Emerging role of cystic fibrosis transmembrane conductance regulator - an epithelial chloride channel in gastrointestinal cancers

Hou, Yuning; Guan, Xiaoqing; Yang, Zhe; Li, Chunying

doi:10.4251/wjgo.v8.i3.282

Cited by 21 publications

(14 citation statements)

References 76 publications

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“…CFTR is an indispensable ion channel for epithelial function and was recently discovered to participate in tumor progression or suppression depending on the type of tumor [35,36]. While CFTR upregulation has been observed in ovarian, cervical, gastric, and nasopharyngeal cancers, hypermethylation and/or downregulation of CFTR were reported in prostate, breast, colorectal, and bladder cancers, non-small cell lung carcinoma (NSCLC), and hepatocellular carcinoma (HCC) [37].…”

Section: Discussionmentioning

confidence: 99%

“…Further study will be required to identify the underlying mechanisms of CFTR methylation in HNC. Studies have introduced a range of diverse signals for each different tumor and its microenvironment that may underlie the contradictory activity of CFTR depending on the type of cancer, but the underlying mechanisms are yet under investigation [35]. CFTR has nonetheless been associated with a broad array of proteins and the regulation of multiple signaling pathways and biological processes, suggesting current study on CFTR-associated signaling has just begun to scratch the surface [63].…”

Section: Discussionmentioning

confidence: 99%

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Epigenetic Modification of CFTR in Head and Neck Cancer

Shin

Kim

Won

et al. 2020

JCM

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Cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-regulated chloride channel, is critical for secretion and absorption across diverse epithelia. Mutations or absence of CFTR result in pathogeneses, including cancer. While CFTR has been proposed as a tumor suppressing gene in tumors of the intestine, lung, and breast cancers, its effects in head and neck cancer (HNC) have yet to be investigated. This study aimed to define expression patterns and epigenetic modifications of CFTR in HNC. CFTR was expressed in normal but not in HNC cells and tissues. Treatment with 5-aza-2′-deoxycytidine (5-Aza-CdR) was associated with rescued expression of CFTR, whose function was confirmed by patch clamp technique. Further experiments demonstrated that CFTR CpG islands were hypermethylated in cancer cells and tissues and hypomethylated in normal cells and tissue. Our results suggest that CFTR epigenetic modifications are critical in both down-regulation and up-regulation of CFTR expression in HNC and normal cells respectively. We then investigated the impact of CFTR on expressions and functions of cancer-related genes. CFTR silencing was closely associated with changes to other cancer-related genes, suppressing apoptosis while enhancing proliferation, cell motility, and invasion in HNC. Our findings demonstrate that hypermethylation of CFTR CpG islands and CFTR deficiency is closely related to HNC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epigenetic Modification of CFTR in Head and Neck Cancer

Shin

Kim

Won

et al. 2020

JCM

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“…While inflammatory and non-inflammatory mechanisms and their speculated contributions to risk for CRC require serious consideration (Table 5), they fail to fully account for the inherent malignancy risk associated with CFTR mutations alone, particularly with regard to cancers of the digestive organs [49]. In recent years, increasing evidence has arisen that implicates CFTR as one of 77 potential genetic drivers for CRC development [50]; furthermore, loss of expression of CFTR in patients with early-stage CRC has been associated with poorer disease-free outcomes [51].…”

Section: Cystic Fibrosis As a Hereditary Colon Cancer Syndrome?mentioning

confidence: 99%

Cystic Fibrosis & disorders of the large intestine: DIOS, constipation, and colorectal cancer

Abraham

Taylor

2017

Journal of Cystic Fibrosis

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Since 1966 when the Cystic Fibrosis Foundation Patient Registry (CFFPR) was founded, clinicians have witnessed significant advances in both the quality and quantity of life for patients living with Cystic Fibrosis (CF). As patients with CF live longer and fuller lives, increasing encumbrances from gastrointestinal manifestations of CF will be observed. This article serves to discuss "below the diaphragm" concerns involving the large intestine (Distal Intestinal Obstruction Syndrome, Constipation, and Colorectal Cancer). Avenues for development and implementation of clinical care protocols, particularly regarding proactive management of known associated conditions and cancer screening, will continue to be refined in the coming years. It falls to the multidisciplinary CF care team to be actively engaged in addressing these concerns effectively as priority shifts from relative acuity (typically related to early nutrition and lung function) to the travails of longevity as the CF population continues to age.

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“…The role of inflammation in CF gastrointestinal manifestations, such as malabsorption and poor nutritional status are being increasingly recognized [ 10 , 11 , 22 ]. In addition, individuals with CF are reported to be at much greater risk for inflammatory bowel disease [ 2 , 5 ] and subsequent gastrointestinal cancer (reviewed in [ 16 ] and [ 10 ]), both of which are associated with GI inflammation. We have shown previously in mouse models by conditional expression of CFTR that inflammation and goblet cell hyperplasia in the small intestines is due to CFTR's absence from epithelial cells [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Inactivation of CFTR by CRISPR/Cas9 alters transcriptional regulation of inflammatory pathways and other networks

Hao

Roesch

Perez

et al. 2020

Journal of Cystic Fibrosis

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a b s t r a c tBackground: Individuals with cystic fibrosis (CF) experience elevated inflammation in multiple organs, but whether this reflects an inherent feature of CF cells or is a consequence of a pro-inflammatory environment is not clear. Method: Using CRISPR/Cas9-mediated mutagenesis of CFTR, 17 subclonal cell lines were generated from Caco-2 cells. Clonal lines with functional CFTR (CFTR + ) were compared to those without (CFTR − ) to directly address the role of CFTR in inflammatory gene regulation. Results: All lines maintained CFTR mRNA production and formation of tight junctions. CFTR + lines displayed short circuit currents in response to forskolin, while the CFTR − lines did not. Baseline expression of cytokines IL6 and CXCL8 (IL8) was not different between the lines regardless of CFTR genotype. All lines responded to TNF α and IL1 β by increasing IL6 and CXCL8 mRNA levels, but the CFTR − lines produced more CXCL8 mRNA than the CFTR + lines. Transcriptomes of 6 CFTR − and 6 CFTR + lines, before and after stimulation by TNF α, were compared for differential expression as a function of CFTR genotype. While some genes appeared to be differentially expressed simply because of CFTR's absence, others required stimulation for differences to be apparent. Conclusion: Together, these data suggest cells respond to CFTR's absence by modulating transcriptional networks, some of which are only apparent when cells are exposed to different environmental contexts, such as inflammation. With regards to inflammation, these data suggest a model in which CFTR's absence leads to a poised, pro-inflammatory state of cells that is only revealed by stimulation.

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Emerging role of cystic fibrosis transmembrane conductance regulator - an epithelial chloride channel in gastrointestinal cancers

Cited by 21 publications

References 76 publications

Epigenetic Modification of CFTR in Head and Neck Cancer

Epigenetic Modification of CFTR in Head and Neck Cancer

Cystic Fibrosis & disorders of the large intestine: DIOS, constipation, and colorectal cancer

Inactivation of CFTR by CRISPR/Cas9 alters transcriptional regulation of inflammatory pathways and other networks

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