymal Transition

AbstractCircRNA mitochondrial tRNA translation optimization 1 (circMTO1) functions as a tumor suppressor usually and is related to the progression of many tumors, including hepatocellular carcinoma (HCC). CircMTO1 is downregulated in HCC as compared to adjacent nontumor tissue, which may suppress the HCC progression by certain signal pathways. However, the underlying signal pathway remains largely unknown. The interactions between circMTO1 and miR-541-5p were predicted through bioinformatics analysis and verified using pull-down and dual-luciferase reporter assays. CCK-8, transwell, and apoptosis assays were performed to determine the effect of miR-541-5p on HCC progression. Using bioinformatic analysis, dual-luciferase reporter assay, RT-qPCR, and western blot, ZIC1 was found to be the downstream target gene of miR-541-5p. The regulatory mechanisms of circMTO1, miR-541-5p, and ZIC1 were investigated using in vitro and in vivo rescue experiments. The results depicted that silencing circMTO1 or upregulating miR-541-5p expression facilitated HCC cell proliferation, migration, and invasion and inhibited apoptosis. CircMTO1 silencing upregulated the expression of downstream ZIC1 regulators of the Wnt/β-catenin pathway markers, β-catenin, cyclin D1, c-myc, and the mesenchymal markers N-cadherin, Vimentin, and MMP2, while the epithelial marker E-cadherin was downregulated. MiR-541-5p knockdown had the opposite effect and reversed the effect of circMTO1 silencing on the regulation of downstream ZIC1 regulators. Intratumoral injection of miR-541-5p inhibitor suppressed tumor growth and reversed the effect of circMTO1 silencing on the promotion of tumor growth in HCC. These findings indicated that circMTO1 suppressed HCC progression via the circMTO1/ miR-541-5p/ZIC1 axis by regulating Wnt/β-catenin signaling and epithelial-to-mesenchymal transition, making it a novel therapeutic target.

scholarly journals Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sabina Di Matteo ◽  
Lorenzo Nevi ◽  
Diletta Overi ◽  
Nadine Landolina ◽  
Jessica Faccioli ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Primary Cultures ◽  
Chronic Administration ◽  
Migration And Invasion ◽  
Cytokeratin 19 ◽  
Mesenchymal Transition ◽  
Therapeutic Implications

AbstractIntrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with marked resistance to chemotherapeutics without therapies. The tumour microenvironment of iCCA is enriched of Cancer-Stem-Cells expressing Epithelial-to-Mesenchymal Transition (EMT) traits, being these features associated with aggressiveness and drug resistance. Treatment with the anti-diabetic drug Metformin, has been recently associated with reduced incidence of iCCA. We aimed to evaluate the anti-cancerogenic effects of Metformin in vitro and in vivo on primary cultures of human iCCA. Our results showed that Metformin inhibited cell proliferation and induced dose- and time-dependent apoptosis of iCCA. The migration and invasion of iCCA cells in an extracellular bio-matrix was also significantly reduced upon treatments. Metformin increased the AMPK and FOXO3 and induced phosphorylation of activating FOXO3 in iCCA cells. After 12 days of treatment, a marked decrease of mesenchymal and EMT genes and an increase of epithelial genes were observed. After 2 months of treatment, in order to simulate chronic administration, Cytokeratin-19 positive cells constituted the majority of cell cultures paralleled by decreased Vimentin protein expression. Subcutaneous injection of iCCA cells previously treated with Metformin, in Balb/c-nude mice failed to induce tumour development. In conclusion, Metformin reverts the mesenchymal and EMT traits in iCCA by activating AMPK-FOXO3 related pathways suggesting it might have therapeutic implications.

scholarly journals A Novel Six Metastasis-Related Prognostic Gene Signature for Patients With Osteosarcoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Di Zheng ◽  
Kezhou Xia ◽  
Ling Yu ◽  
Changtian Gong ◽  
Yubo Shi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Epithelial To Mesenchymal Transition ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Gene Signature ◽  
Suppressor Gene ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Osteosarcoma is the most common malignant bone tumor, and although there has been significant progress in its management, metastases often herald incurable disease. Here we defined genes differentially expressed between primary and metastatic osteosarcoma as metastasis-related genes (MRGs) and used them to construct a novel six-MRG prognostic signature for overall survival of patients with osteosarcoma. Validation in internal and external datasets confirmed satisfactory accuracy and generalizability of the prognostic model, and a nomogram based on the signature and clinical variables was constructed to aid clinical decision-making. Of the six MRGs, FHIT is a well-documented tumor suppressor gene that is poorly defined in osteosarcoma. Consistent with tumor suppressor function, FHIT was downregulated in osteosarcoma cells and human osteosarcoma samples. FHIT overexpression inhibited osteosarcoma proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, FHIT overexpression upregulate the epithelial marker E-cadherin while repressing the mesenchymal markers N-cadherin and vimentin. Our six-MRG signature represents a novel and clinically useful prognostic biomarker for patients with osteosarcoma, and FHIT might represent a therapeutic target by reversing epithelial to mesenchymal transition.

scholarly journals CtBP modulates Snail-mediated tumor invasion in Drosophila

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chenxi Wu ◽  
Xiang Ding ◽  
Zhuojie Li ◽  
Yuanyuan Huang ◽  
Qian Xu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Invasion ◽  
Epithelial To Mesenchymal Transition ◽  
Model Organism ◽  
Underlying Mechanism ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Invasive Cell

AbstractCancer is one of the most fatal diseases that threaten human health, whereas more than 90% mortality of cancer patients is caused by tumor metastasis, rather than the growth of primary tumors. Thus, how to effectively control or even reverse the migration of tumor cells is of great significance for cancer therapy. CtBP, a transcriptional cofactor displaying high expression in a variety of human cancers, has become one of the main targets for cancer prediction, diagnosis, and treatment. The roles of CtBP in promoting tumorigenesis have been well studied in vitro, mostly based on gain-of-function, while its physiological functions in tumor invasion and the underlying mechanism remain largely elusive. Snail (Sna) is a well-known transcription factor involved in epithelial-to-mesenchymal transition (EMT) and tumor invasion, yet the mechanism that regulates Sna activity has not been fully understood. Using Drosophila as a model organism, we found that depletion of CtBP or snail (sna) suppressed RasV12/lgl-/--triggered tumor growth and invasion, and disrupted cell polarity-induced invasive cell migration. In addition, loss of CtBP inhibits RasV12/Sna-induced tumor invasion and Sna-mediated invasive cell migration. Furthermore, both CtBP and Sna are physiologically required for developmental cell migration during thorax closure. Finally, Sna activates the JNK signaling and promotes JNK-dependent cell invasion. Given that CtBP physically interacts with Sna, our data suggest that CtBP and Sna may form a transcriptional complex that regulates JNK-dependent tumor invasion and cell migration in vivo.

scholarly journals Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 2885 ◽  
Author(s):  
Monserrat Olea-Flores ◽  
Miriam Daniela Zuñiga-Eulogio ◽  
Miguel Angel Mendoza-Catalán ◽  
Hugo Alberto Rodríguez-Ruiz ◽  
Eduardo Castañeda-Saucedo ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Extracellular Signal ◽  
Epithelial Phenotype

Epithelial–mesenchymal transition (EMT) is a reversible cellular process, characterized by changes in gene expression and activation of proteins, favoring the trans-differentiation of the epithelial phenotype to a mesenchymal phenotype. This process increases cell migration and invasion of tumor cells, progression of the cell cycle, and resistance to apoptosis and chemotherapy, all of which support tumor progression. One of the signaling pathways involved in tumor progression is the MAPK pathway. Within this family, the ERK subfamily of proteins is known for its contributions to EMT. The ERK subfamily is divided into typical (ERK 1/2/5), and atypical (ERK 3/4/7/8) members. These kinases are overexpressed and hyperactive in various types of cancer. They regulate diverse cellular processes such as proliferation, migration, metastasis, resistance to chemotherapy, and EMT. In this context, in vitro and in vivo assays, as well as studies in human patients, have shown that ERK favors the expression, function, and subcellular relocalization of various proteins that regulate EMT, thus promoting tumor progression. In this review, we discuss the mechanistic roles of the ERK subfamily members in EMT and tumor progression in diverse biological systems.

scholarly journals TRAIL promotes epithelial-to-mesenchymal transition by inducing PD-L1 expression in esophageal squamous cell carcinomas

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Huanyu Zhang ◽  
Guohui Qin ◽  
Chaoqi Zhang ◽  
Huiyun Yang ◽  
Jinyan Liu ◽  
...  
Keyword(s):  
Western Blot ◽  
Squamous Cell ◽  
Mechanism Of Action ◽  
Epithelial To Mesenchymal Transition ◽  
Biological Function ◽  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Mesenchymal Transition

Abstract Background Tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) was initially considered an immunity guard; however, its function remains controversial. Besides immune cells, lung and colon cancer cells have also been reported to express TRAIL, which can promote tumor invasion and metastasis. However, the biological function and underlying mechanism of action of TRAIL in esophageal squamous cell carcinoma (ESCC) remain poorly elucidated. Methods The ESCC cells stemness, migration, and proliferation ability was assessed by sphere formation, Transwell, and CCK8 assay. The stemness- and epithelial-mesenchymal transition (EMT)- related genes expression levels were analyzed by Western blot and RT-qPCR. The signal activation was conducted by Western blot. The xenograft mouse experiments and lung metastasis model were performed to confirm our findings in vitro. Results Herein, we found that TRAIL is a negative predictor in patients with ESCC. To further investigate the biological function of TRAIL, we established TRAIL knockdown and overexpression ESCC cell lines and found that TRAIL induced EMT and promoted tumor aggressiveness. Furthermore, we demonstrated that TRAIL- overexpressing cells upregulated PD-L1 expression, which was dependent on the p-ERK/STAT3 signaling pathway. We obtained similar results when using recombinant human TRAIL. Finally, we validated the biological role and mechanism of action of TRAIL in vivo. Conclusions These findings demonstrate that TRAIL promotes ESCC progression by enhancing PD-L1 expression, which induces EMT. This may explain the failure of TRAIL preclinical trials.

scholarly journals WASF2 Overexpression and Promoter Hypomethylation Are Associated With Poor Clinical Outcomes in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Hye Ri Ahn ◽  
Geum Ok Baek ◽  
Moon Gyeong Yoon ◽  
Ju A Son ◽  
Jung Hwan Yoon ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Regulatory Mechanism ◽  
Cpg Island ◽  
Methylation Status ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Hcc Cells

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Wiskott-Aldrich syndrome protein family member 2 (WASF2) is an integral member of the actin cytoskeleton pathway that plays a crucial role in cell motility. In this study, we aimed to explore the role of WASF2 in HCC carcinogenesis and its regulatory mechanism. Methods: WASF2 expression in HCC was analyzed using six public RNA-seq datasets and 66 paired tissues from patients with HCC. Role of WASF2 in HCC cell phenotypes was evaluated using small interfering RNA (siRNA) in vitro and in vivo. Epigenetic regulatory mechanism of WASF2 was assessed in the Cancer Genome Atlas liver hepatocellular carcinoma project (TCGA_LIHC) dataset and also validated in 38 paired HCC tissues. Results: WASF2 is overexpressed in HCC and is clinically correlated with prognosis. WASF2 inactivation decreased the viability, growth, proliferation, migration, and invasion of Huh-7 and SNU475 HCC cells by restoring G2/M checkpoint function, inducing cell death, and inhibiting epithelial-mesenchymal transition, and hindering actin polymerization. In addition, WASF2 knockdown using siWASF2 in a xenograft mouse model exerted tumor suppressive effect. Furthermore, we observed a negative correlation between WASF2 methylation status and mRNA expression. The cg24162579 CpG island in the WASF2 5′ promoter region was hypomethylated in HCC compared to matched non-tumor samples. Patients with high WASF2 methylation and low WASF2 expression displayed the highest overall survival.Conclusions: WASF2 is overexpressed and hypomethylated in HCC and correlates with patient prognosis. Moreover, WASF2 inactivation exerts anti-tumorigenic effects on HCC cells in vitro and in vivo, suggesting that WASF2 could be a potential therapeutic target for HCC.

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