scholarly journals LncRNA LL22NC03-N14H11.1 promoted hepatocellular carcinoma progression through activating MAPK pathway to induce mitochondrial fission

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Tingzhuang Yi ◽  
Hongcheng Luo ◽  
Fengxue Qin ◽  
Qi Jiang ◽  
Shougao He ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Leucine Zipper ◽  
Epithelial To Mesenchymal Transition ◽  
Mapk Pathway ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition ◽  
Potential Biomarker

Abstract Involvement of long non-coding RNAs (lncRNAs) in hepatocarcinogenesis has been largely documented. Mitochondrial dynamics is identified to impact survival and metastasis in tumors including hepatocellular carcinoma (HCC), but the underlying mechanism remains poorly understood. This study planned to explore the regulation of lncRNA LL22NC03-N14H11.1 on HCC progression and mitochondrial fission. Dysregulated lncRNAs in HCC are identified through circlncRNAnet and GEPIA bioinformatics tools. Biological function of LL22NC03-N14H11.1 in HCC was detected by CCK-8 assay, flow cytometry analysis, transwell invasion, and wound healing assays. Molecular interactions were determined by RNA immunoprecipitation, RNA pull-down, and co-immunoprecipitation assays. Results showed that LL22NC03-N14H11.1 was upregulated in HCC tissues and cells. Functionally, LL22NC03-N14H11.1 contributed to cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) in HCC. Moreover, LL22NC03-N14H11.1 facilitated mitochondrial fission in HCC cells. Mechanistically, LL22NC03-N14H11.1 recruited Myb proto-oncogene (c-Myb) to repress the transcription of leucine zipper-like transcription regulator 1 (LZTR1), so as to inhibit LZTR1-mediated ubiquitination of H-RAS (G12V), leading to the activation of mitogen-activated protein kinase (MAPK) signaling and induction of p-DRP1 (Serine 616). In conclusion, this study firstly revealed that lncRNA LL22NC03-N14H11.1 promoted HCC progression through activating H-RAS/MAPK pathway to induce mitochondrial fission, indicating LL22NC03-N14H11.1 as a novel potential biomarker for HCC treatment.

scholarly journals Beneficial Actions of Orostachys japonica and Its Compounds against Tumors via MAPK Signaling Pathways

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 555
Author(s):  
Soyoung Hur ◽  
Eungyeong Jang ◽  
Jang-Hoon Lee
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Malignant Tumors ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Perennial Plant

Tumors are one of the most life-threatening diseases, and a variety of cancer treatment options have been continuously introduced in order to overcome cancer and improve conventional therapy. Orostachys japonica (O. japonica), which is a perennial plant belonging to the genus Orostachys of the Crassulaceae family, has been revealed to exhibit pharmacological properties against various tumors in numerous studies. The present review aimed to discuss the biological actions and underlying molecular mechanisms of O. japonica and its representative compounds—kaempferol and quercetin—against tumors. O. japonica reportedly has antiproliferative, anti-angiogenic, and antimetastatic activities against various types of malignant tumors through the induction of apoptosis and cell cycle arrest, a blockade of downstream vascular endothelial growth factor (VEGF)-VEGFR2 pathways, and the regulation of epithelial-to-mesenchymal transition. In addition, emerging studies have highlighted the antitumor efficacy of kaempferol and quercetin. Interestingly, it was found that alterations of the mitogen-activated protein kinase (MAPK) signaling cascades are involved in the pivotal mechanisms of the antitumor effects of O. japonica and its two compounds against cancer cell overgrowth, angiogenesis, and metastasis. In summary, O. japonica could be considered a preventive and therapeutic medicinal plant which exhibits antitumor actions by reversing altered patterns of MAPK cascades, and kaempferol and quercetin might be potential components that can contribute to the efficacy and underlying mechanism of O. japonica.

scholarly journals miR-19 Promotes Cell Proliferation, Invasion, Migration, and EMT by Inhibiting SPRED2-mediated Autophagy in Osteosarcoma Cells

2020 ◽  
Vol 29 ◽  
pp. 096368972096246
Author(s):  
Chuhai Xie ◽  
Shengyao Liu ◽  
Boyi Wu ◽  
Yu Zhao ◽  
Binwei Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mapk Pathway ◽  
Biological Effects ◽  
Rapid Development ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Osteosarcoma Cells ◽  
Mesenchymal Transition ◽  
Erk Mapk

Osteosarcoma is an aggressive malignancy with rapid development and poor prognosis. microRNA-19 (miR-19) plays an important role in several biological processes. Sprouty-related EVH1 domain protein 2 (SPRED2) is a suppressor of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling to inhibit tumor development and progression by promoting autophagy. In this study, we investigated the roles of miR-19, SPRED2, and autophagy in osteosarcoma. We detected the expression of miR-19, SPRED2, epithelial–mesenchymal transition (EMT) markers, and autophagy-related proteins via quantitative real-time polymerase chain reaction or western blot. To evaluate the function of miR-19 and SPRED2, we used MTT and colony formation assays to detect cell proliferation, Transwell, and wound-healing assays to detect cell invasion and migration. Targetscan and luciferase reporter assays confirmed the relationship between SPRED2 and miR-19. The expression of miR-19 was significantly upregulated in osteosarcoma, while SPRED2 was downregulated. miR-19 inhibitor reduced cell proliferation, invasion, migration, and EMT, while its cell biological effects were partially reversed by addition of autophagy inhibitor 3-methyladenine (3-MA) or SPRED2 siRNA in osteosarcoma. SPRED2, a suppressor of ERK/MAPK pathway that is known to trigger autophagy, was identified as a direct target of miR-19. SPRED2 overexpression increased cell proliferation, invasion, migration, and EMT by promoting autophagy, and the effects could be inhibited by 3-MA. Collectively, these findings reveal an underlying mechanism for development of osteosarcoma. miR-19 was upregulated in osteosarcoma cells, and negatively regulated SPRED2, thus promoting the malignant transformation of osteosarcoma cells via inhibiting SPRED2-induced autophagy. Therefore, miR-19/SPRED2 may be a potential target for the treatment of osteosarcoma.

scholarly journals Methionine Sulfoxide Reductase B1 Regulates Hepatocellular Carcinoma Cell Proliferation and Invasion via the Mitogen-Activated Protein Kinase Pathway and Epithelial-Mesenchymal Transition

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Qiang He ◽  
Hui Li ◽  
Fanzhi Meng ◽  
Xiangjun Sun ◽  
Xu Feng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Methionine sulfoxide reductase B1 (MsrB1) is a member of the selenoprotein family, which contributes to the reduction of methionine sulfoxides produced from reactive oxygen species (ROS) by redox processes in energy pathways. However, few studies have examined the role of MsrB1 in human hepatocellular carcinoma (HCC). We observed that MsrB1 is highly expressed in HCC tissues and that its expression correlated with the prognoses of patients with HCC after hepatectomy. In vitro, knockdown of MsrB1 inhibits HCC cell growth by MTT and EdU proliferation assay, and MsrB1 interference enhances H2O2/trx-induced apoptosis. We observed that phosphorylation of the key proteins of the MAPK pathway, namely, ERK, MEK, and p53, was inhibited, but PARP and caspase 3 were increased, thus infecting mitochondrial integrity. In vivo, MsrB1 knockdown effectively inhibited tumor growth. Furthermore, MsrB1 knockdown reduced HCC cell migration and invasion in a transwell assay through inhibition of cytoskeletal rearrangement and spread. This change was linked to epithelial-mesenchymal transition (EMT) inhibition resulting from increases in E-cadherin expression and decreases in expression in TGF-β1, Slug, MMP-2/9, and so on. MsrB1 regulates HCC cell proliferation and migration by modulating the MAPK pathway and EMT. Thus, MsrB1 may be a novel therapeutic target with respect to the treatment of HCC.

scholarly journals MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming

2019 ◽  
Vol 122 (2) ◽  
pp. 209-220 ◽  
Author(s):  
Ze Zhang ◽  
Tian-En Li ◽  
Mo Chen ◽  
Da Xu ◽  
Ying Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Mitochondrial Dynamics ◽  
Tumour Progression ◽  
Aerobic Glycolysis ◽  
Mitochondrial Fusion ◽  
Metabolic Reprogramming ◽  
Mesenchymal Transition

Abstract Background Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear. Methods The mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo. Results Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1. Conclusions Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.

scholarly journals Reversible EMT and MET mediate amnion remodeling during pregnancy and labor

2020 ◽  
Vol 13 (618) ◽  
pp. eaay1486 ◽  
Author(s):  
Lauren S. Richardson ◽  
Robert N. Taylor ◽  
Ramkumar Menon
Keyword(s):  
Oxidative Stress ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Membrane Damage ◽  
Mechanical Damage ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Human Amnion ◽  
Mesenchymal Transition

The amnion is remodeled during pregnancy to protect the growing fetus it contains, and it is particularly dynamic just before and during labor. By combining ultrastructural, immunohistochemical, and Western blotting analyses, we found that human and mouse amnion membranes during labor were subject to epithelial-to-mesenchymal transition (EMT), mediated, in part, by the p38 mitogen-activated protein kinase (MAPK) pathway responding to oxidative stress. Primary human amnion epithelial cell cultures established from amnion membranes from nonlaboring, cesarean section deliveries exhibited EMT after exposure to oxidative stress, and the pregnancy maintenance hormone progesterone (P4) reversed this process. Oxidative stress or transforming growth factor–β (TGF-β) stimulated EMT in a manner that depended on TGF-β–activated kinase 1 binding protein 1 (TAB1) and p38 MAPK. P4 stimulated the reverse transition, MET, in primary human amnion mesenchymal cells (AMCs) through progesterone receptor membrane component 2 (PGRMC2) and c-MYC. Our results indicate that amnion membrane cells dynamically transition between epithelial and mesenchymal states to maintain amnion integrity and repair membrane damage, as well as in response to inflammation and mechanical damage to protect the fetus until parturition. An irreversible EMT and the accumulation of AMCs characterize the amnion membranes at parturition.

scholarly journals Suppressors of a Saccharomyces cerevisiae pkc1 mutation identify alleles of the phosphatase gene PTC1 and of a novel gene encoding a putative basic leucine zipper protein.

Genetics ◽  
1995 ◽  
Vol 141 (4) ◽  
pp. 1275-1285 ◽  
Author(s):  
K N Huang ◽  
L S Symington
Keyword(s):  
Protein Kinase ◽  
Leucine Zipper ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Growth Defect ◽  
Temperature Sensitive ◽  
Gene Encoding ◽  
Basic Leucine Zipper ◽  
Mapk Cascades ◽  
Synthetically Lethal

Abstract The PKC1 gene product, protein kinase C, regulates a mitogen-activated protein kinase (MAPK) cascade, which is implicated in cell wall metabolism. Previously, we identified the pkc1-4 allele in a screen for mutants with increased rates of recombination, indicating that PKC1 may also regulate DNA metabolism. The pkc1-4 allele also conferred a temperature-sensitive (ts) growth defect. Extragenic suppressors were isolated that suppress both the ts and hyperrecombination phenotypes conferred by the pkc1-4 mutation. Eight of these suppressors for into two complementation groups, designated KCS1 and KCS2. KCS1 was cloned and found to encode a novel protein with homology to the basic leucine zipper family of transcription factors. KCS2 is allelic with PTC1, a previously identified type 2C serine/threonine protein phosphatase. Although mutation of either KCS1 or PTC1 causes little apparent phenotype, the kcs1 delta ptc1 delta double mutant fails to grow at 30 degrees. Furthermore, the ptc1 deletion mutation is synthetically lethal in combination with a mutation in MPK1, which encodes a MAPK homologue proposed to act in the PKC1 pathway. Because PTC1 was initially isolated as a component of the Hog1p MAPK pathway, it appears that these two MAPK cascades share a common regulatory feature.

scholarly journals Anti-Cancer Effects of Glaucarubinone in the Hepatocellular Carcinoma Cell Line Huh7 via Regulation of the Epithelial-To-Mesenchymal Transition-Associated Transcription Factor Twist1

2021 ◽  
Vol 22 (4) ◽  
pp. 1700
Author(s):  
Jihye Seo ◽  
Jain Ha ◽  
Eunjeong Kang ◽  
Haelim Yoon ◽  
Sewoong Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Wound Healing ◽  
Transcription Factor ◽  
Cell Migration ◽  
Cell Line ◽  
Intracellular Signaling ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Huh7 Cells ◽  
Anti Cancer

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a leading cause of cancer-related deaths. As HCC has a high mortality rate and its incidence is increasing worldwide, understanding and treating HCC are crucial for resolving major public health concerns. In the present study, wound healing screening assays were performed using natural product libraries to identify natural chemicals that can inhibit cancer cell migration. Glaucarubinone (GCB) showed a high potential for inhibiting cell migration. The anti-cancer effects of GCB were evaluated using the HCC cell line, Huh7. GCB showed anti-cancer effects, as verified by wound healing, cell migration, invasion, colony formation, and three-dimensional spheroid invasion assays. In addition, cells treated with GCB showed suppressed matrix metalloproteinase activities. Immunoblotting analyses of intracellular signaling pathways revealed that GCB regulated the levels of Twist1, a crucial transcription factor associated with epithelial-to-mesenchymal transition, and mitogen-activated protein kinase. The invasive ability of cancer cells was found to be decreased by the regulation of Twist1 protein levels. Furthermore, GCB downregulated phosphorylation of extracellular signal-regulated kinase. These results indicate that GCB exhibits anti-metastatic properties in Huh7 cells, suggesting that it could be used to treat HCC.

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