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.