What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer?

Abstract

One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and the increased long-term survival rate of individuals with cystic fibrosis (CF), this is a novel challenge emerging at the forefront of this disease. However, the mechanisms linking dysfunctional CFTR to carcinogenesis have yet to be unravelled. Clues to this challenging open question emerge from key findings in an increasing number of studies showing that CFTR plays a role in fundamental cellular processes such as foetal development, epithelial differentiation/polarization, and regeneration, as well as in epithelial–mesenchymal transition (EMT). Here, we provide state-of-the-art descriptions on the moonlight roles of CFTR in these processes, highlighting how they can contribute to novel therapeutic strategies. However, such roles are still largely unknown, so we need rapid progress in the elucidation of the underlying mechanisms to find the answers and thus tailor the most appropriate therapeutic approaches.

KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway

“…Besides its function as a chloride/bicarbonate channel, CFTR has also been implicated in epithelial differentiation and regeneration [ 3 ], being, however, unclear how this occurs mechanistically. Here, we investigated whether the Krüppel-like factors (KLFs), a family of evolutionary conserved zinc finger transcription factors that regulate a variety of biological processes including proliferation, differentiation, and apoptosis [ 6 ], have an impact on CFTR expression and function.…”

“…We speculate that this may be due to the fact that CF cells display a partial EMT/cancer-like phenotype [ 3 ], which leads to altered signaling pathways, namely those linking KLF4 to CFTR. Indeed, KLF4 regulates gene expression through transcriptional activation or repression via either DNA binding or protein-to-protein interactions, and thus the outcome of KLF4-mediated regulation largely depends on the cellular context, e.g., the presence of oncogenic drivers among other factors [ 29 ].…”

“…The F508del mutation impairs CFTR protein folding and plasma membrane (PM) trafficking, causing CFTR retention at the level of the endoplasmic reticulum (ER), with only a minimal fraction reaching the PM [ 2 ] with decreased function and stability. The association of CFTR to epithelial differentiation has been described in several studies (reviewed recently in [ 3 ]).…”

Impact of KLF4 on Cell Proliferation and Epithelial Differentiation in the Context of Cystic Fibrosis

“…CFTR has been shown to play a role in fundamental cellular processes related to differentiation, such as fetal development [4], epithelial differentiation/polarization [5], regeneration [6], and epithelial-mesenchymal transition (EMT) [7]. The multiple associations of CFTR and epithelial differentiation/EMT have been recently reviewed and reflect the idea that CF cells display a more cancer-like (vs. non-CF cells) phenotype due to the occurrence of a partial EMT [8], considered as a first stage into carcinogenesis [9]. Moreover, KLF4 has been linked to tumor metastasis through the regulation of EMT in several forms of human cancers [10].…”

“…KLF4 transcriptional profiling reveals its key role in cell-cycle regulation and epithelial differentiation [21]. Therefore, here we aim at understanding the role of KLF4 on cell proliferation, wound healing, EMT, and differentiation in the context of CF since these processes are disrupted in CF [6,8]. It has been demonstrated that KLF4 may exert very distinctive effects, depending on the cell context, i.e., its effects are dependent on the cell expression profile.…”