Role of ion channels in gastrointestinal cancer

Table 1 Potassium channels

Gene name (s)	Cancer	Role	Functional activity
KCNA3/Kv1.3	Colorectal	Unclear	One report that Kv1.3 is frequently hypermethylated and expression down-regulated in CRC; a different report that Kv1.3 is upregulated in human and mouse colon carcinomas[4,76,88]
	Pancreatic	Tumor suppressor	Expression down-regulated by promoter hypermethylation; promotes metastasis[65,82,89]
KCNA5/Kv1.5	Gastric	Oncogene	Expression up-regulated; silencing in GC cells inhibits proliferation; alters drug resistance[73,78-80]
	Colorectal	Oncogene	Expression up-regulated[79]
KCNC1/Kv3.1	Colorectal	Oncogene	Expression up-regulated[76]
KCND1/Kv4.1	Gastric	Oncogene	Expression up-regulated[81]
KCNE2/MiRP1	Gastric	Tumor suppressor	Expression down-regulated; deficiency promotes tumor progression; knockout mice develop gastritis cystic profundal and neoplasia, pyloric polyadenomas; invasive adenocarcinomas; upregulation of cyclin D1; down-regulated in gastric cancer tissues and cell lines; overexpression in cell lines suppressed growth in soft agar and mouse tumor xenografts[54-58]
KCNH1/EAG1/Kv10.1	Colorectal	Oncogene	Up-regulated; one report showed 75% of CRC tumors positive for Eag1; another report found overexpression in 3.4% of adenocarcinomas[18,75,76]
	Esophageal	Oncogene	Expression up-regulated; associated with depth of invasion; independent negative prognostic factor[75]
	Hepatocellular	Oncogene	Expression up-regulated[16,62,75,77]
KCNH2/hERG1/Kv11.1	Colorectal	Oncogene	Expression up-regulated; triggers angiogenesis and tumor progression via inducement of PI3K/AKT signaling and HIF1-induced activation of VEGF-A; associated with invasiveness, poor prognosis for stage I and II; up-regulation in ApcMin and AOM mouse models enhanced cancer phenotypes[59-62]
	Pancreatic	Oncogene	Expression up-regulated in 59% of pancreatic cancers; promotes migration of cancer cells by modulation of f-actin organization; associated with lymph node involvement, tumor grade, TNM stage, poor patient prognosis; linked to EGFR pathway; down-regulated by miR-96; overexpressed in pancreatic cancer cell lines[62-66]
	Esophageal	Oncogene	Expression upregulated; promotes progression from Barrett’s esophagus to esophageal cancer; associated with poor patient prognosis[67-70]
	Gastric	Oncogene	Expression up-regulated; stimulates angiogenesis by promoting VEGF-A secretion via AKT-dependent regulation of HIF1; positive in 69% of gastric cancers; associated with poor patient prognosis[62,71-74]
KCNH5/EAG2/Kv10.2	Esophageal	Tumor suppressor	Expression down-regulated by promoter hypermethylation[90]
KCNJ3/Kir3.1	Pancreatic	Oncogene	Expression up-regulated[62,82]
KCNN4/Kca3.1	Colorectal	Oncogene	Expression upregulated; promotes EMT[5,14,83]
	Pancreatic	Oncogene	Expression up-regulated[65,84]
	Hepatocellular	Oncogene	Expression up-regulated[62]
KCNS3/Kv9.3	Colorectal	Oncogene	Silencing causes inhibition of proliferation of HCT15 CRC cells[85]
KCNK9/K2p9.1/Task3	Colorectal	Oncogene	Expression up-regulated[5,86,87]
KCNN3/Kca2.3/SK3	Colorectal	Oncogene	Expression and activity up-regulated; regulated by SigmaR1; physically coupled to Orai1[5,91]
KCNQ1/KvLqt1	Colorectal	Tumor suppressor	Identified as a top 10 common insertion site (CIS) gene in a sleeping beauty transposon mutagenesis screen in mice; predicted loss of function in the screen; knockout mouse developed enhanced GI cancer phenotype in ApcMin model; expression down-regulated in human colorectal cancer, associated with poor prognosis in stage II, III, and IV disease; found to be down-regulated by β- catenin, which promotes EMT; in turn, KCNQ1 physically interacts with β-catenin, sequestering β-catenin at the plasma membrane[33-38,45]
	Pancreatic	Not determined	Identified as a common insertion site (CIS) gene in two sleeping beauty transposon mutagenesis screens in mice[39,40]
	Gastric	Tumor suppressor	Identified as a CIS gene in a Sleeping Beauty transposon mutagenesis screen; predicted loss of function; knockout mouse susceptible to chronic gastritis, hyperplasia and metaplasia; atrial natriuretic peptide reduced proliferation of gastric cancer cells by upregulating KCNQ1[31,32,42,43]
	Hepatocellular	Tumor suppressor	Expression down-regulated by promoter hypermethylation; associated with poor patient prognosis; KCNQ1 regulated EMT; KCNQ1 regulates β-catenin physical interactions at the plasma membrane[41,44]
KCNQ1OT1	Colorectal	Oncogene	Expression up-regulated; promotes Wnt/β-catenin signaling and migration, poor patient prognosis[49,52]
	Esophageal	Oncogene	Expression up-regulated; promotion of metastasis; poor patient prognosis[50]
	Hepatocellular	Oncogene	Expression up-regulated; competes with endogenous miR-504; promotes cell proliferation, associated with TNM stage and poor survival[51]

CRC: Colorectal cancer; GC: Gastric cancer; CIS: Common insertion site; EMT: Epithelial to mesenchymal transition; GI: Gastrointestinal.

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.

Table 3 Calcium channels

Gene name (s)	Cancer	Role	Functional activity
TRPC1	Colorectal	Oncogene	Expression up-regulated; promotes metastasis[5,256,274]
	Esophageal	Oncogene	Expression up-regulated[275]
	Gastric	Oncogene	Expression up-regulated[276]
	Hepatocellular	Oncogene	Expression up-regulated[249]
TRPC6	Esophageal	Oncogene	Expression up-regulated; necessary for Ca2+ increase to promote G2 progression; associated with tumor stage and poor prognosis[276,277]
	Gastric	Oncogene	Expression up-regulated[5,278]
	Hepatocellular	Oncogene	Expression up-regulated[4]
TRPM2	Colorectal	Oncogene	Expression up-regulated[270]
	Pancreatic	Oncogene	Expression up-regulated; enhanced proliferation, invasion & metastasis[272,273]
	Gastric	Oncogene	Expression up-regulated; inhibition reduced proliferation of gastric cancer cells, increased autophagy and sensitized cells to paxlitaxel and doxorubicin[68,272,273]
TRPM6	Colorectal	Tumor suppressor	Expression down-regulated in 16/20 (80%) of primary tumors; high expression associated with better patient survival[285]
TRPM7	Colorectal	Not determined	Genetic polymorphism associated with enhanced risk of adenomas, linked to high Ca2+:Mg2+ ratio in diet[268]
	Pancreatic	Oncogene	Expression up-regulated; increased tumor growth, invasiveness and metastasis; targeted silencing induced replicative senescence[5,258-261,263-267]
	Gastric	Oncogene	Highly expressed in gastric cancer cell lines; required for GC survival linked to Mg; suppression induces cell death in culture[4,269-271]
TRPM8	Pancreatic	Oncogene	Expression up-regulated; regulates proliferation and migration; silencing in cell lines induces replicative senescence [259-262]
L-type/a1c subunit/CACNA1C	Colorectal	Oncogene	Expression up-regulated[283]
Sig1R/SIGMAR1	Colorectal	Oncogene	Expression up-regulated in CRC cell lines and primary CRC tumors[280-282]
Stim1/Stromal interaction protein 1	Colorectal	Oncogene	Expression up-regulated; increased CRC cell motility; STIM1 overexpression enhanced lung and liver metastases in mouse xenograft models; also associated with poor prognosis in CRC patients[15,255,256]
	Pancreatic	Oncogene	Expression up-regulated; promotes invasion and metastasis; STIM1 and Orai1 are the molecular components of SOCE[14]
Stim2/Stromal interaction protein 2	Colorectal	Tumor suppressor	Expression down-regulated; depletion causes apoptosis resistance[15,256,274]
Orai1/CRAMC1	Colorectal	Oncogene	Expression up-regulated; activated by STIM1[5]
	Pancreatic	Oncogene	Expression up-regulated; mediate SOCE and promote apoptotic resistance in pancreatic cancer cells[91,279]
	Esophageal	Oncogene	Expression up-regulated; promotes tumor-promoting Ca2+ oscillations in EC[275]
	Gastric	Oncogene	Expression up-regulated; promotes metastasis[68]
T-type CACNA1G/CaV3.1	Colorectal	Tumor suppressor	expression down-regulated by promoter hypermethylation[284,286]
	Pancreatic	Tumor suppressor	Expression down-regulated by promoter hypermethylation[284,287]
	Gastric	Tumor suppressor	Expression down-regulated by promoter hypermethylation; high expression associated with improved overall survival[284,288]
T-type CACNA1I/CaV3.3	Gastric	Oncogene	High expression associated with poor survival[284]
T-type CACNA1H/CaV3.2	Gastric	Oncogene	High expression associated with poor survival[284]
CACNA2D3	Gastric	Tumor suppressor	Expression down-regulated by promoter hypermethylation, associated with worse prognosis[91,289]
CACNB2	Esophageal	Tumor suppressor	Expression down-regulated by promoter hypermethylation[90]

GC: Gastric cancer; CRC: Colorectal cancer; EC: Esophageal cancer; SOCE: Store-operated calcium entry; STIM1: Stromal interaction protein 1.

Table 4 Sodium channels

Gene name (s)	Cancer	Role	Functional activity
SCN1A/Nav1.1	Colorectal	Oncogene	Time to reoccurrence of stage II and III CRC is shorter in patients carrying Nav1.1 variants[302]
SCN5A/Nav1.5	Colorectal	Oncogene	Expression up-regulated; mediates invasion via MAPK signaling; key regulator of a transcriptional network that includes Wnt/β-catenin signaling; associated with poor patient prognosis; linked to upregulation of ER-β[5,294-296]
SCN8A/Nav1.6	Colorectal	Tumor suppressor	Expression down-regulated in CRC tumor tissues compared with control[303]
SCN9A/Nav1.7	Gastric	Oncogene	Expression up-regulated; mechanistically related to upregulation of MACC1 and NHE1[297]

CRC: Colorectal cancer.

Table 5 Zinc transporters

Gene name	Cancer	Role	Functional activity
ZnT1/SLC30A1	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
ZnT2/SLC30A2	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
ZnT3/SLC30A3	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
ZnT4/SLC30A4	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
ZnT5/SLC30A5	Colorectal	Oncogene	Increased mRNA expression in tumors[337]
ZnT6/SLC30A6	Colorectal	Oncogene	Increased mRNA expression in tumors[337]
ZnT7/SLC30A7	Esophageal colorectal	Oncogene oncogene	Increased mRNA expression in tumors[308,335] Increased mRNA expression in tumors[337]
ZnT8/SLC30A8	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
ZnT9/SLC30A9	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
ZIP1/SLC39A1	Gastric	Oncogene	Increased mRNA expression in tumors, worse patient prognosis[338]
	Pancreatic	Tumor suppressor	Down regulated mRNA expression in tumors[313]
ZIP2/SLC39A2	Gastric	Oncogene	Increased mRNA expression in tumors, worse patient prognosis[338]
	Pancreatic	Tumor suppressor	mRNA expression down-regulated in tumors[313]
ZIP3/SLC39A3	Pancreatic	Tumor suppressor	Decreased expression in adenocarcinoma[308,313,331,343]
		Oncogene	Medium to high mRNA expression in multiple human PC cell lines[313]
ZIP4/SLC39A4	Hepatocellular	Oncogene	Increased mRNA and protein expression, repressed apoptosis, enhanced cell cycle and migration[308,325,344-346]
	Pancreatic	Oncogene	Increased expression in PDAC and PC cell lines, link to CREB-miR-373 axis, promotes cancer xenograft growth in nude mice[313,325-327]
	Gastric	Oncogene	Increased mRNA expression in tumors, worse patient prognosis[338]
ZIP5/SLC39A5	Esophageal	Oncogene	Increased expression in ESCC, knockdown in cell lines inhibited migration and invasion[308,334]
	Gastric	Oncogene	Increased mRNA expression in tumors, worse patient prognosis[338]
	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
ZIP6/LIV-1/SLC39A6	Pancreatic	Oncogene	Increased expression in tumors and cell lines[313,330]
		Tumor suppressor	Decreased mRNA expression in tumors[313]
	Hepatocellular	Oncogene	Increased mRNA and protein expression[308,347]
	Esophageal	Oncogene	Increased expression in ESCC[308,333]
	Colorectal	Oncogene	Increased mRNA expression in tumors[337]
	Gastric	Oncogene	Increased mRNA expression in tumors, worse patient prognosis[338]
ZIP7/SLC39A7	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
		Oncogene	Medium to high mRNA expression in multiple human cell lines[313]
	Colorectal	Oncogene	Increased mRNA expression in tumors and CRC cell lines, knockdown inhibits cell growth and induces apoptosis in cell lines[339]
	Gastric	Undetermined	Increased mRNA expression, but better patient prognosis[338]
ZIP8/SLC39A8	Gastric	Oncogene	Increased mRNA expression in tumors, worse patient prognosis[338]
	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
		Oncogene	Medium to high mRNA expression in multiple human cell lines[313]
ZIP9/SLC39A9	Colorectal	Oncogene	Increased mRNA expression in tumors[337]
	Gastric	Oncogene	Increased mRNA expression in tumors, worse patient prognosis[338]
	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
		Oncogene	Medium to high mRNA expression in multiple human cell lines[313]
ZIP10/SLC39A10	Colorectal	Oncogene	Increased mRNA expression in tumors[337]
	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
		Oncogene	Medium to high mRNA expression in multiple human cell lines[313]
ZIP11/SLC39A11	Colorectal	Oncogene	Increased mRNA expression in tumors[337]
	Gastric	Undetermined	Increased mRNA expression in tumors, better patient prognosis[338]
	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
		Oncogene	Medium to high mRNA expression in multiple human cell lines[313]
ZIP12/SLC39A12	Gastric	Oncogene	Increased mRNA expression in tumors, worse patient prognosis[338]
	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
ZIP13/SLC39A13	Gastric	Oncogene	Increased mRNA expression in tumors, worse patient prognosis[338]
	Pancreatic	Tumor suppressor	Decreased mRNA expression in tumors[313]
		Oncogene	Medium to high mRNA expression in multiple human cell lines[313]
ZIP14/SLC39A14	Hepatocellular	Tumor suppressor	Decreased expression in hepatoma tissues[308,348]
	Gastric	Undetermined	Increased mRNA expression in tumors, but better patient prognosis[338]
		Tumor suppressor	Decreased mRNA expression in tumors[313]
	Pancreatic	Oncogene	Medium to high mRNA expression in multiple human cell lines[313]

PDAC: Pancreatic ductal adenocarcinoma; ESCC: Esophageal squamous cell carcinoma; CRC: Colorectal cancer; PC: Pancreatic cancer.