Author Correction: MiR218 Modulates Wnt Signaling in Mouse Cardiac Stem Cells by Promoting Proliferation and Inhibiting Differentiation through a Positive Feedback Loop

AbstractThe leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) is considered to be a stem cell marker in many normal tissues and promotes tissue development, regeneration, and repair. LGR6 is also related to the initiation and progression of some malignant tumors. However, the role of LGR6 in cervical cancer has not been reported. Here, immunohistochemistry and western blotting showed that LGR6 was significantly upregulated in cervical cancer, compared with the normal cervix. By analyzing The Cancer Genome Atlas database, LGR6 was found to be correlated with a poor prognosis of cervical cancer. Then, a small population of LGR6high cells isolated by using the fluorescence-activated cell sorting exhibited enhanced properties of cancer stem cells including self-renewal, differentiation, and tumorigenicity. Moreover, RNA sequencing revealed that LGR6 was correlated with the Wnt signaling pathway and TOP/FOP, reverse transcription-PCR, and western blotting further proved that LGR6 could activate the Wnt/β-catenin signaling pathway. Interestingly, LGR6 upregulated the expression of TCF7L2 by activating the Wnt/β-catenin pathway. Then, TCF7L2 combining with β-catenin in the nucleus enhanced LGR6 transcription by binding the promoter of LGR6, which further activated the Wnt signaling to form a positive feedback loop. Thus, our study demonstrated that LGR6 activated a novel β-catenin/TCF7L2/LGR6-positive feedback loop in LGR6high cervical cancer stem cells (CSCs), which provided a new therapeutic strategy for targeting cervical CSCs to improve the prognosis of cervical cancer patients.

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The Dickkopf1 and FOXM1 positive feedback loop promotes tumor growth in pancreatic and esophageal cancers

Oncogene ◽

10.1038/s41388-021-01860-z ◽

2021 ◽

Author(s):

Hirokazu Kimura ◽

Ryota Sada ◽

Naoki Takada ◽

Akikazu Harada ◽

Yuichiro Doki ◽

...

Keyword(s):

Cell Proliferation ◽

Wnt Signaling ◽

Cancer Cell ◽

Positive Feedback ◽

Feedback Loop ◽

Ductal Adenocarcinoma ◽

Cancer Cell Proliferation ◽

Positive Feedback Loop ◽

Dkk1 Expression ◽

Foxm1 Expression

AbstractDickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5ʹ-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.

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miR-29 Modulates Wnt Signaling in Human Osteoblasts through a Positive Feedback Loop

Journal of Biological Chemistry ◽

10.1074/jbc.m110.116137 ◽

2010 ◽

Vol 285 (33) ◽

pp. 25221-25231 ◽

Cited By ~ 264

Author(s):

Kristina Kapinas ◽

Catherine Kessler ◽

Tinisha Ricks ◽

Gloria Gronowicz ◽

Anne M. Delany

Keyword(s):

Wnt Signaling ◽

Positive Feedback ◽

Feedback Loop ◽

Positive Feedback Loop ◽

Human Osteoblasts

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Survival of hypoxic human mesenchymal stem cells is enhanced by a positive feedback loop involving miR-210 and hypoxia-inducible factor 1

Journal of Veterinary Science ◽

10.4142/jvs.2013.14.1.69 ◽

2013 ◽

Vol 14 (1) ◽

pp. 69 ◽

Cited By ~ 41

Author(s):

Woochul Chang ◽

Chang Youn Lee ◽

Jun-Hee Park ◽

Moon-Seo Park ◽

Lee-So Maeng ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Positive Feedback ◽

Feedback Loop ◽

Hypoxia Inducible Factor ◽

Human Mesenchymal Stem Cells ◽

Positive Feedback Loop ◽

Hypoxia Inducible Factor 1

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Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop

10.21203/rs.3.rs-56902/v1 ◽

2020 ◽

Author(s):

In-Gyu Kim ◽

Jei-Ha Lee ◽

Seo-Yeon Kim ◽

Chang-Kyu Heo ◽

Rae-Kwon Kim ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Transcriptional Activation ◽

Positive Feedback ◽

Feedback Loop ◽

Nuclear Translocation ◽

Positive Feedback Loop ◽

Targeting Therapy ◽

Mesenchymal Transition

Abstract Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; however, practical targeting approaches are limited. Here, we identify testis-specific Y-like protein 5 (TSPYL5) as a CSC-associated factor that promotes stemness and epithelial-to-mesenchymal transition in therapy-resistant non-small cell lung cancer (NSCLC) cells. Aberrantly activated PI3K/AKT pathway in therapy-resistant NSCLC cells promotes TSPYL5 phosphorylation at threonine-120 (pT120), which inhibits ubiquitination and stabilizes TSPYL5. TSPYL5 pT120 also supports SUMOylation, which leads to its nuclear translocation and functions as a transcriptional repressor of PTEN. Nuclear TSPYL5 also activates the transcription of CSC-associated genes, ALDH1 and CD44. Collectively, TSPYL5 pT120 maintains persistent CSC-like characteristics via transcriptional activation of CSC-associated genes and via a positive-feedback loop between the AKT/TSPYL5/PTEN and PTEN/PI3K/AKT signaling pathways. However, inhibition of TSPYL5 pT120 can block aberrant AKT/TSPYL5/PTEN cyclic signaling and cancer stemness. Our study suggests TSPYL5 as a novel target for cancer therapy.

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