The relationship between cancer risk and cystic fibrosis: the role of CFTR in cell growth and cancer development

Abstract

Cystic fibrosis (CF) is a life-limiting genetic disease that affects multiple organ systems. It is caused by a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which results in the absence or damage of a relevant protein. If left untreated, it causes death in early childhood. The advent of more efficacious treatments has resulted in a notable increase in the life expectancy of CF patients. This has, in turn, led to an elevated risk of developing specific types of cancer. This review commences with an examination of CF from the standpoint of its etiology and therapeutic modalities. Subsequently, it presents a list of epidemiological studies that suggest an altered predisposition to certain cancers. A heightened risk is well documented, particularly in relation to the gastrointestinal tract. The following section addresses the role of CFTR in view of its potential involvement in the progression of various types of cancer. Several studies have indicated that the levels of the CFTR protein are reduced in many tumors and that this reduction is associated with the progression of the tumors. These decreased expressions are known to occur in the gastrointestinal tract, lungs, bladder, and/or prostate cancer. Conversely, ovarian, stomach, and cervical cancer are connected with its higher expression. The final section of the review focuses on the molecular mechanism of action of the CFTR protein in signaling pathways that affect cell proliferation and the process of carcinogenesis. This section attempts to explain the increased predisposition to cancer observed in patients with CF.

Fig. 1. Chemical structures of approved modulators. A) Potentiators B) correctors.

Fig. 2. The impact of the cftr protein on the β-catenin signaling pathway in kidney epithelial cells (A) and intestinal non-epithelial (C) cells and epithelial cells (B) is illustrated. In kidney epithelial cells (A), the interaction of cftr with Dvl-2 has been demonstrated to result in the activation of the destruction complex and the subsequent degradation of β-catenin. In non-epithelial cells (B), the interaction of CFTR protein with phosphoprotein phosphatase results in its deactivation. consequently, the destruction complex is inactivated through the interaction with phosphorylated LRP, which allows β-catenin to be transported into the nucleus. Furthermore, CFTR has been shown to inhibit DPR1, which promotes the ubiquitination of Dvl2. This, in turn, may inhibit the destruction complex. In intestinal epithelial cells (C), a reduction in the functionality of the cftr protein consequently leads to an increase in intracellular pH, which stabilises the interaction between the wnt receptor and Dvl-2 and thus inhibits the destruction complex.

Fig. 3. The impact of CFTR on NF-κB is manifesting in two distinct ways. Firstly, CFTR interacts with β-catenin in small intestine or esophagus, stabilising it and thereby inhibiting the NF-κB pathway. In the absence or damage of CFTR protein, there is degradation of β-catenin and translocation of NF-κB into the nucleus (A). Secondly, the cftr protein interacts with TRADD, resulting in its subsequent degradation. Absent this interaction, TRADD activates the NF-κB pathway (B).