. Author manuscript; available in PMC: 2018 Jun 1.

Published in final edited form as: Gastroenterology. 2017 Mar 30;152(8):1845–1875. doi: 10.1053/j.gastro.2017.03.035

TABLE 1.

SP/KLF Family Members in the Digestive System

	Adult GI system		GI Disorder

Name	Expression	Function	Expression	Function

SP1			ESCC: Upregulated²⁰	ESCC: Expression associated with LNM and TNM staging²⁰

	Stomach: Peptic cells of the stomach fundus³⁶	Stomach: Promotes production of REG1 under stress-induced damage²⁵⁵; Stimulates the production of chromogranin A (CgA)³⁸	Gastric cancer: Upregulated^{40, 41}	Gastric cancer: Promotes cell invasion⁴²

	Pancreas: Acinar cells^{154, 162}	Maintains acinar cell function by promoting expression of PTF1A¹⁵⁴; Inhibits acinar cell proliferation by interacting with MIST1¹⁶²	PDAC: Upregulated⁸⁵	Regulates mucin production^163-165; Regulates expression of KRT19 with KLF4²²

	Pancreas: Beta cells^155-157	Regulates expression of vesicular glucose transporter 2¹⁵⁶ and pyruvate carboxylase¹⁵⁷, and regulates expression of PDX1 with SP3¹⁵⁵	Mild fasting hyperglycemia: mutation to the cis-regulatory region in Gck promoter¹⁵⁶	Mutations cause loss of binding from SP1 to the cis-regulatory element¹⁵⁶

	Pancreas: Ductal epithelial cells¹⁵³	Regulates expression of secretin receptor gene with SP3¹⁵³

	Liver^192-194	Mediates response to oxidative stress¹⁹²; Maintains expression of protein S^{193, 194}	Cirrhotic Liver: Upregulated¹⁹⁵	Increases fibrosis by increasing COL1AI expression¹⁹⁵

			Alcohol-induced liver injury: crosslinking¹⁹⁶	Cross-linked by tranglutaminase 2 leading to loss of transcription factor function and induction of apoptosis¹⁹⁶

			HCC: Upregulated⁸⁵	Promotes tumor invasion and migration through expression of matrix metalloproteinase 2¹⁹⁷ and transactivation of CD151¹⁹⁸; involved in aberrant histone acetylation¹⁹⁹; Promotes proliferation²⁵⁶; Promotes expression of HULC lnRNA, which induces cell proliferation and survival²⁰⁰

SP2			Gastric cancer: Upregulated⁴³	Gastric cancer: Promotes cell proliferation⁴³

SP3	The Gastric epithelium	Stomach: Promotes production of REG1 under stress-induced damage²⁵⁵	Gastric cancer: Expressed but no differential expression pattern noted	Gastric cancer: Promotes cell invasion⁴⁵

	Intestinal epithelium	Promotes apoptosis ^{79, 80}; Promotes expression of Na+/H+ exchangers NHEs^69-71; Promotes expression of EK1⁷⁶	CRC: Expression pattern not noted	CRC: Promotes cell proliferation, survival, and invasion⁸⁵; Promotes apoptosis ⁹¹

	Pancreas: beta cell¹⁵⁵	Regulate expression of PDX1 with SP1¹⁵⁵	PDAC: Upregulated⁸⁵

	Pancreas: ductal epithelial cell¹⁵³	Regulates expression of SCTR, secretin receptor gene with SP1¹⁵³

			HCC: Upregulated⁸⁵	Promotes expression of HULC lnRNA, which increases cell proliferation and survival²⁰⁰

SP4			CRC: Expression pattern not noted	CRC: promotes cell proliferation, survival, and invasion⁸⁵

			PDAC: Upregulated⁸⁵

			HCC: Upregulated⁸⁵	Promotes expression of HULC lnRNA, which increases cell proliferation and survival²⁰⁰

SP5			Gastric cancer: Upregulated⁴⁴

			CRC: Upregulated⁴⁴

SP6	Low expression in the crypts of the duodenum²⁵⁷

SP7	Stomach: Parietal cells³⁷

	Intestines: Differentiated cells³⁷

SP8	ND (not determined)		ND

SP9	ND		ND

KLF1	ND		ND

KLF2	Pancreas¹⁹⁰		PDAC: Downregulated²⁵⁸	Inhibits cell proliferation and migration²⁵⁸

	Liver²²²		Acute Liver Injury: Downregulated²²³	Vasoprotective, promotes autophagy in liver sinusoid endothelial cells²²³

			Cirrhotic Liver: Downregulated^{222, 226, 227}	Protects against endothelial damage, reduce portal hypertension²²²; Inhibits the activation of HSCs ^{226, 227}

KLF3	ND		ND

KLF4	Oral Mucosa¹⁸		OSCC: Downregulated in high grade cancer^{14, 18, 19}	Has tumor suppressor function^{18, 19} and has higher expression in low grade OSCC¹⁴

	Esophagus: Suprabasal layer²⁶	Esophagus: Cell differentiation and maturation²⁶	Barrett’s esophagus: Overexpressed in BE specimens;	Barrett’s esophagus: Involved in the metaplasia of squamous epithelium to columnar epithelium^{29, 30};
	Esophagus: Suprabasal layer²⁶	Esophagus: Cell differentiation and maturation²⁶	Esophageal squamous carcinoma: Loss of expression in human ESCC specimens³²; increased expression observed in advanced stage ESCC³¹	ESCC: Context-dependent functions as an oncoprotein or tumor-suppressor depending on the stage. At early stage, functions as a tumor suppressor and induces cell differentiation ^{32, 259}. At later stage, increased expression was observed³¹

	Stomach: Differentiated mid- to upper part of the epithelium⁴⁶	Stomach: Cell proliferation and cell fate determination⁴⁷; ghrelin and histamine production^{46, 48}	Gastric cancer: Loss of KLF4 expression^{49, 50}	Gastric cancer: Functions as a tumor suppressor by inhibiting cell proliferation and inducing apoptosis^{49, 54}

	Small and large intestines: Differentiated cells of the small intestinal villi or luminal surface of the colonic epithelium^100-103	Small and large intestines: Cell cycle regulation^100-102; Anti-apoptotic factor^{97, 98, 103, 104}; Cell differentiation^{96, 99, 107, 112}	Colorectal cancer: Loss of KLF4 exprssion^127-130	IBD: protects against DSS-induced colitis; CRC: Functions as a tumor suppressor; Associated with LNM and poor survival^{129, 130}; Regulates cell cycle^{127, 131}; Inhibits cell invasion¹³⁵; Functions as an oncogenic factor by promoting anti-apoptotic effects in cells with mutant KRAS^{V12 260}

	Pancreas: Ductal Epithelial Cells^{22, 176}	Transactivates KRT19 expression^{174, 175}	PDAC: Required for precursor lesion formation during early tumorigenesis; Downregulated in later stages of tumorigenesis^{171, 172, 177}	Cell cycle arrest via upregulate p27Kip1 expression¹⁷¹; Inhibits LDHA expression¹⁷¹; Suppresses metastasis^{171, 172}; Required for acinar-to-ductal metaplasia and PanIN formation¹⁷⁷

	Liver²³²		HCC: Downregulated^{232, 234-236}	Tumor suppressor by inhibiting migration and invasion^{232, 234-236}

KLF5	Oral Mucosa¹⁵		OSCC: Upregulated¹⁵	Promotes cancer growth and survival¹⁵

	Esophagus: Basal (proliferative) layer²⁵	Esophagus: Cell proliferation²⁵; cell migration²⁸	ESCC: Downregulated^33-35	ESCC: Inhibits tumor invasion³³; Anti-proliferative factor³⁴; Pro-apoptotic factor³⁵

	Gastric epithelium^{56, 57}		Gastric cancer: Upregulated^{56, 57}	Gastric cancer: Associated with higher tumor grade LMN, and lower survival rate⁵⁷; Involved in H pylori-infection mediated gastric-to-intestinal trans-differentiation^{58, 59}

	The intestinal epithelium: Expressed in proliferating cells of the crypts²⁴	Regulates cell proliferation^{117, 261}; Regulates cell cycle progression^{139, 146, 262}; Promotes cell differentiation and barrier function¹¹⁶; Maintains stem cell markers and functions^{117, 119, 120}; Involved in intestinal epithelial regeneration^{124, 125}; DNA damage repair¹²⁵	IBD: Intestinal epithelial regeneration^121-123	CRC: Increased cell proliferation^139-141; Promotes nuclear translocation of β-catenin and transcriptional functions^{144, 145}; Promotes oncogenic transformation of Lgr5-expressing stem cells¹³⁸; Mediates the oncogenic functions of KRAS^{V12G146, 147}

	Pancreas¹⁸³		PDAC: Upregulated^{179-181, 183, 184}	Promotes cancer cell growth^179-181 and cell survival¹⁸⁴; Promotes epithelial phenotype¹⁸³

	Liver²¹⁹		Non-alcoholic steatohepatitis: Upregulated²¹⁹	Promote triglyceride synthesis by activating PPARG expression²¹⁹

KLF6			Gastric cancer: downregulated^{61, 62}; Variant form of KLF6 (KLF6-SV1) expressed⁶⁴	Gastric cancer: Functions as a tumor suppressor by transcriptionally regulating CDKN1A, c-MYC⁶²; Associated with poor cell differentiation, LMN and TNM stage⁶³; KLF6-SV1 functions as an oncogenic factor and dominant negative regulator of full-length KLF6⁶⁴

			CRC: Downregulated or lost^148-150

	Liver²⁰¹	Required for organogenesis of liver^{191, 201}	Non-alcoholic steatohepatitis: Upregulated^{214, 215, 217}	KLF6-IVS1-27G>A single nucleotide polymorphism is associated with increased SV1 spliced variant, increased steatosis²¹⁵ and decreased fibrosis²¹⁴; Increase steatosis by expression of PPARA and PPARG²¹⁷

			HCC: Full length variant downregulated; SV1 spliced variant upregulated²⁴⁴	Full length variant act as a tumor suppressor^239,240-244; SV1 variant inhibits tumor suppressor function of full length variant²⁴⁴

KLF7	ND		ND

KLF8			Gastric cancer: Upregulated^{65, 66}	GC: Associated with poor prognosis, LNM and TNM staging^{65, 66}; Promotes cell proliferation and EMT^{67, 68}

			HCC: Upregulated²⁴⁸	Increases tumor invasion^{248, 249}; Promotes cancer cell proliferation and survival²⁴⁸

KLF9	Esophagus²⁶³		ESCC: Downregulated²⁶³	ESCC: Tumor suppressor; Forced expression inhibits growth, migration, and metastasis²⁶³

	Small and large intestines: smooth muscle cells¹²⁶	Regulates proliferation and intestinal morphogenesis¹²⁶	CRC: Downregulated¹⁵²	CRC: Prevents tumor formation¹⁵²

	Liver: Hepatocytes^206-208	Regulates the expression of P450 enzymes important for detoxification^{207, 208}; Has a role in regulating CYP7A in bile acid synthesis²⁰⁶	Non-alcoholic steatohepatitis: Upregulated²¹⁷	Activates expression of PPARG, as does KLF6²¹⁷

			HCC: Downregulated²⁵¹	Tumor suppressor functions through increasing expression of TP53²⁵¹

KLF10	Pancreas¹⁸⁵	Islet Cell: Important for maintaining beta-cell mass and function¹⁸⁵	PDAC: Downregulated^{170, 252}	Inhibits cell growth and induces apoptosis in response to TGFB^{170, 252}

			HCC: Downregulated²⁵²	Mediates the TGFB induced apoptosis²⁵²

KLF11	Pancreas: Acinar cells¹⁶⁶	Promotes acinar cell differentiation and senescence and suppresses oxidative stress response genes¹⁶⁶	PDAC: Downregulated^{166, 168, 169}	Inhibits cell proliferation; induces apoptosis in response to TGFB^{166, 168, 169}

	Pancreas: Islet cells¹⁸⁷	Maintains normal beta-cell function¹⁸⁷	French mature-onset diabetes of the young; mutations in KLF11 gene¹⁸⁷	Loss of ability to transactivate PDX1, required for beta-cell function¹⁸⁷

			Neonatal diabetes mellitus: Mutation in cis-regulatory element in insulin promoter¹⁸⁹	Mutation in insulin promoter prevents KLF11 transactivation of the insulin gene¹⁸⁹

	Liver²⁶⁴		Non-alcoholic steatohepatitis: Upregulated²¹⁸	Activates expression of PPARA and promotes steatosis²¹⁸

			Cirrhotic Liver: Upregulated²³¹	Directly activates expression of collagen 1a2 and induce fibrosis²³¹

KLF12	ND		ND

KLF13	ND		ND

KLF14	Liver: Hepatocytes^{209, 210}	Increases signaling lipid production by activating SK1²⁰⁹; Regulates expression of APOAI gene²¹⁰

KLF15	Liver: Hepatocytes^{204, 205}	Regulates gluconeogenesis by regulating amino acid utilization²⁰⁴ and PEPCK expression²⁰⁵	Non-alcoholic steatohepatitis: Upregulated²²⁰	Promotes steatosis by promoting insulin resistance and lipid accumulation²²⁰

KLF16	ND		ND

KLF17	Esophagus²⁶⁵		ESCC: Downregulated²⁶⁵	ESCC: Decreased expression correlated with metastasis²⁶⁵

			Gastric cancer: Downregulated²⁶⁶	Gastric cancer: Associated with tumor size, LMN, and poor survival²⁶⁶

			HCC: Downregulated^{253, 254}	Inhibits tumor invasion and migration^{253, 254}