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A novel long non‑coding RNA regulates the integrin, ITGA2 in breast cancer

journal contribution
posted on 2023-05-21, 06:01 authored by Tristan VerhoeffTristan Verhoeff, Adele HollowayAdele Holloway, Joanne DickinsonJoanne Dickinson

Purpose

ITGA2 encodes the integrin, α2 which mediates metastatic progression, and is a predictor of poor prognosis and chemoresistance in breast cancer. Decreased ITGA2 promoter methylation is implicated as a driver of increased gene expression in aggressive prostate and pancreatic tumours, however the contribution of altered methylation to ITGA2 expression changes in breast tumours has not been examined.

Methods

ITGA2 gene methylation and gene expression was examined in publicly available breast cancer datasets, and ITGA2 promoter methylation was mapped by targeted bisulphite sequencing analysis in breast tumour cell lines. The expression of a putative regulatory long noncoding RNA (lncRNA) was examined by qPCR and its’ functionality was investigated using gene knockdown (antisense oligonucleotides) and over expression in breast cancer cell lines.

Results

In breast tumours and breast cancer cell lines the ITGA2 promoter is largely unmethylated, with gene expression variable in tumour subtypes, irrespective of promoter methylation. A novel lncRNA (AC025180.1;ENSG00000249899), named herein I2ALR, was identified at the ITGA2 gene locus, and was variably expressed in breast tumours and breast cancer cell subtypes. I2LAR knockdown resulted in upregulation of ITGA2 gene expression, whilst over-expression of I2ALR resulted in downregulation of ITGA2 mRNA. Further, examination of two downstream targets of ITGA2 associated with breast tumor stemness and metastasis (CCND1 and ACLY), revealed concomitant gene expression changes in response to I2ALR modulation.

Conclusion

I2ALR represents a novel regulatory molecule targeting ITGA2 expression in breast tumours; a finding of significant and topical interest to the development of therapeutics targeting this integrin.

History

Publication title

Breast Cancer Research and Treatment

Volume

192

Pagination

89-100

ISSN

0167-6806

Department/School

Menzies Institute for Medical Research

Publisher

Kluwer Academic Publ

Place of publication

Van Godewijckstraat 30, Dordrecht, Netherlands, 3311 Gz

Rights statement

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Repository Status

  • Restricted

Socio-economic Objectives

Diagnosis of human diseases and conditions; Treatment of human diseases and conditions

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