Distinct mechanisms of regulation of the ITGA6 and ITGB4 genes by RUNX1 in myeloid cells

Phillips, Jessica; Taberlay, Phillippa C.; Woodworth, AM; Hardy, Kristine; Brettingham-Moore, Kate H.; Dickinson, Joanne L.; Holloway, Adele F.

doi:10.1002/jcp.26197

Cited by 11 publications

(13 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The transcription factors, C-MYC and ZKSCAN3 have been reported to directly bind to ITGB4 promoter and regulate ITGB4 transcription in colorectal cancer 11, 27. And the interaction of ITGB4 promoter with some transcription factors in other disease is also reported, such as KLF4 in glioma 21, RUNX1 in myeloid leukemia 22, ZEB1 in prostate cancer 23, TP73 in lung cancer 24, GLI1 in ovarian cancer 25, and JUN in pancreatic cancer 26. Ferraro et al .…”

Section: Discussionmentioning

confidence: 99%

ITGB4 is a novel prognostic factor in colon cancer

Li¹,

Jiang²,

Wang³

et al. 2019

J. Cancer

View full text Add to dashboard Cite

Integrin β4 (ITGB4) has been reported to be involved in carcinomas. Currently, ITGB4 has been characterized in colon cancer, however, its clinical significance is not very clear. In the present study, we utilized the large public datasets from NCBI Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and collected clinical samples in our center to investigate the transcriptional expressions of ITGB4 in colon cancer, and then explored the associations of ITGB4 with clinicopathological features and overall survival. The statistical analyses suggested that ITGB4 mRNA expressions were up-regulated significantly in colon cancer. High ITGB4 expression was observed to be associated with elder onset age, proximal tumor location, and high microsatellite instability (MSH) status. Further, Kaplan-Meier curves and univariate analysis demonstrated high ITGB4 expression was significantly associated with unfavorable overall survival in colon cancer (HR=1.292, 95%CI=1.084-1.540, P=0.004). And significant association was also found after adjusting the confounding factors including age, gender, and stage (adjusted HR=1.254, 95%CI=1.050-1.497, P=0.012). The annotation of ITGB4 co-expressed genes suggested the pathways including cell growth, positive regulation of cell migration, and apoptotic signaling might be involved in the potential mechanisms of ITGB4 in colon cancer development. The molecular regulation mechanism of ITGB4 ectopic expression in colon cancer was also explored and the results indicated that ITGB4 might be up-regulated by the transcription factor FOSL1 (FOS like 1, AP-1 Transcription Factor Subunit) and its promoter hypomethylation. Our results revealed that ITGB4 might be a therapeutic target and prognosis marker for individual therapy of colon cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

ITGB4 is a novel prognostic factor in colon cancer

Li¹,

Jiang²,

Wang³

et al. 2019

J. Cancer

View full text Add to dashboard Cite

show abstract

“…ITGA6 has been shown to be regulated at multiple layers. Many transcription factors, including RUNX1, HIFs and FOSL1, bind to the ITGA6 promoter and enhance its transcription [27,51,52], while KLF9 represses the transcription of ITGA6 by binding its promoter region [53]. More recently, a study showed that MYC can directly control ITGA6 promoter activity in CRC cells, leading to overexpression of the pro-proliferative ITGA6A splice variant [54].…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer

et al. 2019

View full text Add to dashboard Cite

BackgroundAccumulating evidence has revealed the critical roles of N6-methyladenosine (m6A) modification of mRNA in various cancers. However, the biological function and regulation of m6A in bladder cancer (BC) are not yet fully understood.MethodsWe performed cell phenotype analysis and established in vivo mouse xenograft models to assess the effects of m6A-modified ITGA6 on BC growth and progression. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation and luciferase reporter and mutagenesis assays were used to define the mechanism of m6A-modified ITGA6. Immunohistochemical analysis was performed to assess the correlation between METTL3 and ITGA6 expression in bladder cancer patients.FindingsWe show that the m6A writer METTL3 and eraser ALKBH5 altered cell adhesion by regulating ITGA6 expression in bladder cancer cells. Moreover, upregulation of ITGA6 is correlated with the increase in METTL3 expression in human BC tissues, and higher expression of ITGA6 in patients indicates a lower survival rate. Mechanistically, m6A is highly enriched within the ITGA6 transcripts, and increased m6A methylations of the ITGA6 mRNA 3’UTR promotes the translation of ITGA6 mRNA via binding of the m6A readers YTHDF1 and YTHDF3. Inhibition of ITGA6 results in decreased growth and progression of bladder cancer cells in vitro and in vivo. Furthermore, overexpression of ITGA6 in METTL3-depleted cells partially restores the BC adhesion, migration and invasion phenotypes.InterpretationOur results demonstrate an oncogenic role of m6A-modified ITGA6 and show its regulatory mechanisms in BC development and progression, thus identifying a potential therapeutic target for BC.FundThis work was supported by National Natural Science Foundation of China (81772699, 81472999).

show abstract

“…Integrin β4 subunit expression appears to be mainly regulated at the transcript level but the mechanism of its overexpression in CRC cells is still incompletely understood. There have been a number of studies that have reported specific potential interactions of transcription factors with the ITGB4 promoter since its cloning [27] in a variety of cell types including RUNX1 [28], JUN [29] and KLF4 [30]. In CRC cells, MYC was the first transcription factor identified that promotes ITGB4 transcription [25] but recent studies have found others such as ZKSCAN3 [31] and FOSL1 [32] that need to be considered.…”

Section: Regulation Of Expressionmentioning

confidence: 99%

Integrin α6β4 in Colorectal Cancer: Expression, Regulation, Functional Alterations and Use as a Biomarker

Beaulieu

2019

Cancers

View full text Add to dashboard Cite

Integrin α6β4 is one of the main laminin receptors and is primarily expressed by epithelial cells as an active component of hemidesmosomes. In this article, after a brief summary about integrins in the gut epithelium in general, I review the knowledge and clinical potential of this receptor in human colorectal cancer (CRC) cells. Most CRC cells overexpress both α6 and β4 subunits, in situ in primary tumours as well as in established CRC cell lines. The mechanisms that lead to overexpression have not yet been elucidated but clearly involve specific transcription factors such as MYC. From a functional point of view, one key element affecting CRC cell behaviour is the relocalization of α6β4 to the actin cytoskeleton, favouring a more migratory and anoikis-resistant phenotype. Another major element is its expression under various molecular forms that have the distinct ability to interact with ligands (α6β4 ± ctd) or to promote pro- or anti-proliferative properties (α6Aβ4 vs. α6Bβ4). The integrin α6β4 is thus involved in most steps susceptible to participation with CRC progression. The potential clinical significance of this integrin has begun to be investigated and recent studies have shown that ITGA6 and ITGB4 can be useful biomarkers for CRC early detection in a non-invasive assay and as a prognostic factor, respectively.

show abstract

Distinct mechanisms of regulation of the ITGA6 and ITGB4 genes by RUNX1 in myeloid cells

Cited by 11 publications

References 72 publications

ITGB4 is a novel prognostic factor in colon cancer

ITGB4 is a novel prognostic factor in colon cancer

N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer

Integrin α6β4 in Colorectal Cancer: Expression, Regulation, Functional Alterations and Use as a Biomarker

Contact Info

Product

Resources

About