Dataset Information

MYC Regulates ?6 Integrin Subunit Expression and Splicing Under Its Pro-Proliferative ITGA6A Form in Colorectal Cancer Cells.

ABSTRACT: The ?6 integrin subunit (ITGA6) pre-mRNA undergoes alternative splicing to form two splicing variants, named ITGA6A and ITGA6B. In primary human colorectal cancer cells, the levels of both ITGA6 and ?4 integrin subunit (ITGB4) subunits of the ?6?4 integrin are increased. We previously found that the upregulation of ITGA6 is a direct consequence of the increase of the pro-proliferative ITGA6A variant. However, the mechanisms that control ITGA6 expression and splicing into the ITGA6A variant over ITGA6B in colorectal cancer cells remain poorly understood. Here, we show that the promoter activity of the ITGA6 gene is regulated by MYC. Pharmacological inhibition of MYC activity with the MYC inhibitor (MYCi) 10058-F4 or knockdown of MYC expression by short hairpin RNA (shRNA) both lead to a decrease in ITGA6 and ITGA6A levels in colorectal cancer cells, while overexpression of MYC enhances ITGA6 promoter activity. We also found that MYC inhibition decreases the epithelial splicing regulatory protein 2 (ESRP2) splicing factor at both the mRNA and protein levels. Chromatin immunoprecipitation revealed that the proximal promoter sequences of ITGA6 and ESRP2 were occupied by MYC and actively transcribed in colorectal cancer cells. Furthermore, expression studies in primary colorectal tumors and corresponding resection margins confirmed that the up-regulation of the ITGA6A subunit can be correlated with the increase in MYC and ESRP2. Taken together, our results demonstrate that the proto-oncogene MYC can regulate the promoter activation and splicing of the ITGA6 integrin gene through ESRP2 to favor the production of the pro-proliferative ITGA6A variant in colorectal cancer cells.

SUBMITTER: Groulx JF

PROVIDER: S-EPMC5836074 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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MYC Regulates α6 Integrin Subunit Expression and Splicing Under Its Pro-Proliferative ITGA6A Form in Colorectal Cancer Cells.

Groulx Jean-François JF Boudjadi Salah S Beaulieu Jean-François JF

Cancers 20180203 2

The α6 integrin subunit (<i>ITGA6</i>) pre-mRNA undergoes alternative splicing to form two splicing variants, named ITGA6A and ITGA6B. In primary human colorectal cancer cells, the levels of both ITGA6 and β4 integrin subunit (ITGB4) subunits of the α6β4 integrin are increased. We previously found that the upregulation of ITGA6 is a direct consequence of the increase of the pro-proliferative ITGA6A variant. However, the mechanisms that control ITGA6 expression and splicing into the ITGA6A varian ...[more]

PMID: 29401653

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Project description:Eosinophilic inflammation is one of the main pathophysiological features in asthma. Two subtypes of eosinophils exist in the lung and systemic circulation: lung-resident eosinophils (rEOS) and inflammatory eosinophils (iEOS). We evaluated the expression of α4β1 and αMβ2 integrins of eosinophil subtypes and their influence on airway smooth muscle (ASM) cell proliferation and viability in asthma. We included 16 severe non-allergic eosinophilic asthma (SNEA) patients, 13 steroid-free, non-severe allergic asthma (AA) patients, and 12 healthy control subjects (HS). For AA patients, a bronchial allergen challenge with Dermatophagoides pteronyssinus was performed. The eosinophil subtypes were distinguished using magnetic bead-labeled antibodies against surface CD62L, and individual combined cell cultures were prepared with ASM cells. The integrins gene expression was analyzed by a quantitative real-time polymerase chain reaction. Proliferation was assessed by the Alamar blue assay, and viability by annexin V and propidium iodide staining. rEOS-like cells were characterized by the relatively higher gene expression of the β1 integrin subunit, whereas iEOS-like cells were characterized by the αM and β2 integrin subunits. The inclusion of either eosinophil subtypes in co-culture significantly increased the proliferation of ASM cells, and the effect of rEOS-like cells was stronger than iEOS-like cells (p < 0.05). Furthermore, rEOS-like cells had a more pronounced effect on reducing ASM cell apoptosis compared to that of iEOS-like cells (p < 0.05). Lastly, the bronchial allergen challenge significantly enhanced only the iEOS-like cells' effect on ASM cell proliferation and viability in AA patients (p < 0.05). These findings highlight the different expression of α4β1 and αMβ2 integrins on distinct eosinophil subtypes in asthma. Therefore, rEOS-like cells have a stronger effect in stimulating ASM cell proliferation and viability; however, contact with specific allergens mainly enhances pro-proliferative iEOS-like cell properties.

Dataset Information

MYC Regulates ?6 Integrin Subunit Expression and Splicing Under Its Pro-Proliferative ITGA6A Form in Colorectal Cancer Cells.

Publications

MYC Regulates α6 Integrin Subunit Expression and Splicing Under Its Pro-Proliferative ITGA6A Form in Colorectal Cancer Cells.

Similar Datasets

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