scholarly journals KLF2 inhibits TGF-β-mediated cancer cell motility in hepatocellular carcinoma

2020 ◽  
Vol 52 (5) ◽  
pp. 485-494 ◽  
Author(s):  
Yining Li ◽  
Shuo Tu ◽  
Yi Zeng ◽  
Cheng Zhang ◽  
Tian Deng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Motility ◽  
Cancer Cell ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Negative Feedback Loop ◽  
Liver Malignancy ◽  
Cancer Cell Motility

Abstract Feedback regulation plays a pivotal role in determining the intensity and duration of TGF-β signaling and subsequently affecting the pathophysiological roles of TGF-β, including those in liver malignancy. KLF2, a member of the Krüppel-like factor (KLF) family transcription factors, has been implicated in impeding hepatocellular carcinoma (HCC) development. However, the underlying molecular mechanisms are not fully understood. In the present study, we found that TGF-β stimulates the expression of KLF2 gene in several HCC cell lines. KLF2 protein is able to inhibit TGF-β/Smad signaling in HCC cells as assessed by luciferase reporter assay. Further studies indicated that KLF2 inhibits the transcriptional activity of Smad2/3 and Smad4 and ameliorates TGF-β-induced target gene expression, therefore creating a novel negative feedback loop in TGF-β signaling. Functionally, stably expression of KLF2 in HCCLM3 cells attenuated TGF-β-induced cancer cell motility in wound-healing and transwell assays by interfering with TGF-β-mediated upregulation of MMP2. Together, our results revealed that KLF2 protein has a tumor-suppressive function in HCC through a negative feedback loop over TGF-β signaling.

scholarly journals A GYS2/p53 Negative Feedback Loop Restricts Tumor Growth in HBV-Related Hepatocellular Carcinoma

2018 ◽  
Vol 79 (3) ◽  
pp. 534-545 ◽  
Author(s):  
Shi-Lu Chen ◽  
Chris Zhiyi Zhang ◽  
Li-Li Liu ◽  
Shi-Xun Lu ◽  
Ying-Hua Pan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop

scholarly journals MiR-29a Inhibits Glioma Tumorigenesis through a Negative Feedback Loop of TRAF4/Akt Signaling

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Yongjie Liu ◽  
Naiquan Duan ◽  
Shibo Duan
Keyword(s):  
Cell Proliferation ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Akt Signaling ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Negative Feedback Loop ◽  
Expression Correlation ◽  
Qrt Pcr

Background. MiR-29a is known as a repressor of human cancer. However, its relevance in glioma proliferation and invasion remains largely unknown. In this study, we aimed to investigate the function and mechanism of miR-29a in glioma tumorigenesis.Methods. The expression of miR-29a was determined by using qRT-PCR. CCK-8, wound healing, and transwell invasion assays were carried out to analyze the effects of miR-29a in glioblastoma cells. qRT-PCR, luciferase reporter, and western blot experiments were done to validate the targeting of TRAF4/Akt pathway by miR-29a. The expression correlation between levels of TRAF4 and miR-29a was analyzed. Regulation of miR-29a expression by enhanced/reduced TRAF4/Akt expression was finally confirmed by qRT-PCR.Results. MiR-29a was decreased in the glioma tissues, especially in those at higher grades. Following its mimic transfection, we validated that miR-29a inhibited cell proliferation, migration, and invasion. Consistently, miR-29a inhibition induced the opposite effects on cell proliferation, migration, and invasion. We confirmed TRAF4 as a direct target of miR-29a, which might mediate the Akt pathway activation. We showed a significantly negative expression correlation between TRAF4 and miR-29a in normal and glioma tissues. Finally we observed an upregulation of miR-29a in TRAF4/Akt activated cells.Conclusion. MiR-29a is critical tumor suppressor for glioma tumorigenesis by forming a negative feedback loop of TRAF4/Akt signaling and represents a potent therapeutic candidate for treating gliomas.

scholarly journals A Negative Feedback Loop in Ultraviolet A-Induced Senescence in Human Dermal Fibroblasts Formed by SPCA1 and MAPK

2021 ◽  
Vol 8 ◽  
Author(s):  
Hongfu Xie ◽  
Xiao Xiao ◽  
Yuxin Yi ◽  
Mingxing Deng ◽  
Peihui Li ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Secretory Pathway ◽  
Dermal Fibroblasts ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Negative Feedback Loop ◽  
Human Dermal Fibroblasts ◽  
Mapk Activity ◽  
Factor C

Secretory pathway calcium ATPase 1 (SPCA1) is a calcium pump localized specifically to the Golgi. Its effects on UVA-induced senescence have never been examined. In our study, expression of SPCA1 was increased in UVA-irradiated human dermal fibroblasts (HDFs) by activating mitogen-activated protein kinase (MAPK) and its downstream transcription factor, c-jun. Dual-luciferase reporter and chromatin immunoprecipitation assays revealed that c-jun regulated SPCA1 by binding to its promoter. Furthermore, downregulating SPCA1 with siRNA transfection aggravated UVA-induced senescence due to an elevation of intracellular calcium concentrations and a subsequent increase in reactive oxygen species (ROS) and MAPK activity. In contrast, overexpression of SPCA1 reduced calcium overload, consequently lowering the ROS level and suppressing MAPK activation. This alleviated the cellular senescence caused by UVA irradiation. These results indicated that SPCA1 might exert a protective effect on UVA-induced senescence in HDFs via forming a negative feedback loop. Specifically, activation of MAPK/c-jun triggered by UVA transcriptionally upregulated SPCA1. In turn, the increased SPCA1 lowered the intracellular Ca2+ level, probably through pumping Ca2+ into the Golgi, leading to a reduction of ROS, eventually decreasing MAPK activity and diminishing UVA-induced senescence.

scholarly journals A double-negative feedback loop between EZH2 and miR-26a regulates tumor cell growth in hepatocellular carcinoma

2016 ◽  
Vol 48 (3) ◽  
pp. 1195-1204 ◽  
Author(s):  
CHUNBO ZHUANG ◽  
PEI WANG ◽  
DA HUANG ◽  
LUMING XU ◽  
XIAOBEI WANG ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Tumor Cell ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Double Negative ◽  
Tumor Cell Growth

scholarly journals Expression of the gene for Dec2, a basic helix–loop–helix transcription factor, is regulated by a molecular clock system

2004 ◽  
Vol 382 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Hidenori HAMAGUCHI ◽  
Katsumi FUJIMOTO ◽  
Takeshi KAWAMOTO ◽  
Mitsuhide NOSHIRO ◽  
Koji MAEMURA ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Regulatory Protein ◽  
Circadian Oscillation ◽  
Negative Feedback Loop ◽  
Mrna Levels ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
E Boxes

Dec2, a member of the basic helix–loop–helix superfamily, is a recently confirmed regulatory protein for the clockwork system. Transcripts of Dec2, as well as those of its related gene Dec1, exhibit a striking circadian oscillation in the suprachiasmatic nucleus, and Dec2 inhibits transcription from the Per1 promoter induced by Clock/Bmal1 [Honma, Kawamoto, Takagi, Fujimoto, Sato, Noshiro, Kato and Honma (2002) Nature (London) 419, 841–844]. It is known that mammalian circadian rhythms are controlled by molecular clockwork systems based on negative-feedback loop(s), but the molecular mechanisms for the circadian regulation of Dec2 gene expression have not been clarified. We show here that transcription of the Dec2 gene is regulated by several clock molecules and a negative-feedback loop. Luciferase and gel retardation assays showed that expression of Dec2 was negatively regulated by binding of Dec2 or Dec1 to two CACGTG E-boxes in the Dec2 promoter. Forced expression of Clock/Bmal1 and Clock/Bmal2 markedly increased Dec2 mRNA levels, and up-regulated the transcription of the Dec2 gene through the CACGTG E-boxes. Like Dec, Cry and Per also suppressed Clock/Bmal-induced transcription from the Dec2 promoter. Moreover, the circadian expression of Dec2 transcripts was abolished in the kidney of Clock/Clock mutant mice. These findings suggest that the Clock/Bmal heterodimer enhances Dec2 transcription via the CACGTG E-boxes, whereas the induced transcription is suppressed by Dec2, which therefore must contribute to its own rhythmic expression. In addition, Cry and Per may also modulate Dec2 transcription.

scholarly journals A Direct Negative Feedback Loop of miR-4721/FOXA1/Nanog Promotes Nasopharyngeal Cell Stem Cell Enrichment and Metastasis 

2021 ◽  
Author(s):  
Mengyang Zhao ◽  
Zibo Tang ◽  
Yijun Wang ◽  
Jiaojiao Ding ◽  
Ying Guo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Side Population ◽  
Nasopharyngeal Cancer ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Negative Feedback Loop ◽  
Linkage Mechanism

Abstract Objective: The recurrence and metastasis of nasopharyngeal cancer (NPC) may be mainly attributed to the persistence of cancer stem cells (CSCs); however, the linkage mechanism has yet to be fully elucidated. Methods: The levels of miR-4721, FOXA1, and Nanog expression in NPC were detected by in situ hybridization and immunohistochemistry. In vivo and in vitro metastasis assays confirmed miR-4721 promotes cell migration and invasion. Tumor spheroid formation assay, side population (SP) assay, and ALDEFLUOR assay verified miR-4721 regulates cancer stem cell-like properties. Luciferase reporter assay showed that miR-4721 directly regulates FOXA1 and FOXA1 effects the promoter activity of miR-4721 and Nanog. Chromatin immunoprecipitation (ChIP) analysis and electrophoresis mobility shift assay (EMSA) revealed that FOXA1 combined the promoter region of human miR-4721 and Nanog and the possible mechanism was also analyzed.Results: In this study, a new mechanism of NPC tumorigenesis related to miR-4721 was verified. We found that miR-4721, FOXA1 and Nanog control their expressions through a negative feedback loop and then activate the downstream regulator of stem cell signaling to promote the enrichment and metastasis of NPC stem cells. Conclusion: These findings elucidate that the feedback loop of miR-4721/FOXA1/Nanog can regulate stemness and metastasis in NPC and may provide an experimental theoretical basis for metastasis and treatment resistance in NPC.

scholarly journals A direct negative feedback loop of miR-4721/FOXA1/Nanog promotes nasopharyngeal cell stem cell enrichment and metastasis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mengyang Zhao ◽  
Zibo Tang ◽  
Yijun Wang ◽  
Jiaojiao Ding ◽  
Ying Guo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Side Population ◽  
Nasopharyngeal Cancer ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Negative Feedback Loop ◽  
Linkage Mechanism

Abstract Objective The recurrence and metastasis of nasopharyngeal cancer (NPC) may be mainly attributed to the persistence of cancer stem cells (CSCs); however, the linkage mechanism has yet to be fully elucidated. Methods The levels of miR-4721, FOXA1, and Nanog expression in NPC were detected by in situ hybridization and immunohistochemistry. In vivo and in vitro metastasis assays confirmed miR-4721 promotes cell migration and invasion. Tumor spheroid formation assay, side population (SP) assay, and ALDEFLUOR assay verified miR-4721 regulates cancer stem cell-like properties. Luciferase reporter assay showed that miR-4721 directly regulates FOXA1 and FOXA1 effects the promoter activity of miR-4721 and Nanog. Chromatin immunoprecipitation (ChIP) analysis and electrophoresis mobility shift assay (EMSA) revealed that FOXA1 combined the promoter region of human miR-4721 and Nanog and the possible mechanism was also analyzed. Results In this study, a new mechanism of NPC tumorigenesis related to miR-4721 was verified. We found that miR-4721, FOXA1 and Nanog control their expressions through a negative feedback loop and then activate the downstream regulator of stem cell signaling to promote the enrichment and metastasis of NPC stem cells. Conclusion These findings elucidate that the feedback loop of miR-4721/FOXA1/Nanog can regulate stemness and metastasis in NPC and may provide an experimental theoretical basis for metastasis and treatment resistance in NPC.

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