scholarly journals Direct reprogramming of adult hepatocytes to generate LGR5+ endodermal progenitor

2020 ◽  
Author(s):  
Diana Chaker ◽  
Christophe Desterke ◽  
Nicolas Moniaux ◽  
Tony Ernault ◽  
Noufissa Oudrhiri ◽  
...  
Keyword(s):  
Bile Duct ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Disease Modeling ◽  
Epithelial Mesenchymal Transition ◽  
Liver Parenchyma ◽  
Mesenchymal Transition

AbstractWe successfully converted hepatocytes isolated from adult mice into expandable and stable leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)-positive endodermal progenitor cells (EndoPCs). This was accomplished in vitro through transient exposure to four transcriptional factors (OCT3/4, SOX2, KLF4, and cMYC) and STAT3 activators. EndoPCs were generated by a process that involved an epithelial-mesenchymal transition (EMT) without the use of any components of the canonical WNT/β-catenin or LGR5/R-spondin signaling pathways. We showed that the proliferation and capacity for self-renewal of EndoPCs in 2D long-term culture were controlled by three interrelated signaling pathways: gp130/JAK/STAT3, LGR5/R-spondin, and WNT/β-catenin. After long-term maintenance in two- and three-dimensional culture systems, EndoPCs were able to differentiate into liver-restricted lineages such as hepatocyte-like cells and bile duct-like structures in vitro and in vivo. After intra-muscular injection, EndoPCs generated macroscopically visible and well-vascularized liver-like tissue, which contained Alb+ liver parenchyma-like structures and substantial, KRT7/KRT19+ bile duct-like cell organizations.ConclusionWe have developed an efficient method for producing LGR5+ adult endodermal stem cells. These cells will be useful for the in vitro study of the molecular mechanisms of liver development and have important potential for therapeutic strategies, including approaches based on bioengineered liver tissue. These cells also open up new avenues for experiments focused on disease modeling, toxicology studies, and regenerative medicine applications.

scholarly journals Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Hongli Li ◽  
Qingjie Mu ◽  
Guoxin Zhang ◽  
Zhixin Shen ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Biological Significance ◽  
Mesenchymal Transition

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

SOX10 induces epithelial–mesenchymal transition and contributes to nasopharyngeal carcinoma progression

2018 ◽  
Vol 96 (3) ◽  
pp. 326-331 ◽  
Author(s):  
Ping He ◽  
Xiaojie Jin
Keyword(s):  
Cell Proliferation ◽  
Nasopharyngeal Carcinoma ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Objective: The aim of this study was to investigate the role of SOX10 in nasopharyngeal carcinoma (NPC) and the underlying molecular mechanisms. Methods: The expression of SOX10 was initially assessed in human NPC tissues and a series of NPC cell lines through quantitative real-time PCR (qRT-PCR) and Western blot. Then, cell proliferation, cycle, migration, and the invasiveness of NPC cells with knockdown of SOX10 were examined by MTT, flow cytometry, and Transwell migration and invasion assays, respectively. Finally, nude mice tumorigenicity experiments were performed to evaluate the effects of SOX10 on NPC growth and metastasis in vivo. Results: SOX10 was significantly increased in NPC tissues and cell lines. In-vitro experiments revealed that loss of SOX10 obviously inhibited cell proliferation, migration, and invasiveness, as well as the epithelial–mesenchymal transition (EMT) process in NPC cells. In-vivo experiments further demonstrated that disrupted SOX10 expression restrained NPC growth and metastasis, especially in lung and liver. Conclusion: Taken together, our data confirmed the role of SOX10 as an oncogene in NPC progression, and revealed that SOX10 may serve as a novel biomarker for diagnosis of NPC, as well as a potential therapeutic target against this disease.

scholarly journals C1orf61 promotes hepatocellular carcinoma metastasis and affects the therapeutic response to sorafenib

2020 ◽  
Author(s):  
You Yu ◽  
Zhimeng Wang ◽  
Zan Huang ◽  
Xianying Tang ◽  
Wenhua Li
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Therapeutic Response ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Molecular Events ◽  
Carcinoma Metastasis ◽  
And Migration

Abstract Background C1orf61 is a specific transcriptional activator that is highly up-regulated during weeks 4–9 of human embryogenesis, the period in which most organs develop. We have previously demonstrated that C1orf61 acts as a tumor activator in human hepatocellular carcinoma (HCC) tumorigenesis and metastasis. However, the underlying molecular mechanisms of tumor initiation and progression in HCC remain obscure. Methods In this study, we demonstrated that the pattern of C1orf61 expression was closely correlated with metastasis in liver cancer cells. Gene expression profiling analysis indicated that C1orf61 regulated diverse genes related to cell growth, migration, invasion and epithelial-mesenchymal transition (EMT). Results Results showed that C1orf61 promotes hepatocellular carcinoma metastasis by inducing cellular EMT in vivo and in vitro. Moreover, C1orf61-induced cellular EMT and migration are involved in the activation of the STAT3 and Akt cascade pathways. We also found that C1orf61 was associated with HBV infection-induced cell migration in HCC. In addition, C1orf61 expression improved the efficacy of the anticancer therapy sorafenib in HCC patients. For the first time, we report a regulatory pathway by which C1orf61 promoted cancer cell metastasis and regulated the therapeutic response to sorafenib. Conclusions These findings increased our understanding of the molecular events that regulate metastasis and treatment in HCC.

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 LncRNA ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of lung adenocarcinoma

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Rong-Hang Hu ◽  
Zi-Teng Zhang ◽  
Hai-Xiang Wei ◽  
Lu Ning ◽  
Jiang-Shan Ai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Mesenchymal Transition

Abstract Background Growing evidence suggests that suppressor of tumorigenicity 7 antisense RNA 1 (ST7-AS1) is an oncogenic long noncoding RNA (lncRNA). However, little is known on its clinical significance, biological functions, or molecular mechanisms in lung adenocarcinoma (LUAD). Methods The expression of ST7-AS1 and miR-181b-5p were examined by qRT-PCR. The correlations between ST7-AS1 level and different clinicopathological features were analysed. In vitro, LUAD cells were examined for cell viability, migration and invasion by MTT, wound healing and Transwell assay, respectively. Epithelial-mesenchymal transition (EMT) biomarkers were detected by Western blot. The regulations between ST7-AS1, miR-181b-5p, and KPNA4 were examined by luciferase assay, RNA immunoprecipitation, RNA pulldown. Both gain- and loss-of-function strategies were used to assess the importance of different signalling molecules in malignant phenotypes of LUAD cells. The in vivo effect was analysed using the xenograft and the experimental metastasis mouse models. Results ST7-AS1 was upregulated in LUAD tissues or cell lines, correlated with tumours of positive lymph node metastasis or higher TNM stages, and associated with shorter overall survival of LUAD patients. ST7-AS1 essentially maintained the viability, migration, invasion, and EMT of LUAD cells. The oncogenic activities of ST7-AS1 were accomplished by sponging miR-181b-5p and releasing the suppression of the latter on KPNA4. In LUAD tissues, ST7-AS1 level positively correlated with that of KPNA4 and negatively with miR-181b-5p level. In vivo, targeting ST7-AS1 significantly inhibited xenograft growth and metastasis. Conclusions ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of LUAD cells. Targeting ST7-AS1 and KPNA4 or up-regulating miR-181b-5p, therefore, may benefit the treatment of LUAD.

scholarly journals miR-186 Suppresses the Progression of Cholangiocarcinoma Cells Through Inhibition of Twist1

2019 ◽  
Vol 27 (9) ◽  
pp. 1061-1068 ◽  
Author(s):  
Ming Zhang ◽  
Baochang Shi ◽  
Kai Zhang
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Formation ◽  
In Vitro Assays ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Cycle Arrest

Deregulation of miR-186 and Twist1 has been identified to be involved in the progression of multiple cancers. However, the detailed molecular mechanisms underlying miR-186-involved cholangiocarcinoma (CCA) are still unknown. In this study, we found that miR-186 was downregulated in CCA tissues and cell lines, and negatively correlated with the expression of Twist1 protein. In vitro assays demonstrated that miR-186 mimics repressed cell proliferation, in vivo tumor formation, and caused cell cycle arrest. miR-186 mimics also inhibited the migration and invasion of CCLP1 and SG-231 cells. Mechanistically, the 3′-untranslated region (3′-UTR) of Twist1 mRNA is a direct target of miR-186. Further, miR-186 inhibited the expressions of Twist1, N-cadherin, vimentin, and matrix metallopeptidase 9 (MMP9) proteins, whereas it increased the expression of E-cadherin in CCLP1 and SG-231 cells. Silencing of Twist1 expression enhanced the inhibitory effects of miR-186 on the proliferation, migration, and invasion of CCLP1 and SG-231 cells. In conclusion, miR-186 inhibited cell proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) through targeting Twist1 in human CCA. Thus, miR-186/Twist1 axis may benefit the development of therapies for CCA.

scholarly journals Activation of Vimentin Is Critical to Promote a Metastatic Potential of Cholangiocarcinoma Cells

2018 ◽  
Vol 26 (4) ◽  
pp. 605-616 ◽  
Author(s):  
Waraporn Saentaweesuk ◽  
Norie Araki ◽  
Kulthida Vaeteewoottacharn ◽  
Atit Silsirivanit ◽  
Wunchana Seubwai ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Cancer ◽  
Metastatic Tumor ◽  
Migration And Invasion ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Tail Vein

Cholangiocarcinoma (CCA) is a highly metastatic tumor, and the majority of patients with CCA have a short survival time because there are no available effective treatments. Hence, a better understanding regarding CCA metastasis may provide an opportunity to improve the strategies for treatment. A comparison study between the highly metastatic cells and their parental cells is an approach to uncover the molecular mechanisms underlying the metastatic process. In the present study, a lung metastatic CCA cell line, KKU-214L5, was established by the in vivo selection of the tail vein-injected mouse model. KKU-214L5 cells possessed mesenchymal spindle-like morphology with higher migration and invasion abilities in vitro than the parental cells (KKU-214). KKU-214L5 also exhibited extremely aggressive lung colonization in the tail vein-injected metastatic model. Epithelial‐mesenchymal transition (EMT) was clearly observed in KKU-214L5 cells. Significant downregulation of epithelial markers (ZO-1 and claudin-1), with unique upregulation of E-cadherin and mesenchymal markers (vimentin, β-catenin, and slug), was observed in KKU-214L5. Increasing MMP-2 and MMP-9 activities and CD147 expression reflected the high invasion activity in KKU-214L5 cells. Suppression of vimentin using siRNA significantly decreased the migration and invasion capabilities of KKU-214L5 to almost the basal levels of the parental cells without any change on the expression levels of other EMT markers and the activities of MMPs. These results suggest that vimentin activation is essential to potentiate the metastatic characters of CCA cells, and suppression of vimentin expression could be a potential strategy to improve the treatment of CCA, a highly metastatic cancer.

Prognostic value of Mortalin correlates with roles in epithelial–mesenchymal transition and angiogenesis in lung adenocarcinoma

2021 ◽  
Author(s):  
Ziqi Meng ◽  
Rui Zhang ◽  
Xuwei Wu ◽  
Meihua Zhang ◽  
Songnan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Phenotype ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
In Vivo Experiments ◽  
And Migration

Abstract Mortalin is involved in the malignant phenotype of many cancers. However, the specific molecular mechanisms involving Mortalin in lung adenocarcinoma remain unclear. In this study, we showed that both Mortalin mRNA and protein are overexpressed in lung adenocarcinoma. In addition, Mortalin overexpression was positively-correlated with poor overall survival. In vitro experiments showed that Mortalin silencing inhibited the proliferation, colony formation, and migration abilities of A549 and H1299 cells. Mortalin promotes EMT progression, angiogenesis, and tumor progression by activating the Wnt/β-catenin signaling pathway In vivo experiments further confirmed that Mortalin promoted malignant progression of lung adenocarcinoma. Taken together, our data suggest that Mortalin represents an attractive prognostic marker and therapeutic target in lung adenocarcinoma patients.

scholarly journals KIAA1217 Promotes Epithelial-Mesenchymal Transition and Hepatocellular Carcinoma Metastasis by Interacting with and Activating STAT3

2021 ◽  
Vol 23 (1) ◽  
pp. 104
Author(s):  
Yanhong Wang ◽  
Na Li ◽  
Yanping Zheng ◽  
Anqing Wang ◽  
Chunlei Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Adaptor Protein ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Macromolecular Protein ◽  
Carcinoma Metastasis

The survival and prognosis of hepatocellular carcinoma (HCC) are poor, mainly due to metastasis. Therefore, insights into the molecular mechanisms underlying HCC invasion and metastasis are urgently needed to develop a more effective antimetastatic therapy. Here, we report that KIAA1217, a functionally unknown macromolecular protein, plays a crucial role in HCC metastasis. KIAA1217 expression was frequently upregulated in HCC cell lines and tissues, and high KIAA1217 expression was closely associated with shorter survival of patients with HCC. Overexpression and knockdown experiments revealed that KIAA1217 significantly promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) in vitro. Consistently, HCC cells overexpressing KIAA1217 exhibited markedly enhanced lung metastasis in vivo. Mechanistically, KIAA1217 enhanced EMT and accordingly promoted HCC metastasis by interacting with and activating JAK1/2 and STAT3. Interestingly, KIAA1217-activated p-STAT3 was retained in the cytoplasm instead of translocating into the nucleus, where p-STAT3 subsequently activated the Notch and Wnt/β-catenin pathways to facilitate EMT induction and HCC metastasis. Collectively, KIAA1217 may function as an adaptor protein or scaffold protein in the cytoplasm and coordinate multiple pathways to promote EMT-induced HCC metastasis, indicating its potential as a therapeutic target for curbing HCC metastasis.

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