The interplay between ATF2 and NEAT1 contributes to lung adenocarcinoma progression

Abstract Background Activating transcription factor 2 (ATF2), a member of the activator protein 1 (AP-1) transcription factor family, has been shown to be involved in the pathobiology of numerous cancers. However, the biological role and mechanism of ATF2 in lung adenocarcinoma (LUAD) remains to be elucidated. Methods The expression of ATF2, NEAT1 and miR-26a-5p in LUAD tissues and cell lines was detected by qRT-PCR and western blotting. The interaction between ATF2, NEAT1, and miR-26a-5p was validated by chromatin immunoprecipitation, luciferase reporter assay and RNA immunoprecipitation. Cell proliferation, invasion and tumorigenesis of LUAD cells were analyzed by using CCK8, transwell invasion assay and xenograft tumor model. Results We confirmed that ATF2 expression was increased in LUAD tissues compared with normal adjacent lung tissues. Functional experiments showed that ATF2 positively regulated cell proliferation and invasion in LUAD cells. Moreover, we identified that NEAT1 expression was increased in LUAD tissues and positively correlated with ATF2 expression. Mechanistically, ATF2 could bind to the promoter of NEAT1 to promote its transcription. Rescue experiments showed that ATF2 exerted its oncogenic function in LUAD, at least, partly through NEAT1 upregulation. In turn, NEAT1 could positively regulate ATF2 expression and form a positive feedback loop in LUAD cells. Furthermore, we demonstrated that NEAT1 positively regulated ATF2 expression via sponging miR-26a-5p. Conclusion ATF2 and NEAT1 form a positive feedback loop mediated by miR-26a-5p and coordinately contribute to LUAD progression.

Download Full-text

A Positive Feedback Loop Between Gastric Cancer Cells and Tumor-associated Macrophage Induces Malignancy Progression

10.21203/rs.3.rs-1186986/v1 ◽

2022 ◽

Author(s):

Haiyan Piao ◽

Lingfeng Fu ◽

Yang Liu ◽

Yue Wang ◽

Xiangyu Meng ◽

...

Keyword(s):

Gastric Cancer ◽

Transcription Factor ◽

Cancer Cells ◽

Positive Feedback ◽

Feedback Loop ◽

Nuclear Factor Kappa B ◽

Luciferase Reporter ◽

Nuclear Factor ◽

Positive Feedback Loop ◽

Nuclear Factor Kappa

Abstract Background: Hypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood.Methods: Hypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of CXCL8 in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites.The corresponding functions were verified in the complementation test and in vivo animal experiment.Results: Our results revealed that Hypoxia triggered macrophage secreted C-X-C Motif Chemokine Ligand 8 (CXCL8), which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages through the Nuclear Factor kappa B (NF-κB) pathway-dependent mechanism and continued to increase the expression and secretion of CXCL8 through the transcription factor Nuclear Factor Kappa B Subunit 1 (NFKB1, p50). It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient's pessimistic outcome.Conclusion: Our work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome.

Download Full-text

MicroRNA-3613-5p Promotes Lung Adenocarcinoma Cell Proliferation through a RELA and AKT/MAPK Positive Feedback Loop

Molecular Therapy — Nucleic Acids ◽

10.1016/j.omtn.2020.09.024 ◽

2020 ◽

Vol 22 ◽

pp. 572-583

Author(s):

Tao He ◽

Hongyou Shen ◽

Shuangmiao Wang ◽

Yanfang Wang ◽

Zhiwei He ◽

...

Keyword(s):

Cell Proliferation ◽

Lung Adenocarcinoma ◽

Positive Feedback ◽

Feedback Loop ◽

Positive Feedback Loop ◽

Adenocarcinoma Cell

Download Full-text

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Blood ◽

10.1182/blood-2014-05-578575 ◽

2015 ◽

Vol 125 (20) ◽

pp. 3118-3127 ◽

Cited By ~ 36

Author(s):

Rebecca L. Boddicker ◽

N. Sertac Kip ◽

Xiaoming Xing ◽

Yu Zeng ◽

Zhi-Zhang Yang ◽

...

Keyword(s):

Cell Proliferation ◽

Transcription Factor ◽

Positive Feedback ◽

Promoter Activity ◽

Feedback Loop ◽

Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Positive Feedback Loop ◽

Key Points ◽

Oncogenic Transcription Factor

Key Points The NF-κB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells. A positive feedback loop involving CD30, NF-κB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-κB inhibitors.

Download Full-text

LncRNA PVT1 Promotes Bladder Cancer Progression by Forming a Positive Feedback Loop With STAT5B

10.21203/rs.3.rs-883550/v1 ◽

2021 ◽

Author(s):

Zhuo Li ◽

Jian Liu ◽

Huifeng Fu ◽

Yuanwei Li ◽

Qaing Lu ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Progression ◽

Positive Feedback ◽

Feedback Loop ◽

Bioinformatic Analysis ◽

Luciferase Reporter ◽

Positive Feedback Loop ◽

Rna Immunoprecipitation ◽

Transcriptional Effect

Abstract Background: Plasmacytoma Variant Translocation 1 (LncRNA PVT1) and signal transducer and activator of transcription 5B (STAT5B) have been reported to play important roles in various cancers, but their interaction in bladder cancer (BC) remains unclear. Purpose: In this study, we aimed to explore the interaction between lncRNA PVT1 and STAT5B in BC tumorigenesis. Methods: The association of the expression of the lncRNA PVT1 and STAT5B to the prognosis of patient with BC was evaluated via bioinformatic analysis. Loss- and gain-of-function assays were performed to determine the biological functions of lncRNA PVT1 and STAT5B in BC cells. Quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence were used to detect lncRNA PVT1 and STAT5B expression. Fluorescence in situ hybridization, RNA pull-down and RNA immunoprecipitation assays were conducted to determine the regulatory effect of lncRNA PVT1 on STAT5B. The transcriptional effect of STAT5B on lncRNA PVT1 gene was determined using luciferase reporter assay, chromatin immunoprecipitation and DNA-affinity precipitation assays.Results: We found that lncRNA PVT1 and STAT5B enhance the expression of each other and promote the malignant phenotypes in BC, including cell viability and invasion. lncRNA PVT1 stabilizes STAT5B by decreasing ubiquitination, enhances STAT5B phosphorylation, and promotes the translocation to the nucleus of STAT5B to trigger further carcinogenesis activities. In the nucleus, STAT5B activates the transcription of lncRNA PVT1 by binding directly to its promoter region, leading to a positive feedback.Conclusions: We first identified the lncRNA PVT1/STAT5B positive feedback loop for bladder carcinogenesis, which may provide new molecular targets for interventions of BC.

Download Full-text

CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01814-5 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Jin-Chun Qi ◽

Zhan Yang ◽

Tao Lin ◽

Long Ma ◽

Ya-Xuan Wang ◽

...

Keyword(s):

Cell Proliferation ◽

Transcriptional Activation ◽

Positive Feedback ◽

Feedback Loop ◽

Biological Effects ◽

Therapeutic Benefit ◽

Loss Of Function ◽

Positive Feedback Loop

Abstract Background Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa. Methods The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo. Results Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation. Conclusions These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.

Download Full-text

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.

Download Full-text

P53/miR-34a/SIRT1 Positive Feedback Loop regulates cell proliferation and promotes cell apoptosis in the termination stage of liver regeneration.

10.21203/rs.3.rs-108116/v2 ◽

2021 ◽

Author(s):

Junhua Gong ◽

Minghua Cong ◽

Hao Wu ◽

Menghao Wang ◽

He Bai ◽

...

Keyword(s):

Cell Proliferation ◽

Liver Regeneration ◽

Positive Feedback ◽

Cell Apoptosis ◽

Feedback Loop ◽

Late Phase ◽

Liver Weight ◽

Positive Feedback Loop ◽

And Function ◽

Shed Light

Abstract Background The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury or cancer resection. In our study, we found that the P53/miR-34a/SIRT1 positive feedback loop has a remarkable negative regulatory effect, which is related to the termination of liver regeneration. Here, we described how P53/miR-34a/SIRT1 positive feedback loop controls liver regeneration and its possible relationship with liver cancer.Method We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) knock-downing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids. Results We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. Mice from the Ade-P53 group showed smaller livers and higher levels of serum ALT and AST than control mice. While knock-down of miR-34a abolished P53/miR-34a/SIRT1 positive feedback loop during LR. Mice from anti-miR-34a group showed larger livers and lower levels of PCNA-positive cells than control mice. T-β-MCA increased gradually during LR and peaked at 7 days after PH. T-β-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. Conclusion The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings shed light on the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients.

Download Full-text