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

• We examined HAI-1 immunolabeling in the brains of neurologically normal persons and patients with Alzheimer's disease (AD) and cerebral infarction [4].
• HAI enters its first at-risk contract to manage mental health for MetLife [5].

High impact information on SPINT1

• HAI-1 is also a cognate inhibitor of matriptase, a membrane-associated serine proteinase [6].
• HAI-1 is expressed predominantly in epithelial cells in the human body [6].
• Its mRNA is also abundant in human placenta, with HAI-1 specifically expressed by villous cytotrophoblasts [6].
• Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is required for branching morphogenesis in the chorioallantoic placenta [6].
• As early as E9.5, HAI-1-/- embryos showed growth retardation that did not reflect impaired cell proliferation but resulted instead from failed placental development and function [6].

Chemical compound and disease context of SPINT1

• Matriptase activation and shedding with HAI-1 is induced by steroid sex hormones in human prostate cancer cells, but not in breast cancer cells [7].
• During the course of acetic acid-induced murine experimental colitis, HAI-1, but not HAI-2, was indeed upregulated in the recovery phase [8].
• However, the methods that are used to diminish the toxicity of HAI and efficient systemic chemotherapy, such as a combination of 5-FU and leucovorin, are required to prevent extrahepatic metastases [9].
• CONCLUSIONS: Therapy with HAI of FUDR improves the survival of patients with liver metastases over colorectal carcinoma [9].
• PURPOSE: Since systemic and regional (HAI) fluorinated pyrimidine chemotherapies offer similar survival benefit in treatment of colorectal liver metastases (CLM), we sought to identify their impact on quality of life (QoL), which might be a useful indicator of treatment preference [10].

Biological context of SPINT1

• These results suggest that the structural integrity of the SPINT1-positive CTB layer may play an important role in villous differentiation and in maintenance of the villous tree via the HGF signaling system during gestation [11].
• 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 [12].
• HAI-1 and -2 genes consist of 11 and 8 exons spanning 12 kbp and 12.5 kbp, respectively [13].
• The genes were mapped to chromosome 15q15 (HAI-1) and 19q13.11 (HAI-2) [13].
• By screening a placental cDNA library, we discovered a new splice variant of HAI-1 designated HAI-1B that contains an extra 16 amino acids adjacent to the C terminus of KD1 [2].

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

• METHODS: Serum levels of HAI-1 and HAI-2 were measured by enzyme-linked immunosorbent assay in 27 patients with benign prostatic hyperplasia (BPH) and 118 patients with prostate cancer [3].
• In addition to HAI-1, low but distinct expression of HGFA mRNA was observed in the placenta tissue and cultured cytotrophoblasts by using a sensitive RT-PCR method [14].
• The epithelial-selective expression of matriptase and HAI-1 was further confirmed in human breast cancers by immunohistochemistry and in situ hybridization, where the expression of the protease and the inhibitor were found in the carcinoma cells and in surrounding normal breast epithelia [20].
• EXPERIMENTAL DESIGN: We have determined by immunohistochemistry the expression of matriptase and HAI-1 in 54 epithelial ovarian cancers [21].
• HAI was associated with similar survival to systemic chemotherapy but with better sustained QoL [10].

References