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Gene Review

SPINT1  -  serine peptidase inhibitor, Kunitz type 1

Homo sapiens

Synonyms: HAI, HAI-1, HAI1, Hepatocyte growth factor activator inhibitor type 1, Kunitz-type protease inhibitor 1, ...
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Disease relevance of SPINT1

  • Overall, our data demonstrates the important roles of HAI-1 and HAI-2 in cancer metastasis, and reveals that these serine protease inhibitors display strong therapeutic potential [1].
  • An additional ribozyme transgenes study revealed that elimination of HAI-1 and HAI-2 expression, in an MDA-MB-231 breast cancer cell line, significantly enhanced the migratory, proliferative and invasive nature of these breast cancer cells [1].
  • Both isoforms were up-regulated in eight examined ovarian carcinoma specimens, three of which had higher levels of HAI-1B RNA than of HAI-1 RNA [2].
  • Therefore, previously demonstrated roles of HAI-1 in various physiological and pathological processes likely involve both HAI-1B and HAI-1 [2].
  • RESULTS: The mean serum levels of HAI-1 in patients with prostate cancer were significantly higher than those in patients with BPH [3].

Psychiatry related information on SPINT1


High impact information on SPINT1


Chemical compound and disease context of SPINT1


Biological context of SPINT1


Anatomical context of SPINT1

  • In the present study, we investigated the structural integrity of the CTB layer in the normal villous tree by advanced microscopy techniques using an antibody to hepatocyte growth factor (HGF) activator inhibitor type 1 (SPINT1), a potent inhibitor of HGF activators expressed exclusively on villous CTB [11].
  • We generated a retroviral expression system that induced HAI expression in a human fibroblast cell line [1].
  • Three exons were inserted between KD1 and KD2 of each gene, of which the middle one was the low-density lipoprotein (LDL) receptor-like domain (HAI-1) and the testis specific exon (HAI-2) [13].
  • Hepatocyte growth factor activator inhibitor-1 (HAI-1) is an integral membrane protein expressed on epithelial cells and contains two extracellular Kunitz domains (N-terminal KD1 and C-terminal KD2) known to inhibit trypsin-like serine proteases [2].
  • The localization of HAI-I in the proliferating trophoblastic stem cells (Langhans' cells), but not in syncytiotrophoblasts and extravillous trophoblasts, suggest a possible role of HAI-1 in the proliferation of trophoblasts [14].

Associations of SPINT1 with chemical compounds

  • Recent studies demonstrate that HAI-1 and HAI-2 may also potently inhibit a number of other pro-metastatic serine proteases and therefore have direct bearing on the spread of tumours [1].
  • Indeed, all activated matriptase was detected in complexes with HAI-1 only 5 min after suramin stimulation [15].
  • As a result of shedding, the cellular levels of matriptase and HAI-1 were significantly reduced 24 h after exposure to DHT [7].
  • The same regimen of systemic 5-FU also was administered to the HAI group in the event of extrahepatic progression [9].
  • PATIENTS AND METHODS: One hundred sixty-six patients were assigned randomly to HAI of floxuridine (5 fluoro-2'deoxyuridine [FUDR]) 0.3 mg/kg/d for 14 days every 4 weeks or to the control group; this latter group, depending on the investigator's choice, was either under observation or received systemic fluorouracil (5-FU) [9].

Regulatory relationships of SPINT1

  • These results suggest that HAI-1 is a cell-surface acceptor of activated HGFA in regenerative epithelial cells, and functions on the cell surface to localize the active HGFA that is going to enter the repair process [8].
  • In human testis, HAI-2 was strongly expressed whereas HAI-1 mRNA was hardly detectable [16].
  • These results indicate that Kunitz I is the functional domain of HAI-1 for inhibiting the HGF-converting activity of HGF activator [17].
  • Taken together, these results support multiple roles for HAI-1 to regulate matriptase, including its proper expression, intracellular trafficking, activation, and inhibition [18].

Other interactions of SPINT1

  • In addition, the expression levels of SPINT1, ST14, HGF, and MET mRNAs in the villous tree increased over the course of gestation [11].
  • The binding of HGFA to HAI-1 was reversible, and no irreversible modifications affecting the enzyme activity occurred during the binding [12].
  • Hepatocyte growth factor activation inhibitors (HAI-1 and HAI-2) regulate HGF-induced invasion of human breast cancer cells [1].
  • Furthermore, prostasin was isolated with two major HAI-1/1B fragments (40 and 58 kDa) from OVCAR3 cell medium, demonstrating that prostasin.HAI-1/1B complexes are formed naturally [19].
  • Matriptase and HAI-1 were detected at the protein and mRNA levels both in hormone-dependent and hormone-independent cultured breast cancer cells, and this expression correlated with the expression of the epithelial markers E-cadherin or ZO-1 [20].

Analytical, diagnostic and therapeutic context of SPINT1


  1. Hepatocyte growth factor activation inhibitors (HAI-1 and HAI-2) regulate HGF-induced invasion of human breast cancer cells. Parr, C., Jiang, W.G. Int. J. Cancer (2006) [Pubmed]
  2. Tissue expression, protease specificity, and Kunitz domain functions of hepatocyte growth factor activator inhibitor-1B (HAI-1B), a new splice variant of HAI-1. Kirchhofer, D., Peek, M., Li, W., Stamos, J., Eigenbrot, C., Kadkhodayan, S., Elliott, J.M., Corpuz, R.T., Lazarus, R.A., Moran, P. J. Biol. Chem. (2003) [Pubmed]
  3. Serum hepatocyte growth factor activator inhibitor type I (HAI-I) and type 2 (HAI-2) in prostate cancer. Nagakawa, O., Yamagishi, T., Akashi, T., Nagaike, K., Fuse, H. Prostate (2006) [Pubmed]
  4. White matter astrocytes produce hepatocyte growth factor activator inhibitor in human brain tissues. Yamada, T., Tsujioka, Y., Taguchi, J., Takahashi, M., Tsuboi, Y., Shimomura, T. Exp. Neurol. (1998) [Pubmed]
  5. HAI enters its first at-risk contract to manage mental health for MetLife. Bartels-Rabb, L. Contract healthcare. (1988) [Pubmed]
  6. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is required for branching morphogenesis in the chorioallantoic placenta. Tanaka, H., Nagaike, K., Takeda, N., Itoh, H., Kohama, K., Fukushima, T., Miyata, S., Uchiyama, S., Uchinokura, S., Shimomura, T., Miyazawa, K., Kitamura, N., Yamada, G., Kataoka, H. Mol. Cell. Biol. (2005) [Pubmed]
  7. Matriptase activation and shedding with HAI-1 is induced by steroid sex hormones in human prostate cancer cells, but not in breast cancer cells. Kiyomiya, K., Lee, M.S., Tseng, I.C., Zuo, H., Barndt, R.J., Johnson, M.D., Dickson, R.B., Lin, C.Y. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  8. Roles of hepatocyte growth factor activator (HGFA) and its inhibitor HAI-1 in the regeneration of injured gastrointestinal mucosa. Itoh, H., Kataoka, H. J. Gastroenterol. (2002) [Pubmed]
  9. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. Rougier, P., Laplanche, A., Huguier, M., Hay, J.M., Ollivier, J.M., Escat, J., Salmon, R., Julien, M., Roullet Audy, J.C., Gallot, D. J. Clin. Oncol. (1992) [Pubmed]
  10. Effect of regional and systemic fluorinated pyrimidine chemotherapy on quality of life in colorectal liver metastasis patients. Earlam, S., Glover, C., Davies, M., Fordy, C., Allen-Mersh, T.G. J. Clin. Oncol. (1997) [Pubmed]
  11. The cytotrophoblast layer of human chorionic villi becomes thinner but maintains its structural integrity during gestation. Mori, M., Ishikawa, G., Luo, S.S., Mishima, T., Goto, T., Robinson, J.M., Matsubara, S., Takeshita, T., Kataoka, H., Takizawa, T. Biol. Reprod. (2007) [Pubmed]
  12. Hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator (HGFA) and regulates HGFA activity in the pericellular microenvironment. Kataoka, H., Shimomura, T., Kawaguchi, T., Hamasuna, R., Itoh, H., Kitamura, N., Miyazawa, K., Koono, M. J. Biol. Chem. (2000) [Pubmed]
  13. Genomic structure and chromosomal localization of the human hepatocyte growth factor activator inhibitor type 1 and 2 genes. Itoh, H., Yamauchi, M., Kataoka, H., Hamasuna, R., Kitamura, N., Koono, M. Eur. J. Biochem. (2000) [Pubmed]
  14. Localization of hepatocyte growth factor activator inhibitor type 1 in Langhans' cells of human placenta. Kataoka, H., Meng, J.Y., Itoh, H., Hamasuna, R., Shimomura, T., Suganuma, T., Koono, M. Histochem. Cell Biol. (2000) [Pubmed]
  15. Simultaneous activation and hepatocyte growth factor activator inhibitor 1-mediated inhibition of matriptase induced at activation foci in human mammary epithelial cells. Lee, M.S., Kiyomiya, K., Benaud, C., Dickson, R.B., Lin, C.Y. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  16. Expression of hepatocyte growth factor activator inhibitor type 2 (HAI-2) in human testis: identification of a distinct transcription start site for the HAI-2 gene in testis. Yamauchi, M., Itoh, H., Naganuma, S., Koono, M., Hasui, Y., Osada, Y., Kataoka, H. Biol. Chem. (2002) [Pubmed]
  17. Functional characterization of Kunitz domains in hepatocyte growth factor activator inhibitor type 1. Denda, K., Shimomura, T., Kawaguchi, T., Miyazawa, K., Kitamura, N. J. Biol. Chem. (2002) [Pubmed]
  18. HAI-1 regulates activation and expression of matriptase, a membrane-bound serine protease. Oberst, M.D., Chen, L.Y., Kiyomiya, K., Williams, C.A., Lee, M.S., Johnson, M.D., Dickson, R.B., Lin, C.Y. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  19. Identification of hepatocyte growth factor activator inhibitor-1B as a potential physiological inhibitor of prostasin. Fan, B., Wu, T.D., Li, W., Kirchhofer, D. J. Biol. Chem. (2005) [Pubmed]
  20. Matriptase and HAI-1 are expressed by normal and malignant epithelial cells in vitro and in vivo. Oberst, M., Anders, J., Xie, B., Singh, B., Ossandon, M., Johnson, M., Dickson, R.B., Lin, C.Y. Am. J. Pathol. (2001) [Pubmed]
  21. Expression of the serine protease matriptase and its inhibitor HAI-1 in epithelial ovarian cancer: correlation with clinical outcome and tumor clinicopathological parameters. Oberst, M.D., Johnson, M.D., Dickson, R.B., Lin, C.Y., Singh, B., Stewart, M., Williams, A., al-Nafussi, A., Smyth, J.F., Gabra, H., Sellar, G.C. Clin. Cancer Res. (2002) [Pubmed]
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