Role of ion channels in gastrointestinal cancer

Table 2 Chloride channels

Gene name (s)	Cancer	Role	Functional activity
CLCA1/Chloride channel accessory 1	Colorectal	Tumor suppressor	Expression down-regulated; down regulated in primary tumors and CRC cells; acts via inhibition of Wnt/β-catenin signaling; there is one report that high expression associated with non-response to chemo radiation therapy in rectal cancer[4,211-213]
	Pancreatic	Tumor suppressor	Expression down-regulated; low expression associated with poor patient prognosis[214]
CLCA2/Chloride channel accessory 2	Colorectal	Tumor suppressor	Expression down-regulated[4,212]
CLIC1/Chloride intracellular channel 1	Colorectal	Oncogene	Expression up-regulated; overexpressed by MS analysis of human CRCs; expressed on nuclear and plasma membranes[216-219]
	Pancreatic	Oncogene	Expression up-regulated; over expression associated with poor patient prognosis, tumor grade and size; overexpression in 69% of tumors; knockdown of PC cells reduced cell proliferation and anchorage-independent growth on soft agar, and cell migration[65,217-219]
	Gastric	Oncogene	Expression up-regulated; overexpression associated with poor patient prognosis; upregulated in 68% of gastric cancer, correlates with lymph node metastasis, lymphatic invasion, perineural invasion and pathological staging; induced proliferation, apoptosis, invasion and migration of GC cells in culture; promotes progression by regulating MAPK/AKT pathway; regulates migration and invasion via ROS-mediated P38 MAPK pathway[65,220-223]
	Hepatocellular	Oncogene	Expression up-regulated[65,224]
	Gall bladder	Oncogene	Expression up-regulated; knockdown in GBC cells reduced proliferation, migration and invasion of cells; associated with metastasis, based on proteomic analysis[284-286]
CLIC3/Chloride intracellular channel 3	Pancreatic	Oncogene	Expression up-regulated; CLIC3 and Rab25 collaborate to promote integrin recycling from late endosomes/lysosomes to drive PaC progression[65,227]
CLIC4/Chloride intracellular 4	Colorectal	Oncogene	Expression up-regulated; associated with poor 5-yr patient survival; CLIC4 regulated by TP53 and TNF-alpha and is a direct response gene for C-MYC and TP53[218,230]
	Pancreatic	Oncogene	Expression up-regulated; associated with tumor grade, lymph node metastasis, tumor invasion and poor patient survival; expressed in mitochondria and regulates pH and cell volume[231]
CFTR/Cystic fibrosis transmembrane conductance regulator	Colorectal	Tumor suppressor	Expression down-regulated; CF patients at significant risk of early aggressive colorectal tumors based on colonoscopy screening and other clinical findings; CFTR down-regulated in sporadic CRC, associated with worse prognosis; CFTR was a CIS gene in four sleeping beauty transposon mutagenesis screens in mice, both CRC and GC; > 60% conditional CFTR KO mice develop intestinal tumors and crossing to ApcMin model causes an enhanced tumor phenotype and the development of adenocarcinomas; enhanced organoid outgrowth; CFTR deficiency causes an invasive phenotype in CRC cells; loss of CFTR causes upregulation of NF-κB; CFTR modulates Wnt/β-catenin signaling and stem cell proliferation; enhanced risk of CRC in CF patients following lung trans-plants[33-34,36,93,103,119,123-126,128,243-247]
	Pancreatic	Tumor suppressor	Expression down-regulated; increased risk of PC in carriers of 4 specific CFTR mutations[101,118,122,123,197,198,248-250]
	Small intestine	Tumor suppressor	Expression down-regulated[122-123,243]
	Gastric	Oncogene	Expression up-regulated in late stage[101,191,192]
	Esophageal	Tumor suppressor	Expression down-regulated; silencing of CFTR caused upregulation of NFKB; CFTR inhibitors caused enhanced growth of EC cell mouse xenografts; enhanced risk of EC in CF patients following lung transplants; CFTR heterozygous carriers at enhanced risk of EC[195,196,243,251]
	Hepatocellular	Tumor suppressor	Expression down-regulated by promoter hypermethylation[89,252]
ANO1/anoctamin1/TMEM16A/DOG1	Colorectal	Oncogene	Expression up-regulated; negatively regulated by miR-144 miR-9, and miR-132; associated with EMT and poor patient prognosis[232-236]
	Pancreatic	Oncogene	Expression up-regulated; important for cell migration[234,237]
	Esophageal	Oncogene	Expression up-regulated; biomarker for EC progression[234,238]
	Gastric	Oncogene	Expression up-regulated[234,239]
	GI stromal (GIST)	Oncogene	Expression up-regulated; used as a diagnostic biomarker; associated with negative regulation of IGFBP5[240-242]

CRC: Colorectal cancer; PC: Pancreatic cancer; GC: Gastric cancer; GBC: Gall bladder cancer; EMT: Epithelial to mesenchymal transition; EC: Esophageal cancer; GIST: Gastrointestinal stromal tumors; CF: Cystic fibrosis.