The role of collagen-binding α1- and α2-integrins in prostate cancer

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Leena Palotie hall

Topic of the dissertation

The role of collagen-binding α1- and α2-integrins in prostate cancer

Doctoral candidate

MSc Sara Cruz

Faculty and unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, Disease Networks

Subject of study

Molecular and Cellular Biology

Opponent

Professor Jorma Palvimo, University of Eastern Finland

Custos

Professor Aki Manninen, University of Oulu

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The role of collagen-binding α1- and α2-integrins in prostate cancer

Prostate cancer (PCa) is the second most diagnosed cancer in men worldwide. The extracellular matrix (ECM) regulates prostate cancer (PCa) progression. Integrins are the major receptors for cell adhesion to the ECM and they are known to modulate proliferation and invasion of malignant cells.
In the current study, we performed a meta-analysis with combined data from nine PCa cohorts and show that simultaneous loss of α1- and α2-integrin expression via deep deletion of neighboring ITGA1 and ITGA2 genes associates with higher PCa recurrence rate and poor prognosis. Moreover, in vitro models showed that the dual loss of integrin α1 and α2 in benign prostate epithelial cells (RWPE1) modulated their tumorigenic potential by enhancing invasiveness via activation of Epithelial-to-Mesenchymal Transition (EMT). EMT was driven by enhanced secretion and activation of TGFβ by the α1/α2-double-negative cells. In vivo metastasis experiments showed that α1/α2-deficient cells could induce micro-metastases in the lungs of immunocompromised mice.
Moreover, we identified Tef-1 encoded by TEA Domain Transcription Factor 1 (TEAD1) gene, as a regulator of ITGA1 and ITGA2 expression. Tef-1 ChIP-qPCR analysis confirmed multiple functional TEAD1-binding sites in the ITGA1/ITGA2 genomic locus. Ablation of TEAD1 in PCa cells led to downregulation of α1- and α2-integrins and resulted in similar functional traits as was seen for α1/α2-deprived cells suggesting that the loss of α1/α2-integrin expression significantly contributes to tumorigenic properties of TEAD1-deficient PCa cells. Taken together, the current study shows that PCa progression is correlated with reduced α1-and α2-integrin levels and implicate Tef-1 as one of the key regulators of their expression. The α1-integrin/α2-integrin/Tef-1-signaling axis could potentially be used as a novel prognostic biomarker for prostate cancer.
Last updated: 1.3.2023