Emerging role of transcription factor-microRNA-target gene feed-forward loops in cancer

Wu, Qian; Hua, Qi; Zhao, Qiu; He, Xingxing

doi:10.3892/br.2015.477

Cited by 26 publications

(24 citation statements)

References 68 publications

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“…There are two input transcription factors, one of which regulates the other and both regulate a target gene in conjunction. 31, 32 Elevation of ARNT by transient transfection increased reporter gene expression in normoxia and hypoxia. Noteworthily this effect can be mediated by functional HIF complexes of different composition including HIF-1 α /ARNT heterodimers.…”

Section: Discussionmentioning

confidence: 99%

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A HIF-1α-driven feed-forward loop augments HIF signalling in Hep3B cells by upregulation of ARNT

Mandl

Mk²,

Depping

2016

Cell Death Dis

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Oxygen-deprived (hypoxic) areas are commonly found within neoplasms caused by excessive cell proliferation. The transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT) is part of the hypoxia-inducible factor (HIF) pathway, which mediates adaptive responses to ensure cellular survival under hypoxic conditions. HIF signalling leads to metabolic alterations, invasion/metastasis and the induction of angiogenesis in addition to radio-chemoresistance of tumour cells. Activation of the HIF pathway is based on the abundance of HIF-α subunits, which are regulated in an oxygen-dependent manner and form transcriptional active complexes with ARNT or ARNT2 (also referred as HIF-1β and HIF-2β, respectively). ARNT is considered to be unaffected by hypoxia but certain cell lines, including Hep3B cells, are capable to elevate this transcription factor in response to oxygen deprivation, which implies an advantage. Therefore, the aim of this study was to elucidate the mechanism of hypoxia-dependent ARNT upregulation and to determine implications on HIF signalling. Gene silencing and overexpression techniques were used to alter the expression pattern of HIF transcription factors under normoxic and hypoxic conditions. qRT-PCR and western blotting were performed to measure gene and protein expression, respectively. HIF activity was determined by reporter gene assays. The results revealed a HIF-1α-dependent mechanism leading to ARNT upregulation in hypoxia. Forced expression of ARNT increased reporter activity under normoxic and hypoxic conditions. In conclusion, these findings indicate a novel feed-forward loop and suggest that ARNT might be a limiting factor. Augmented HIF signalling in terms of elevated target gene expression might be advantageous for tumour cells.

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Section: Discussionmentioning

confidence: 99%

“…FFLs have an important role in human signalling networks and cancer. 29, 30, 31 According to the definition, a FFL is a network motif, which is composed of three elements. There are two input transcription factors, one of which regulates the other and both regulate a target gene in conjunction.…”

Section: Discussionmentioning

confidence: 99%

A HIF-1α-driven feed-forward loop augments HIF signalling in Hep3B cells by upregulation of ARNT

Mandl

Mk²,

Depping

2016

Cell Death Dis

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“…MicroRNAs (miRNAs) are small, non‐protein coding RNA molecules, able to bind to mRNAs, and repress mRNA translation or cause mRNA degradation . MiRNAs may regulate multiple targets, and many genes are targeted by a multitude of miRNAs, creating complex regulatory networks . MiRNAs and TFs both have the ability to act as oncogenes or tumor suppressors depending on different conditions, simultaneously regulating many biological pathways, including those important to cancer development, and progression .…”

Section: Introductionmentioning

confidence: 99%

“…MiRNAs may regulate multiple targets, and many genes are targeted by a multitude of miRNAs, creating complex regulatory networks . MiRNAs and TFs both have the ability to act as oncogenes or tumor suppressors depending on different conditions, simultaneously regulating many biological pathways, including those important to cancer development, and progression . TFs are able to alter miRNA expression as much or more so than somatic changes and epigenetic factors, and while miRNAs may not drastically reduce cellular protein levels, they are known to have a marked influence on cell‐fate determination and contribute to many diseases, including cancer .…”

Section: Introductionmentioning

confidence: 99%

“…MiRNAs and TFs both have the ability to act as oncogenes or tumor suppressors depending on different conditions, simultaneously regulating many biological pathways, including those important to cancer development, and progression . TFs are able to alter miRNA expression as much or more so than somatic changes and epigenetic factors, and while miRNAs may not drastically reduce cellular protein levels, they are known to have a marked influence on cell‐fate determination and contribute to many diseases, including cancer . Additionally, miRNAs are known to interact with TFs, forming feed‐forward, and feedback loops that regulate various processes and diseases …”

Section: Introductionmentioning

confidence: 99%

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Transcription factor‐microRNA associations and their impact on colorectal cancer survival

Mullany

Herrick

Wolff

et al. 2017

Molecular Carcinogenesis

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MicroRNAs (miRNAs) and Transcription Factors (TFs) both influence messenger RNA (mRNA) expression, disrupting biological pathways involved in carcinogenesis and prognosis. As many miRNAs target multiple mRNAs, thus influencing a multitude of biological pathways, deciphering which miRNAs are important for cancer development and survival is difficult. In this study, we (i) determine associations between TF and survival (N = 168 colon cancer cases); (ii) identify miRNAs associated with TFs related to survival; and (iii) determine if factors derived from TF‐specific miRNA principal component analysis (PCA) influence survival. Cox Proportional hazard models were run for each PCA factor to determine Hazard Ratios (HR) and 95% Confidence Intervals (CI) adjusting for age, center, and AJCC stage. Thirty TFs improved survival when differential expression increased; 27 of these were associated significantly with normal colonic mucosa expression of 65 unique miRNAs when an FDR q‐value of <0.05 was applied. Five factors, comprising 21 miRNAs, altered survival in rectal cancer subjects; four of these five factors improved survival and one factor reduced survival. One factor comprising four miRNAs reduced survival in colon cancer subjects. In summary, our data suggest that expression of TFs and their related miRNAs influence survival after diagnosis with colorectal cancer.

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Challenges and Opportunities of Genomic Approaches in Therapeutics Development

Gray

Campbell

2020

Methods in Molecular Biology

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Emerging role of transcription factor-microRNA-target gene feed-forward loops in cancer

Cited by 26 publications

References 68 publications

A HIF-1α-driven feed-forward loop augments HIF signalling in Hep3B cells by upregulation of ARNT

A HIF-1α-driven feed-forward loop augments HIF signalling in Hep3B cells by upregulation of ARNT

Transcription factor‐microRNA associations and their impact on colorectal cancer survival

Challenges and Opportunities of Genomic Approaches in Therapeutics Development

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