Role of COUP‑TFII in cardiovascular diseases and colorectal cancer: Insights into the molecular mechanisms and clinical relevance (Review)

Abstract

Chicken ovalbumin upstream promoter‑transcription factor II (COUP‑TFII), also known as nuclear receptor subfamily 2 group F member 2, is an orphan nuclear receptor that controls various biological processes, including development, angiogenesis, metabolism and tissue homeostasis. Structurally, COUP‑TFII comprises a DNA‑binding domain and a ligand‑binding domain, facilitating its interaction with various signaling pathways, and thereby exerting diverse biological effects. Alterations of the expression or transcriptional activity of COUP‑TFII are associated with various diseases, including cardiovascular diseases (CVDs) and different types of cancer such as colorectal cancer (CRC). In the context of CVDs, COUP‑TFII serves a key role in the development and function of the vascular system. Dysregulation of COUP‑TFII leads to aberrant angiogenesis and vascular remodeling, contributing to the pathogenesis of various CVDs. In CRC, COUP‑TFII acts as either a tumor suppressor or a tumor promoter, depending on the cellular context. The present review explores the structure and regulatory mechanisms of COUP‑TFII, its functions and molecular mechanisms in CVDs and CRC, and its emerging role in linking these diseases, offering insights into potential treatments and future research directions.

Keywords: COUP‑TFII; CRC; CVD.

Figure 1.

Structure and transcriptional regulatory mechanism of COUP-TFII. (A) Schematic structure of the human COUP-TFII protein. The numbers represent the positions of amino acids. (B) Transcriptional regulatory mechanism of COUP-TFII. COUP-TFII binds to the 5′-AGGTCA-3′ motif or palindromic sequences with various spacings (DR site), either directly (homodimer) or indirectly, through heterodimer formation with other proteins (such as RXR) to regulate downstream target gene expression. COUP-TFII can also bind to Sp1 sites via interaction with Sp1 to cooperatively activate gene expression. COUP-TFII, chicken ovalbumin upstream promoter-transcription factor II; RXR, retinoid X receptor; Sp1, specificity protein 1; TSS1, transcription start site 1; DBD, DNA-binding domain; LBD, ligand-binding domain; AF, activation function; DR, direct repeat.

Figure 2.

Schematic illustration of the molecular mechanisms by which COUP-TFII functions as a common regulator in both CVDs and CRC. Although CVDs and CRC are distinct disease entities, they share common pathophysiological features. In particular, chronic inflammation, oxidative stress, angiogenesis and metabolic dysregulation by COUP-TFII may serve roles in the pathogenesis of both conditions. COUP-TFII, chicken ovalbumin upstream promoter-transcription factor II; EC, endothelial cell; EndMT, endothelial-to-mesenchymal transition; ETC, electron transport chain; Ang-1, angiopoietin-1; EMT, epithelial-to-mesenchymal transition; CVD, cardiovascular disease; CRC, colorectal cancer; PAH, pulmonary arterial hypertension.