scholarly journals Melatonin Promotes Heterotopic Ossification Through Regulation of Endothelial-Mesenchymal Transition in Injured Achilles Tendons in Rats

2021 ◽  
Vol 9 ◽  
Author(s):  
Jie Zhang ◽  
Jiajun Tang ◽  
Jie Liu ◽  
Bo Yan ◽  
Bin Yan ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Healing Process ◽  
Marker Gene ◽  
Underlying Mechanism ◽  
Heterotopic Bone ◽  
Mesenchymal Transition ◽  
Gene And Protein Expression ◽  
Endothelial Mesenchymal Transition

Although heterotopic ossification (HO) has been reported to be a common complication of the posttraumatic healing process, the underlying mechanism remains unknown. Endothelial-mesenchymal transition (EndMT) is known to play a role in HO, and our recent study observed that neuroendocrine signals can promote HO by modulating EndMT. Melatonin, a neuroendocrine hormone secreted mainly by the pineal gland, has been documented to perform its function in the skeletal system. This study aimed at describing the expression of melatonin during the formation of HO in rat models of Achilles tendon injury and to further investigate its role in regulating EndMT in HO. Histological staining revealed the expression of melatonin throughout the formation of heterotopic bone in injured Achilles tendons, and the serum melatonin levels were increased after the initial injury. Double immunofluorescence showed that the MT2 melatonin receptor was notably expressed at the sites of injury. Micro-CT showed the enhancement of heterotopic bone volume and calcified areas in rats treated with melatonin. Additionally, our data showed that melatonin induced EndMT in primary rat aortic endothelial cells (RAOECs), which acquired traits including migratory function, invasive function and EndMT and MSC marker gene and protein expression. Furthermore, our data exhibited that melatonin promoted the osteogenic differentiation of RAOECs undergoing EndMT in vitro. Importantly, inhibition of the melatonin-MT2 pathway by using the MT2 selective inhibitor 4-P-PDOT inhibited melatonin-induced EndMT and osteogenesis both in vivo and in vitro. In conclusion, these findings demonstrated that melatonin promoted HO through the regulation of EndMT in injured Achilles tendons in rats, and these findings might provide additional directions for the management of HO.

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 HCK promotes glioblastoma progression by TGFβ signaling

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhenlin Wang ◽  
Chenting Ying ◽  
Anke Zhang ◽  
Houshi Xu ◽  
Yang Jiang ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
B Lymphocyte ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Gene Set Enrichment Analysis ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition

Abstract The hematopoietic cell kinase (HCK), a member of the Src family protein-tyrosine kinases (SFKs), is primarily expressed in cells of the myeloid and B lymphocyte lineages. Nevertheless, the roles of HCK in glioblastoma (GBM) remain to be examined. Thus, we aimed to investigate the effects of HCK on GBM development both in vitro and in vivo, as well as the underlying mechanism. The present study found that HCK was highly expressed in both tumor tissues from patients with GBM and cancer cell lines. HCK enhanced cell viability, proliferation, and migration, and induced cell apoptosis in vitro. Tumor xenografts results also demonstrated that HCK knockdown significantly inhibited tumor growth. Interestingly, gene set enrichment analysis (GSEA) showed HCK was closed associated with epithelial mesenchymal transition (EMT) and TGFβ signaling in GBM. In addition, we also found that HCK accentuates TGFβ-induced EMT, suggesting silencing HCK inhibited EMT through the inactivation of Smad signaling pathway. In conclusion, our findings indicated that HCK is involved in GBM progression via mediating EMT process, and may be served as a promising therapeutic target for GBM.

scholarly journals Arctigenin Suppressed Epithelial-Mesenchymal Transition Through Wnt3a/β-Catenin Pathway in PQ-Induced Pulmonary Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Fei Gao ◽  
Yun Zhang ◽  
Zhizhou Yang ◽  
Mengmeng Wang ◽  
Zhiyi Zhou ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Lung Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Underlying Mechanism ◽  
Alveolar Type ◽  
Mesenchymal Transition

Arctigenin (ATG), a major bioactive substance of Fructus Arctii, counters renal fibrosis; however, whether it protects against paraquat (PQ)-induced lung fibrosis remains unknown. The present study was to determine the effect of ATG on PQ-induced lung fibrosis in a mouse model and the underlying mechanism. Firstly, we found that ATG suppressed PQ-induced pulmonary fibrosis by blocking the epithelial-mesenchymal transition (EMT). ATG reduced the expressions of Vimentin and α-SMA (lung fibrosis markers) induced by PQ and restored the expressions of E-cadherin and Occludin (two epithelial markers) in vivo and in vitro. Besides, the Wnt3a/β-catenin signaling pathway was significantly activated in PQ induced pulmonary fibrosis. Further analysis showed that pretreatment of ATG profoundly abrogated PQ-induced EMT-like phenotypes and behaviors in A549 cells. The Wnt3a/β-catenin signaling pathway was repressed by ATG treatment. The overexpression of Wnt3a could weaken the therapeutic effect of ATG in A549 cells. These findings suggested that ATG could serve as a new therapeutic candidate to inhibit or even reverse EMT-like changes in alveolar type II cells during PQ-induced lung fibrosis, and unraveled that the Wnt3a/β-catenin pathway might be a mechanistic tool for ATG to control pulmonary fibrosis.

scholarly journals TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin

2019 ◽  
Vol 27 (4) ◽  
pp. 1355-1368 ◽  
Author(s):  
Kefei Yuan ◽  
Kunlin Xie ◽  
Tian Lan ◽  
Lin Xu ◽  
Xiangzheng Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Disease Free Survival ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Mesenchymal Transition ◽  
Protein Protein Interaction

Abstract Metastasis is one of the main contributors to the poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism of HCC metastasis remains largely unknown. Here, we showed that TXNDC12, a thioredoxin-like protein, was upregulated in highly metastatic HCC cell lines as well as in portal vein tumor thrombus and lung metastasis tissues of HCC patients. We found that the enforced expression of TXNDC12 promoted metastasis both in vitro and in vivo. Subsequent mechanistic investigations revealed that TXNDC12 promoted metastasis through upregulation of the ZEB1-mediated epithelial–mesenchymal transition (EMT) process. We subsequently showed that TXNDC12 overexpression stimulated the nuclear translocation and activation of β-catenin, a positive transcriptional regulator of ZEB1. Accordingly, we found that TXNDC12 interacted with β-catenin and that the thioredoxin-like domain of TXNDC12 was essential for the interaction between TXNDC12 and β-catenin as well as for TXNDC12-mediated β-catenin activation. Moreover, high levels of TXNDC12 in clinical HCC tissues correlated with elevated nuclear β-catenin levels and predicted worse overall and disease-free survival. In summary, our study demonstrated that TXNDC12 could activate β-catenin via protein–protein interaction and promote ZEB1-mediated EMT and HCC metastasis.

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.

In vitro and in vivo wound healing-promoting activities of β-lapachone

2008 ◽  
Vol 295 (4) ◽  
pp. C931-C943 ◽  
Author(s):  
Hsiu-Ni Kung ◽  
Mei-Jun Yang ◽  
Chi-Fen Chang ◽  
Yat-Pang Chau ◽  
Kuo-Shyan Lu
Keyword(s):  
Wound Healing ◽  
Endothelial Cells ◽  
Healing Process ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Diabetic Patients ◽  
Impaired Wound Healing

Impaired wound healing is a serious problem for diabetic patients. Wound healing is a complex process that requires the cooperation of many cell types, including keratinocytes, fibroblasts, endothelial cells, and macrophages. β-Lapachone, a natural compound extracted from the bark of the lapacho tree ( Tabebuia avellanedae), is well known for its antitumor, antiinflammatory, and antineoplastic effects at different concentrations and conditions, but its effects on wound healing have not been studied. The purpose of the present study was to investigate the effects of β-lapachone on wound healing and its underlying mechanism. In the present study, we demonstrated that a low dose of β-lapachone enhanced the proliferation in several cells, facilitated the migration of mouse 3T3 fibroblasts and human endothelial EAhy926 cells through different MAPK signaling pathways, and accelerated scrape-wound healing in vitro. Application of ointment with or without β-lapachone to a punched wound in normal and diabetic ( db/ db) mice showed that the healing process was faster in β-lapachone-treated animals than in those treated with vehicle only. In addition, β-lapachone induced macrophages to release VEGF and EGF, which are beneficial for growth of many cells. Our results showed that β-lapachone can increase cell proliferation, including keratinocytes, fibroblasts, and endothelial cells, and migration of fibroblasts and endothelial cells and thus accelerate wound healing. Therefore, we suggest that β-lapachone may have potential for therapeutic use for wound healing.

scholarly journals Secreted Frizzled Related Protein 2 Modulates Epithelial–Mesenchymal Transition and Stemness via Wnt/β-Catenin Signaling in Choriocarcinoma

2018 ◽  
Vol 50 (5) ◽  
pp. 1815-1831 ◽  
Author(s):  
Xianling Zeng ◽  
Yafei Zhang ◽  
Huiqiu Xu ◽  
Taohong Zhang ◽  
Yan Xue ◽  
...  
Keyword(s):  
Cell Lines ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Tumor Promoter ◽  
Related Protein ◽  
Mesenchymal Transition ◽  
Jar Cells

Background/Aims: Choriocarcinoma (CC) is a highly aggressive gestational trophoblastic neoplasia; however, the underlying molecular mechanisms of its invasiveness and metastasis remain poorly understood. Human secreted frizzled-related protein 2 (SFRP2) could function as a tumor promoter or suppressor in different tumors, yet the role it plays in CC’s invasion and metastasis is thoroughly unclear. The current study was aimed to explore the function and underlying mechanism of SFRP2 in CC. Methods: The expression of SFRP2 in CC tissues was examined via immunohistochemistry. The methylation level and expression of SFRP2 in CC cell lines, JEG-3 and JAR were examined via bisulfite sequencing PCR (BSP), western blotting and quantitative RT-PCR. The biological role of increasing expressed SFRP2 through its promoter demethylation with 5-Aza-2’-deoxycytidine (5-Aza) was examined by a series of in vitro functional studies. Furthermore, lentivirus transfection technology was adopted to investigate the biological roles of SFRP2 knockdown in JEG-3 and JAR cells in vitro and in vivo. Moreover, its downstream signaling pathway was investigated. Results: SFRP2 was downregulated in CC tissues, and its expression was inversely related to its promoter hypermethylation frequency in JEG-3 and JAR cells. Increased SFRP2 through its promoter demethylation inhibited cell migration, invasion and colony formation in JEG-3 and JAR cells, whereas decreased SFRP2 reversed the epithelial-mesenchymal transition (EMT) process and stemness in JEG-3 and JAR cells both in vitro and vivo. Mechanistically, SFRP2 regulated the EMT and stemness of CC cell lines via canonical Wnt/β-catenin signaling, validated by the usage of a Wnt activator and inhibitor. Conclusion: The current study indicates that downregulated SFRP2 has potent tumor-promotive effects in CC through the modulation of cancer stemness and the EMT phenotype via activation of Wnt/β-catenin signaling in vitro and in vivo.

scholarly journals Lactate Promotes Myoblast Differentiation and Myotube Hypertrophy via a Pathway Involving MyoD In Vitro and Enhances Muscle Regeneration In Vivo

2018 ◽  
Vol 19 (11) ◽  
pp. 3649 ◽  
Author(s):  
Sakuka Tsukamoto ◽  
Ayako Shibasaki ◽  
Ayano Naka ◽  
Hazuki Saito ◽  
Kaoruko Iida
Keyword(s):  
Gene Expression ◽  
Myogenic Differentiation ◽  
Underlying Mechanism ◽  
Myoblast Differentiation ◽  
Dependent Manner ◽  
Gene And Protein Expression ◽  
Myotube Hypertrophy ◽  
Myod Gene

Lactate is a metabolic substrate mainly produced in muscles, especially during exercise. Recently, it was reported that lactate affects myoblast differentiation; however, the obtained results are inconsistent and the in vivo effect of lactate remains unclear. Our study thus aimed to evaluate the effects of lactate on myogenic differentiation and its underlying mechanism. The differentiation of C2C12 murine myogenic cells was accelerated in the presence of lactate and, consequently, myotube hypertrophy was achieved. Gene expression analysis of myogenic regulatory factors showed significantly increased myogenic determination protein (MyoD) gene expression in lactate-treated cells compared with that in untreated ones. Moreover, lactate enhanced gene and protein expression of myosin heavy chain (MHC). In particular, lactate increased gene expression of specific MHC isotypes, MHCIIb and IId/x, in a dose-dependent manner. Using a reporter assay, we showed that lactate increased promoter activity of the MHCIIb gene and that a MyoD binding site in the promoter region was necessary for the lactate-induced increase in activity. Finally, peritoneal injection of lactate in mice resulted in enhanced regeneration and fiber hypertrophy in glycerol-induced regenerating muscles. In conclusion, physiologically high lactate concentrations modulated muscle differentiation by regulating MyoD-associated networks, thereby enhancing MHC expression and myotube hypertrophy in vitro and, potentially, in vivo.

scholarly journals Knockdown of LncRNA-H19 Ameliorates Kidney Fibrosis in Diabetic Mice by Suppressing miR-29a-Mediated EndMT

2020 ◽  
Vol 11 ◽  
Author(s):  
Sen Shi ◽  
Li Song ◽  
Hao Yu ◽  
Songlin Feng ◽  
Jianhua He ◽  
...  
Keyword(s):  
Kidney Diseases ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Non Coding Rnas ◽  
Endothelial Mesenchymal Transition

Diabetic nephropathy is the leading cause of kidney fibrosis. Recently, altered expressed or dysfunction of some long non-coding RNAs (lncRNAs) has been linked to kidney fibrosis; however, the mechanisms of lncRNAs in kidney fibrosis remain unclear. We have shown that the DPP-4 inhibitor linagliptin can inhibit endothelial-mesenchymal transition (EndMT) and ameliorate diabetic kidney fibrosis associated with DPP-4 protein levels via the induction of miR-29. Here, we found that expression of the lncRNA H19 was significantly up-regulated in TGF-β2-induced fibrosis in human dermal microvascular endothelial cells (HMVECs) in vitro, and in kidney fibrosis of streptozotocin-induced diabetic CD-1 mice. We also detected up-regulated H19 expression and down-regulated miR-29a expression in the early and advanced mouse models of diabetic kidney fibrosis. H19 knockdown significantly attenuated kidney fibrosis in vitro and in vivo, which was associated with the inhibition of the EndMT-associated gene FSP-1. We also found that the up-regulation of H19 observed in fibrotic kidneys associated with the suppression of miR-29a in diabetic mice. H19, miR-29a, and EndMT contribute to a regulatory network involved in kidney fibrosis, and are associated with regulation of the TGF-β/SMAD3 singling pathway. This study indicates that inhibition of LncRNA H19 represents a novel anti-fibrotic treatment for diabetic kidney diseases.

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