SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1)

2014-12-01 Hannu Koistinen , Outi Itkonen , Ulf-Hakan Stenman Affiliation

Department of Clinical Chemistry, University of Helsinki (HK,OI, UHS),, Laboratory Division HUSLAB, Helsinki University Central Hospital (OI), Helsinki, Finland hannu.k.koistinen@helsinki.fi; outi.itkonen@hus.fi; ulf-hakan.stenman@helsinki.fi

Identity

HGNC

SPINK1

LOCATION

5q32

LOCUSID

6690

ALIAS

PCTT,PSTI,Spink3,TATI,TCP

FUSION GENES

Show Gene Fusions

Abstract

Review on SPINK1, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Note

Some other SPINK family members are similar in size, are encoded for by 4 exons and contain a single Kazal type serine protease inhibitor domain.

Chromosomal location and gene structure of SPINK1 gene (extracted from Ensembl database release 73). Some putative regulatory elements are also shown (Ohmachi et al., 1993; Yasuda et al., 1993; Yasuda et al., 1998; Boulling et al., 2011). After the translation-initiating codon (ATG) exons of the major transcript are shown in black. One splicing variant also contains parts outside of these exons. *, CAATCAATAAC, potential pancreas-specific regulatory element; IL6RE, interleukin-6 responsive element; AP-1, activator protein-1 element; HNF1, hepatic nuclear factor; PTF1, pancreas-specific transcription factor 1.

Description

Maps to chromosomal region 5q32: 147,204,131-147,211,349 on reverse (minus) strand (7,219 bp). Gene consists of 4 exons (Horii et al., 1987). Region between 3.8 and 4.0 kb upstream from the translation initiation codon contains an interleukin-6 responsive element (IL6RE) and two potential AP-1 binding sites (Ohmachi et al., 1993; Yasuda et al., 1993). CAATCAATAAC sequence (-149 to -139) is a potential pancreas-specific regulatory element (Yasuda et al., 1998). This region in the SPINK1 promoter has been subsequently identified as a binding site for hepatic nuclear factor (HNF1) (Boulling et al., 2011). A putative binding site for pancreas-specific transcription factor 1 (PTF1) has also been identified within the SPINK1 promoter (Boulling et al., 2011).

Transcription

SPINK1 mRNA (NCBI Reference Sequence: NM_003122.3) has 454 bp (Yamamoto et al., 1985). Expression, at least in some cell lines, is regulated by IL-6 (Yasuda et al., 1993). Three differentially spliced mRNA forms have been described (Ensembl, release 73). Two of these have been classified as protein encoding.

Proteins

Note

In the literature, SPINK1 is widely referred to as TATI (tumor-associated trypsin inhibitor) and PSTI (pancreatic secretory trypsin inhibitor).

Ribbon diagram of recombinant SPINK1 variant (RSCB Protein Data Bank code 1HPT (Hecht et al., 1991)). Protein Workshop program (Moreland et al., 2005) with the surfaces feature (Xu and Zhang, 2009) was used for visualization. Cysteines, forming three disulfide bonds, are shown as balls and sticks. The atoms of asparagine-34 (N34) residue, mutation in which is associated with chronic pancreatitis, and reactive site lysine (K41) are shown as balls without side-chains. Alpha-helix is shown in blue and beta-sheets in yellow.

Description

SPINK1(NCBI Reference Sequence: NP_003113.2 ; UniProtKB/Swiss-Prot: ISK1_HUMAN, P00995; PDB: 1cgj; 1cgi; 1hpt) is a 6242 Da secreted protein, containing 79 amino acids. Mature SPINK1 contains 56 amino acids and three disulfide bonds. It has a Kazal-type serine protease inhibitor domain and belongs to the SPINK (serine peptidase inhibitor, Kazal-type) family. SPINK1 has been reported to inhibit several proteases, including human trypsin-1 and -2 (cationic and anionic trypsins), acrosin and granzyme A (Pubols et al., 1974; Huhtala et al., 1984; Turpeinen et al., 1988; Tsuzuki et al., 2003).

Expression

SPINK1 was first characterized in bovine pancreas (Kazal et al. 1948) and pancreatic juice (Greene 1966), and later from human pancreatic juice (Fritz et al 1967). SPINK1 is mainly expressed in the pancreas, but to a lesser extent also in several other tissues, e.g., in the gastrointestinal tract, including the liver, duodenum, small intestine, gall bladder, colon, appendix, stomach, and in the genitourinary tract, e.g., prostate and urothelium (Paju and Stenman, 2006; Itkonen and Stenman, 2014). Expression has been found also in kidney, lung, breast, brain, spleen and ovary. SPINK1 is often strongly expressed in ETS-rearrangement-negative prostate cancers (Tomlins et al., 2008). A putative bipartite pancreas-specific transcription factor 1 (PTF1)-binding sequence has been identified (Boulling et al., 2011) in the SPINK1 gene. Outside the pancreas, SPINK1 has been considered an inflammatory pleiotropic cytokine, which is regulated by immune and inflammatory responses. In some cell lines, the expression is regulated by IL-6 (Yasuda et al., 1993). In cultured prostate cancer cells, SPINK1 expression has been shown to be regulated by androgens (Paju et al., 2007). In mouse, the synthesis of Spink3 (mouse orthologue of SPINK1) is dependent upon testicular androgens in the sex accessory tissues, but not in the pancreas (Mills et al., 1987). Very high serum and urine concentrations occur in patients with pancreatitis (Ogawa, 1988). Serum levels of SPINK1 may also be elevated in several cancers, including prostate cancer, ovarian cancer and benign cysts, renal-cell carcinoma, bladder carcinoma, and colorectal cancer (Paju and Stenman, 2006; Itkonen and Stenman, 2014). Severe inflammation, tissue destruction and major trauma leads to an acute phase reaction causing increased circulating SPINK1 concentrations.

Relative mRNA expression levels of SPINK1 in different tissues. The data is from the IST4 database containing gene expression data in ~10 000 samples (http://ist.medisapiens.com/) (Kilpinen et al., 2008).

Localisation

SPINK1 is highly expressed in the pancreas (Kazal et al., 1948). It has been localized to the zymogen granules of pancreatic acinar cells, where it protects the pancreas from premature activation of trypsinogens. SPINK1 is secreted into the pancreatic fluid along with digestive enzymes. Many cancers secrete SPINK1 causing elevated serum concentrations (Paju and Stenman, 2006; Itkonen and Stenman, 2014).

Function

SPINK1 is a protease inhibitor and has been reported to inhibit human trypsin-1 and -2 (cationic and anionic trypsins), but not trypsin-3 (mesotrypsin)(Sahin-Tóth, 2005). SPINK1 also inhibits granzyme A (Tsuzuki et al., 2003), plasmin, urokinase, tissue plasminogen activator (Turpeinen et al., 1988) and acrosin (Huhtala et al., 1984). SPINK1 has been reported to exert growth stimulation of cultured cells (Niinobu et al., 1990) and to activate the EGF-receptor (Ozaki 2009; Ateeq et al., 2011). However, growth stimulation by mechanisms other than via EGF receptor cannot be ruled out. It has been suggested that SPINK1 mediates tumor growth, differentiation, and angiogenesis via stimulation of the EGF-receptor or by suppression of serine-protease- or caspase-dependent apoptosis (Ateeq et al., 2011; Gouyer et al., 2008). There is evidence that SPINK1 plays a role in tissue differentiation (Ohmuraya et al., 2005) and repair (Marchbank et al., 1996), reproduction (Huhtala, 1984) and regulation of apoptosis (Lu et al., 2011). Over-expression of SPINK1 in cancer could block cancer cell apoptosis resulting in suppression of the immune response and escape of cancer cells from immune surveillance (Lamontagne et al., 2010).

Homology

SPINK1 contains a Kazal-type serine protease inhibitor domain, found in many other proteins and especially in members of SPINK family. Apart from this domain, SPINKs do not share high sequence similarity. Apart from SPINK5, SPINKs are of similar size and most genes contain the same number of exons. Some of the family members lack functional annotatation. A functional SPINK1 orthologue, Spink3 (NP_033284.1), has been found in mouse. The rat has two orthologues, Spink1 (NP_690919.1) and Spink3 (NP_036806.1) (HomoloGene, Release 67). Orhologues have been found also in common chimpanzee (XP_001160275.1), rhesus macaque (XP_001102888.1), grey wolf (XP_850557.1) and cattle (NP_001020519.1). Sequence similarity between SPINK1 and EGF has been reported (Hunt et al., 1974).

Mutations

Note

NCBI SNP database (http://www.ncbi.nlm.nih.gov/SNP/) reports 631 SPINK1 SNPs (Homo sapiens, December 29., 2014). At least 15 missense mutations have been described in the mature polypeptide and three in the signal peptide (Chen and Férec, 2009). Association of mutations with familial pancreatitis and other diseases has been described (see below).

Implicated in

Entity name

Liver cancer

Note

Up-regulation of SPINK1 in tissue has been shown to distinguish hepatocellular carcinoma (HCC) from benign liver disease and normal liver (Marshall A 2013). Elevated serum concentrations of SPINK1 are associated with adverse prognosis of hepatocellular cancer (Lyytinen et al., 2013). Serum SPINK1 is also a useful marker for distinguishing between patients with or without liver metastasis of colorectal and breast cancer (Taccone W 1991; Gaber A 2010).

Disease

HCC is the fifth most frequently diagnosed cancer and the second most common cause of cancer death worldwide in men (Jemal et al., 2011). In females the rate is about half of that of men. Half of the cases occur in China and liver cancer is less common in Western countries. HCC is the most common type of liver cancer. It may be caused by viral infections, like hepatitis B and C, or cirrhosis. Most tumors in the liver are not primary liver cancers, but metastases of other cancers.

Prognosis

Plasma SPINK1 concentration is elevated in HCC patients and it correlates with tumor size (Ohmachi et al., 1993). Overexpression of SPINK1 mRNA is a stage-independent prognostic factor and a predictor of early tumor recurrence in HCC (Lee et al., 2007) and in cholangiocarcinoma (Tonouchi et al., 2006). Serum SPINK1 has been shown to predict adverse prognosis in HCC (Lyytinen I 2013).

Entity name

Prostate cancer

Note

SPINK1 is often overexpressed in ETS-rearrangement-negative prostate cancers (Tomlins et al., 2008).

Disease

Prostate cancer is a considerable health care problem with 342 000 new cases and about 71 000 deaths annually in the EU countries, it is the most frequently diagnosed cancer in men and the third most common cause of cancer death (data from GLOBOCAN 2008). Prostate cancer can be diagnosed by screening at an early stage, when most patients can be cured by radical prostatectomy or radiotherapy. However, about one third of the tumors relapse. Most of these cases can be treated by androgen ablation, but within 3 - 5 years the tumor usually becomes castration-resistant.

Prognosis

High SPINK1 expression has been associated with adverse prognosis in prostate cancer in some (Tomlins et al., 2008; Paju et al., 2007), but not all studies (Leinonen et al., 2013; Grupp et al., 2013; Lippolis et al., 2013). The differences may be related to the type of treatment, e.g., surgery or androgen ablation (Leinonen et al., 2013).

Entity name

Breast cancer

Disease

Breast cancer is the most common cancer among women worldwide, accounting for 23% of all cases (Jemal et al., 2011). Although the prognosis has improved due to early diagnosis and therapies, breast cancer remains a major cause of death among women (14% of the cancer deaths). Most neoplasms of the breast originate from the ductal epithelium, while a minority originates from the lobular epithelium. A family history of breast cancer is associated with a 2-3-fold higher risk of the disease.

Prognosis

SPINK1 expression is associated with poor prognosis in estrogen receptor-positive breast cancer (Soon et al., 2011).

Entity name

Colorectal cancer

Note

Elevated serum SPINK1 has been observed in some patients with colorectal cancer. (Solakidi et al., 2004; Pasanen et al., 1995)

Disease

Colorectal cancer is the third most commonly diagnosed cancer in males and the second in females (Jemal et al., 2011). It originates from colon or rectum, but, based on genetic studies, these are the same tumor. When locally confined, colorectal cancer is often curable by surgery.

Prognosis

High expression of SPINK1 has been associated with adverse prognosis and liver metastases (Gaber et al., 2010; Gaber at al., 2009)

Entity name

Bladder cancer

Note

Urinary SPINK1 is a useful marker for high-grade bladder cancer (Kelloniemi et al., 2003; Shariat et al., 2005; Gkialas et al., 2008, Patschan et al., 2012).

Disease

Bladder cancer is more common in males than in females and there is great geographic variation in incidence (Jemal et al., 2011). The highest incidence rates are found in Europe, North America and Northern Africa. Smoking, occupational exposures and chronic infection with Schistosoma hematobium are major risk factors. Most bladder cancers originate from the epithelial lining of the urinary bladder. Transitional cell carcinoma is the most common type of bladder cancer.

Prognosis

Serum SPINK1 has been shown to be an independent prognostic factor for bladder cancer (Kelloniemi et al., 2003) and for prediction of the response to chemotherapy (Pectasides et al., 1996). SPINK1 expression is stronger in noninvasive than in invasive tumors and decreases with advancing tumor stage (Hotakainen et al., 2006; Patschan et al., 2012).

Entity name

Ovarian cancer

Note

The association of SPINK1 (TATI) and cancer was first observed in a patients with ovarian cancer (Stenman et al. 1982)

Disease

Ovarian cancer is the leading cause of death from gynecologic cancer. Most cases are diagnosed at advanced stages and, thus have relatively poor prognosis. The vast majority of ovarian cancers are epithelial. Cancer of the fallopian tubes is similar to ovarian cancer.

Prognosis

Increased SPINK1 expression is associated with adverse outcome in epithelial ovarian cancer (Huhtala et al., 1983; Paju et al., 2004). Elevated serum SPINK1 is an independent prognostic factor (Venesmaa et al., 1994; Venesmaa et al., 1998; Paju et al., 2004).

Entity name

Gastric cancer

Note

SPINK1 is detected in the normal gastric mucosa.

Disease

Gastric cancers account for 8% of all cancer cases and 10% of the deaths (Jamal et al., 2011). Over 70% of new cases and deaths occur in developing countries and rates are higher in males than in females. Helicobacter pylori infection is the main risk factor, but smoking also increases the risk of gastric cancer.

Prognosis

The prognosis of gastric cancer is generally poor and metastases develop frequently. High tissue expression of SPINK1 is a sign of favorable outcome and loss of SPINK1 immunoreactivity in tumor tissue is associated with adverse prognosis (Wiksten et al., 2008). Serum SPINK1 is elevated in 50% of patients with gastric cancer (Solakidi et al., 2004).

Entity name

Renal cell carcinoma

Disease

Renal cancer comprises five distinct histological types. Within each type, there is considerable variation in clinical course and survival. Presently, many tumors are detected at an early stage by sonography performed for various reasons.

Prognosis

Prognosis of metastatatic and advanced disease is poor, but surgical treatment of localized disease is often curative. There are no specific serum markers for RCC. Elevated serum SPINK1 has been shown to be an independent prognostic factor in renal cell carcinoma (Meria et al., 1995; Paju et al., 2001).

Entity name

Pancreatitis, hereditary (Online Mendelian Inheritance in Man (OMIM): 167800)

Note

SPINK1 polymorphisms are found more frequently in patients with hereditary and idiopatic chronic pancreatitis (23%) than in healthy controls (0.4%) (Witt et al., 2000; Chen and Férec, 2009). Several mutations of SPINK1 cause loss-of-function by splicing, frameshift, deletion or initiation codon mutation. Some missense mutations have been suggested to affect polypeptide folding, leading to intracellular retention and degradation of the mutated polypeptide (Boulling et al., 2012). These mutations are suggested to cause pancreatitis because of SPINK1 deficiency. The most common mutation worldwide is a 101A>G transition within exon 3 resulting in the substitution of Asp by Ser at codon 34 (N34S) (Witt et al., 2000). The frequency of the N34S mutation in pancreatitis patients is 9-29 % as compared to 0.5-2.5 % in the general population. In functional studies no differences in SPINK1 expression, trypsin inhibitory activity or binding to trypsin have been found between wild-type and N34S-SPINK1. The mutations D50E, Y54H and R67C result in marked reduction or complete loss of SPINK1 secretion, and are classified as disease-causing mutations although trypsin inhibitory activity of the mutated proteins was retained (Király et al., 2007). The P55S mutation of SPINK1 is found in healthy controls as well as in pancreatitis patients with an incidence of 0.5-1.3 % and 0.9-7 %, respectively (Witt et al., 2000; Pfutzer et al., 2000). The role of this mutation in pancreatitis remains unclear.

Disease

Elevated serum and urine concentrations are caused by pancreatitis, i.e., inflammation of pancreas. Some hereditary mutations of the SPINK1 gene, increase the risk of pancreatitis. These cases are characterized by recurrent episodes of pancreatitis starting at young age. These episodes often lead to tissue damage and loss of pancreatic function, including insulin production. This also increases the risk of pancreatic cancer.

Prognosis

The life expectancy of the pancreatitis patients is close to normal. However, patients have an increased risk of developing pancreatic cancer (Weiss, 2014).

Entity name

Tropical calcific pancreatitis

Note

SPINK1 mutations, especially the N34S mutation has been reported to associate with tropical calcific pancreatitis (Bhatia et al., 2002).

Disease

Tropical calcific pancreatitis (OMIM: 608189) is a special type of chronic pancreatitis that occurs only in tropical countries.

Prognosis

Patients usually present at young age with recurrent abdominal pain and nutritional deficiencies. The disease often leads to beta-cell deficiency and diabetes requiring insulin before the age of 30. Prognosis is dismal and many patients succumb to complications caused by malnutrition.

Bibliography

Pubmed ID	Last Year	Title	Authors
21368222	2011	Therapeutic targeting of SPINK1-positive prostate cancer.	Ateeq B et al
12360463	2002	Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations.	Bhatia E et al
22343981	2012	Functional analysis of eight missense mutations in the SPINK1 gene.	Boulling A et al
19453252	2009	Chronic pancreatitis: genetics and pathogenesis.	Chen JM et al
4231655	1967	[On protease inhibitors, V. On the chemistry and physiology of the specific trypsin inhibitors from the ox, dog, pig and human pancreas].	Fritz H et al
19384300	2009	High expression of tumour-associated trypsin inhibitor correlates with liver metastasis and poor prognosis in colorectal cancer.	Gaber A et al
20849596	2010	Increased serum levels of tumour-associated trypsin inhibitor independently predict a poor prognosis in colorectal cancer patients.	Gaber A et al
18514770	2008	Evaluation of urine tumor-associated trypsin inhibitor, CYFRA 21-1, and urinary bladder cancer antigen for detection of high-grade bladder carcinoma.	Gkialas I et al
5928200	1966	Trypsin inhibitor from bovine pancreatic juice.	Greene LJ et al
23843146	2013	SPINK1 expression is tightly linked to 6q15- and 5q21-deleted ERG-fusion negative prostate cancers but unrelated to PSA recurrence.	Grupp K et al
1870127	1991	Three-dimensional structure of the complexes between bovine chymotrypsinogen A and two recombinant variants of human pancreatic secretory trypsin inhibitor (Kazal-type).	Hecht HJ et al
3501289	1987	Primary structure of human pancreatic secretory trypsin inhibitor (PSTI) gene.	Horii A et al
16327984	2006	Differential expression of trypsinogen and tumor-associated trypsin inhibitor (TATI) in bladder cancer.	Hotakainen K et al
6384012	1984	Demonstration of a new acrosin inhibitor in human seminal plasma.	Huhtala ML et al
6190763	1983	Excretion of a tumor-associated trypsin inhibitor (TATI) in urine of patients with gynecological malignancy.	Huhtala ML et al
4429557	1974	Epidermal growth factor: internal duplication and probable relationship to pancreatic secretory trypsin inhibitor.	Hunt LT et al
24583226	2014	TATI as a biomarker.	Itkonen O et al
21296855	2011	Global cancer statistics.	Jemal A et al
18882536	1948	Isolation of a crystalline trypsin inhibitor-anticoagulant protein from pancreas.	KAZAL LA et al
12893328	2003	Tumor-associated trypsin inhibitor as a prognostic factor during follow-up of bladder cancer.	Kelloniemi E et al
18803840	2008	Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues.	Kilpinen S et al
17525091	2007	Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation.	Király O et al
22526274	2012	Do genetic variants in the SPINK1 gene affect the level of serum PSTI?	Kume K et al
19864383	2010	Hepatitis B and hepatitis C virus replication upregulates serine protease inhibitor Kazal, resulting in cellular resistance to serine protease-dependent apoptosis.	Lamontagne J et al
17267202	2007	Overexpression of tumour-associated trypsin inhibitor (TATI) enhances tumour growth and is associated with portal vein invasion, early recurrence and a stage-independent prognostic factor of hepatocellular carcinoma.	Lee YC et al
24083995	2013	Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer.	Leinonen KA et al
23459095	2013	A high-density tissue microarray from patients with clinically localized prostate cancer reveals ERG and TATI exclusivity in tumor cells.	Lippolis G et al
22043941	2011	Role of the inflammatory protein serine protease inhibitor Kazal in preventing cytolytic granule granzyme A-mediated apoptosis.	Lu F et al
23889187	2013	Prognostic significance of tumor-associated trypsin inhibitor (TATI) and human chorionic gonadotropin-β (hCGβ) in patients with hepatocellular carcinoma.	Lyytinen I et al
8774127	1996	Distribution and expression of pancreatic secretory trypsin inhibitor and its possible role in epithelial restitution.	Marchbank T et al
23527199	2013	Global gene expression profiling reveals SPINK1 as a potential hepatocellular carcinoma marker.	Marshall A et al
7601186	1995	Tumour-associated trypsin inhibitor and renal cell carcinoma.	Meria P et al
3428272	1987	A secretory protease inhibitor requires androgens for its expression in male sex accessory tissues but is expressed constitutively in pancreas.	Mills JS et al
15694009	2005	The Molecular Biology Toolkit (MBT): a modular platform for developing molecular visualization applications.	Moreland JL et al
2170560	1990	Identification and characterization of receptors specific for human pancreatic secretory trypsin inhibitor.	Niinobu T et al
2449986	1988	Pancreatic secretory trypsin inhibitor as an acute phase reactant.	Ogawa M et al
8244568	1993	Specific expression of the pancreatic-secretory-trypsin-inhibitor (PSTI) gene in hepatocellular carcinoma.	Ohmachi Y et al
16083722	2005	Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice.	Ohmuraya M et al
19737965	2009	Serine protease inhibitor Kazal type 1 promotes proliferation of pancreatic cancer cells through the epidermal growth factor receptor.	Ozaki N et al
17306443	2007	Increased expression of tumor-associated trypsin inhibitor, TATI, in prostate cancer and in androgen-independent 22Rv1 cells.	Paju A et al
11176522	2001	Tumor associated trypsin inhibitor as a prognostic factor in renal cell carcinoma.	Paju A et al
16517420	2006	Biochemistry and clinical role of trypsinogens and pancreatic secretory trypsin inhibitor.	Paju A et al
15269150	2004	Expression of trypsinogen-1, trypsinogen-2, and tumor-associated trypsin inhibitor in ovarian cancer: prognostic study on tissue and serum.	Paju A et al
7667604	1995	Tumour-associated trypsin inhibitor (TATI) in patients with colorectal cancer: a comparison with CEA, CA 50 and CA 242.	Pasanen P et al
21739120	2012	Association of tumor-associated trypsin inhibitor (TATI) expression with molecular markers, pathologic features and clinical outcomes of urothelial carcinoma of the urinary bladder.	Patschan O et al
10982753	2000	SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis.	Pfützer RH et al
4818832	1974	Trypsin inhibitor from human pancreas and pancreatic juice.	Pubols MH et al
16029158	2005	Human mesotrypsin defies natural trypsin inhibitors: from passive resistance to active destruction.	Sahin-Tóth M et al
15963628	2005	Urinary levels of tumor-associated trypsin inhibitor (TATI) in the detection of transitional cell carcinoma of the urinary bladder.	Shariat SF et al
14675563	2004	Tumour-associated trypsin inhibitor, carcinoembryonic antigen and acute-phase reactant proteins CRP and alpha1-antitrypsin in patients with gastrointestinal malignancies.	Solakidi S et al
21656687	2011	Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer.	Soon WW et al
3202976	1988	Characterization of a tumor-associated serine protease.	Stenman UH et al
1780686	1991	Evaluation of TATI and other markers in solid tumors.	Taccone W et al
18538735	2008	The role of SPINK1 in ETS rearrangement-negative prostate cancers.	Tomlins SA et al
16863567	2006	Relationship between pancreatic secretory trypsin inhibitor and early recurrence of intrahepatic cholangiocarcinoma following surgical resection.	Tonouchi A et al
12590650	2003	Purification and identification of a binding protein for pancreatic secretory trypsin inhibitor: a novel role of the inhibitor as an anti-granzyme A.	Tsuzuki S et al
2461702	1988	Reaction of a tumour-associated trypsin inhibitor with serine proteinases associated with coagulation and tumour invasion.	Turpeinen U et al
9637119	1998	Pre-operative serum level of tumour-associated trypsin inhibitor and residual tumour size as prognostic indicators in Stage III epithelial ovarian cancer.	Venesmaa P et al
24600409	2014	Pancreatic cancer risk in hereditary pancreatitis.	Weiss FU et al
18751407	2008	Comparison of the prognostic value of a panel of tissue tumor markers and established clinicopathological factors in patients with gastric cancer.	Wiksten JP et al
10835640	2000	Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis.	Witt H et al
19956577	2009	Generating triangulated macromolecular surfaces by Euclidean Distance Transform.	Xu D et al
3877508	1985	Molecular cloning and nucleotide sequence of human pancreatic secretory trypsin inhibitor (PSTI) cDNA.	Yamamoto T et al
7691687	1993	Identification of the IL-6-responsive element in an acute-phase-responsive human pancreatic secretory trypsin inhibitor-encoding gene.	Yasuda T et al
9852108	1998	Identification of novel pancreas-specific regulatory sequences in the promoter region of human pancreatic secretory trypsin inhibitor gene.	Yasuda T et al

Other Information

Locus ID:

NCBI: 6690
MIM: 167790
HGNC: 11244
Ensembl: ENSG00000164266

Variants:

dbSNP: 6690
ClinVar: 6690
TCGA: ENSG00000164266
COSMIC: SPINK1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000164266	ENST00000296695	P00995
ENSG00000164266	ENST00000510027	D6RIU5

Expression (GTEx)

500

1000

1500

2000

2500

3000

3500

4000

4500

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19372376	2009	Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans.	299
18538735	2008	The role of SPINK1 in ETS rearrangement-negative prostate cancers.	108
21368222	2011	Therapeutic targeting of SPINK1-positive prostate cancer.	54
22427236	2013	CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?	53
20442300	2010	Association of SPINK1 expression and TMPRSS2:ERG fusion with prognosis in endocrine-treated prostate cancer.	44
20977904	2011	Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis.	41
20977904	2011	Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis.	41
11950815	2002	The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease.	38
11950815	2002	The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease.	38
18414673	2008	Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis.	37

Citation

Hannu Koistinen ; Outi Itkonen ; Ulf-Hakan Stenman

SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1)

Atlas Genet Cytogenet Oncol Haematol. 2014-12-01

Online version: http://atlasgeneticsoncology.org/gene/42375/spink1