scholarly journals Super-Enhancer-Associated TMEM44-AS1 Aggravated Glioma Progression by Forming a Positive Feedback Loop With Myc

2021 ◽  
Author(s):  
Erbao Bian ◽  
Xueran Chen ◽  
Li Cheng ◽  
Meng Cheng ◽  
Zhigang Chen ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Colony Formation ◽  
Feedback Loop ◽  
Xenograft Model ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Positive Feedback Loop ◽  
Mouse Xenograft ◽  
Super Enhancer ◽  
Mouse Xenograft Model

Abstract BackgroundLong non-coding RNAs (lncRNAs) have been considered as one type of gene expression regulator for cancer development, but it is not clear how these are regulated. This study aimed to identify a specific lncRNA that promotes the glioma progression.MethodsRNA sequencing (RNA-seq) and quantitative real-time PCR were performed to screen differentially expressed genes. CCK-8, transwell migration, invasion assays and a mouse xenograft model were performed to determine the functions of TMEM44-AS1. Co-IP, ChIP, Dual-luciferase reporter assays, RNA pulldown and RNA immunoprecipitation assays were performed to study the molecular mechanism of TMEM44-AS1 and the downstream target.ResultsWe identified a novel lncRNA TMEM44-AS1, which was aberrantly expressed in glioma tissues, and that increased TMEM44-AS1 expression was correlated with malignant progression and poor survival for patients with glioma. Expression of TMEM44-AS1 increased the proliferation, colony formation, migration, and invasion of glioma cells. Knockdown of TMEM44-AS1 in glioma cells reduced cell proliferation, colony formation, migration and invasion, and tumor growth in a nude mouse xenograft model. Mechanistically, TMEM44-AS1 is directly bound to the SerpinB3, and sequentially activated Myc signaling; Myc transcriptionally induced TMEM44-AS1 and directly bound to the promoter and super-enhancer of TMEM44-AS1, thus forming a positive feedback loop with TMEM44-AS. Further studies demonstrated that Myc interacts with MED1 regulates the super-enhancer of TMEM44-AS1. More importantly, a novel small-molecule Myc inhibitor, Myci975, alleviated TMEM44-AS1-promoted the growth of glioma cells. Finally, TMEM44-AS1 activated IL-6 signaling by recruiting EGR1 to the promoter of IL-6 in glioma cells. ConclusionsOur study implicates a crucial role of the TMEM44-AS1-Myc axis in glioma progression and provides a possible anti-glioma therapeutic agent.

scholarly journals Transcriptional Regulation of GDF15 by EGR1 Promotes Head and Neck Cancer Progression through a Positive Feedback Loop

2021 ◽  
Vol 22 (20) ◽  
pp. 11151
Author(s):  
Yanli Jin ◽  
Seung-Nam Jung ◽  
Mi Ae Lim ◽  
Chan Oh ◽  
Yudan Piao ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Transforming Growth Factor ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Positive Feedback Loop ◽  
Mouse Xenograft Model

Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGF-β) superfamily, has been reported to be overexpressed in different kinds of cancer types. However, the function and mechanism of GDF15 in head and neck cancer (HNC) remains unclear. The Cancer Genome Atlas (TCGA) data show that the expression of GDF15 is significantly associated with tumor AJCC stage, lymph vascular invasion and tumor grade in HNC. In this study, we confirmed that knockdown of GDF15 attenuated: cell proliferation, migration and invasion via regulation of EMT through a canonical pathway; SMAD2/3 and noncanonical pathways; PI3K/AKT and MEK/ERK in HNC cell lines. Furthermore, we found that early growth response 1 (EGR1) was a transcription factor of GDF15. Interestingly, we also demonstrated that GDF15 could regulate the expression of EGR1, which meant a positive feedback loop occurred between these two factors. Moreover, combined inhibition of both GDF15 and EGR1 in a HNC mouse xenograft model showed significantly decreased tumor volume compared to inhibition of EGR1 or GDF15 alone. Our study showed that the GDF15–EGR1 signaling axis may be a good target in HNC patients.

scholarly journals THAP9-AS1/miR-133b/SOX4 positive feedback loop facilitates the progression of esophageal squamous cell carcinoma

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Jiwei Cheng ◽  
Haibo Ma ◽  
Ming Yan ◽  
Wenqun Xing
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Malignant Tumors ◽  
Migration And Invasion ◽  
Positive Feedback Loop

AbstractEsophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in the digestive system with a high incidence and poor prognosis. Long non-coding RNAs (LncRNA) have been reported to be closely associated with the occurrence and development of various human cancers. Data from GSE89102 shows an increase of THAP9-AS1 expression in ESCC. However, its functions and mechanisms underlying ESCC progression remain to be investigated. In this study, we found that THAP9-AS1 was overexpressed in ESCC tissues and cells. High THAP9-AS1 expression was positively correlated with tumor size, TNM stage, lymph node metastasis, and worse prognosis. Functionally, depletion of THAP9-AS1 suppressed cell proliferation, migration, and invasion, while enhanced apoptosis in vitro. Consistently, knockdown of THAP9-AS1 inhibited xenograft tumor growth in vivo. Mechanistically, THAP9-AS1 could serve as a competing endogenous RNA (ceRNA) for miR-133b, resulting in the upregulation of SOX4. Reciprocally, SOX4 bound to the promoter region of THAP9-AS1 to activate its transcription. Moreover, the anti-tumor property induced by THAP9-AS1 knockdown was significantly impaired due to miR-133b downregulation or SOX4 overexpression. Taken together, our study reveals a positive feedback loop of THAP9-AS1/miR-133b/SOX4 to facilitate ESCC progression, providing a potential molecular target to fight against ESCC.

scholarly journals An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis

2021 ◽  
Author(s):  
Changhao Chen ◽  
Yuting Li ◽  
Yuming Luo ◽  
Hanhao Zheng ◽  
Yan Lin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Positive Feedback ◽  
Noncoding Rna ◽  
Feedback Loop ◽  
Xenograft Model ◽  
Positive Feedback Loop ◽  
Reciprocal Interactions ◽  
Orthotopic Xenograft Model ◽  
Bladder Cancer Cells

Abstract Cancer-associated fibroblasts (CAFs) are essential etiologic actors in promoting tumor progression via extensive reciprocal interactions with cancer cells. Yet, the biological role and regulatory mechanism of CAFs phenotype underlying lymph node (LN) metastasis of bladder cancer (BCa) remain unclear. Here, we report that BCa cell-secreted extracellular vesicles (EVs) played an important role in the CAF-enriched microenvironment, which correlated with BCa lymphangiogenesis and LN metastasis. RNA sequencing identified an EV-associated long noncoding RNA, LINC00665, which acted as a crucial mediator of CAF infiltration in BCa. LINC00665 mediated EV release from BCa cells to endow fibroblasts with the CAF phenotype, which reciprocally induced LINC00665 upregulation to form a RAB27B-HGF-c-Myc positive feedback loop, facilitating BCa lymphangiogenesis and LN metastasis. Importantly, we demonstrate that Cabozantinib significantly suppressed LINC00665-mediated BCa LN metastasis in an orthotopic xenograft model. Our study highlights a molecular mechanism by which LINC00665 induces a RAB27B-HGF-c-Myc positive feedback loop between cancer cells and fibroblasts to sustain BCa LN metastasis, and represents LINC00665 as a potential therapeutic target in BCa LN metastasis.

The positive feedback loop of RNASEH1-AS1/has-miR-218-5p/NET1 mediated by POU2F1 contributes to the development and progression of human lung squamous carcinoma

2020 ◽  
Author(s):  
Jing-hao Jia ◽  
Jing Wang ◽  
Jia-rui Yu ◽  
Peng Gao ◽  
Yan-kun Liu ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Human Lung ◽  
Squamous Carcinoma ◽  
Carcinoma Cells ◽  
Human Lung Cancer ◽  
Migration And Invasion ◽  
Positive Feedback Loop ◽  
Squamous Carcinoma Cells ◽  
Lung Squamous Carcinoma

Abstract Background In molecular level, competing endogenous RNAs (ceRNAs) regulates other RNA transcripts through competing for shared microRNAs (miRNA). miRNA negatively regulate gene expression at the levels of mRNAs stability and translation suppression. Methods We tested the mRNA level of miR-218-5p and RNASEH1-AS1 in clinical lung squamous cell carcinoma tissues by qRT-PCR. In the exploring of the role of miR-218-5p and RNASEH1-AS1 in the malignant phenotype of NCI-H520 cells, colony formation and MTT assay were used to test the cell viability and proliferation capability, trans-well invasion and wound healing assay were performed to examine the cell migration and invasion. ChIP assay was conducted to confirm the direct interact of POU2F1 and RNASEH1-AS1 promoter. Results In this investigation, we found that LncRNA RNASEH1-AS1 is up-regulated in human lung cancer, and serves as a miRNA sponge for hsa-miR-218-5p in human lung squamous carcinoma cells. lncRNA RNASEH1-AS1 facilitates growth and motility of lung squamous carcinoma cells, while miR-218-5p does the opposite. NET1 and POU2F1 are validated as direct and functional targets of miR-218-5p. The downregulation of miR-218-5p releases the suppression of NET1 and POU2F1. POU2F1 binds directly to the lncRNA-RNASEH1-AS1 promoter and acts as transcription factor to enhance the promoter activity of RNASEH1-AS1. Conclusion Above all, the positive feedback loop of RNASEH1-AS1/ hsa-miR-218-5p/ NET1/ POU2F1 can help us to understand the regulatory mechanism behind genesis and progression of human lung squamous carcinoma, possibly providing new biomarkers for its diagnosis and treatment.

Positive feedback loop of HMGB1 and tumor-associated macrophages plays a key role in osteosarcoma metastasis

2021 ◽  
Author(s):  
Changhe Hou ◽  
Ming Lu ◽  
Zixiong Lei ◽  
Shuangwu Dai ◽  
Wei Chen ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Macrophage Polarization ◽  
Migration And Invasion ◽  
M2 Macrophages ◽  
Osteosarcoma Cells ◽  
Invasion And Metastasis ◽  
Tumor Associated Macrophages ◽  
Positive Feedback Loop ◽  
Hmgb1 Expression

Abstract Background Numerous studies have demonstrated the important roles of tumor-associated macrophages (TAMs) in osteosarcoma metastasis. In osteosarcoma, higher levels of HMGB1 correlate with osteosarcoma progression. However, whether HMGB1 is involved in the polarization of M2 macrophages into M1 macrophages in osteosarcoma still remains largely unknown. Methods HMGB1 and CD206 mRNA expression was measured by qRT-PCR in osteosarcoma tissues and cells. HMGB1 and RAGE protein expression was measured by western blotting. Osteosarcoma migration was measured using a Transwell and wound-healing assay. Osteosarcoma invasion was measured using a Transwell assay. Macrophage subtypes were detected using flow cytometry. Results HMGB1 is aberrantly overexpressed in osteosarcoma, and positively correlates with the TNM III & IV stages, lymph node metastasis, and distant metastasis. Silencing HMGB1 inhibits migration, invasion, and metastasis-related proteins in osteosarcoma cells. Furthermore, the reduced HMGB1 expression in the conditioned media derived from osteosarcoma cells also induces the polarization of M2 TAMs to M1 TAMs. In addition, silencing HMGB1 inhibits the liver and lung metastases of osteosarcoma and reduces the expression of HMGB1, CD163, and CD206 in vivo experiments. HMGB1 regulates macrophage polarization through RAGE. Interestingly, the polarized M2 macrophages could induce osteosarcoma migration and invasion, which in turn results in activation of HMGB1 expression in osteosarcoma cells to form a positive feedback loop. Conclusions HMGB1 and M2 macrophages enhance osteosarcoma migration, invasion, and metastasis capability through positive feedback regulation. These findings reveal the significance of tumor cell and TAM interaction in the metastatic microenvironment.

scholarly journals Overexpression of CXCR7 accelerates tumor growth and metastasis of lung cancer cells

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Huan Liu ◽  
Qian Cheng ◽  
Dong-sheng Xu ◽  
Wen Wang ◽  
Zheng Fang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Human Lung ◽  
Lung Tumor ◽  
Xenograft Model ◽  
Cell Polarization ◽  
Human Lung Cancer ◽  
Migration And Invasion ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Abstract Background Under physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in more than 20 human malignancies, among which lung cancer is the leading cause of cancer-associated deaths worldwide. Thus, the mechanism of CXCR7 in the progression of lung cancer is urgently needed. Methods First, we explored CXCR4 and CXCR7 expression in human lung cancer specimens and cell lines by immunohistochemistry, western blot and flow cytometry. Then, we chose the human lung adenocarcinoma cell line A549 that stably overexpressed CXCR7 through the way of lentivirus-mediated transduction. Next, “wound healing” assay and transwell assay were applied to compare the cell migration and invasion ability, and stripe assay was used to evaluate the cell polarization. Last, our team established a mouse xenograft model of human lung cancer and monitored tumor proliferation and metastasis by firefly luciferase bioluminescence imaging in SCID/Beige mice. Results In clinical lung cancer samples, CXCR7 expression was almost not detected in normal tissue but upregulated in lung tumor tissue, whereas, CXCR4 was highly expressed in both normal and tumor tissues. Furthermore, overexpression of CXCR7 enhanced A549 cell migration and polarization in vitro. Besides, mouse xenograft model of human lung cancer showed that CXCR7 promoted primary lung tumor’s growth and metastasis to the second organ, such as liver or bone marrow in SCID/Beige mice in vivo. Conclusions This study describes the multiple functions of CXCR7 in lung cancer. Thus, these results suggest that CXCR7 may be a malignancy marker and may provide a novel target for anticancer therapy.

scholarly journals Knockdown of NF-E2-related factor 2 inhibits the proliferation and growth of U251MG human glioma cells in a mouse xenograft model

2013 ◽  
Vol 30 (1) ◽  
pp. 157-164 ◽  
Author(s):  
XIANG-JUN JI ◽  
SUI-HUA CHEN ◽  
LIN ZHU ◽  
HAO PAN ◽  
YUAN ZHOU ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Glioma Cells ◽  
Related Factor ◽  
Human Glioma ◽  
Human Glioma Cells ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

scholarly journals A Positive Feedback Loop of lncRNA-RMRP/ZNRF3 axis and Wnt/β-catenin Signaling Regulates Temozolomide Resistance in Glioma

2020 ◽  
Author(s):  
Tie Liu ◽  
Jie Hu ◽  
Bo Han ◽  
Shishan Tan ◽  
Wenqing Jia ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Mrna Stability ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Positive Feedback Loop ◽  
Protein Levels ◽  
Glioma Xenograft ◽  
Rna Immunoprecipitation

Abstract Background: Drug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP was found to be implicated in glioma progression. However, the effects of RMRP on TMZ resistance along with related molecular mechanisms are poor defined in glioma. Methods: RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic patterns were estimated by flow cytometry. The effects of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors were explored in vivo. The relationships among IGF2BP3, RMRP and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation and RNA pull-down assays. Results: RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3 and β-catenin promoted RMRP expression in glioma cells. Conclusion: RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP contributes the better management of cancers.

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