CFTR is a tumor suppressor gene in murine and human intestinal cancer

Abstract

CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid–base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated ApcMin mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc+/+ mice aged to ~ 1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc+/+ Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival.

ABC gene expression profiles have clinical importance and possibly form a new hallmark of cancer

“…Defective CFTR is widely known to cause cystic fibrosis; however, there is accumu lating evidence that suggests an unexpected role of CFTR in various cancers, especially in gastroenterological can cers, such as pancreatic and colon cancers. [33][34][35] From the abovementioned previously published ABC studies, Park et al 26 and Hlavata et al 16 included ABCC7 in the ABC expression profiles with clinical consequences. Furthermore, each of the ABCA3, A8, A12, and C8 genes was present between the most deregulated ABC genes in five general ABC profiles.…”

CF airway smooth muscle transcriptome reveals a role for PYK2

“…Interestingly, many of the proposed upstream regulators, such as phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and phosphodiesterase signaling, have been implicated in airway smooth muscle function and disease (18,19). Others, such as WNT and CREB, have been studied in CF (20)(21)(22).…”

A low DNA methylation epigenotype in lung squamous cell carcinoma and its association with idiopathic pulmonary fibrosis and poorer prognosis

“…Genes targeted by polycomb repressor complex in embryonic stem cells were shown by black bars ( top right ; ref. ). Bottom , source of tissue and IPF status.…”

“…DLEC1 , CFTR , MT1M , CRIP3 and ALDH7A1 were established as HME‐specific markers, of which DLEC1 , CFTR and MT1M were previously reported as tumor suppressor genes . Hypermethylation of CRIP3 and ALDH7A1 was not described previously for lung cancer, while hypermethylation of CRIP3 has been reported in prostate cancers, although the physiological significance of this epigenetic lesion is unknown.…”