Disease relevance of SPINT2

• Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma [1].
• Overall a low level of HAI-2 in the breast cancer tissues was associated with an overall poor outlook [2].
• 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 [3].
• There were no significant differences in serum HAI-2 levels among prostate cancer subgroups according to clinical stage [4].
• Because the expression of HAI-2/B is inversely related to glioma invasiveness and degree of malignancy, this finding may provide insight into glioma initiation and progression as well as potentially providing new therapeutic targets [5].

Psychiatry related information on SPINT2

• The form of the test amino acid (CAA = crystalline, PB = protein-bound) had little effect on choice behavior, but sudden transfer of WCS from a PB acclimation diet to test diets with a large total CAA concentration increased the latency of effective choice by 2-3 days [6].

High impact information on SPINT2

• As activating mutations in the MET proto-oncogene (the HGF receptor) cause familial RCC, we investigated whether HAI-2/SPINT2 might act as a RCC tumor suppressor gene [1].
• Following treatment with a demethylating agent, 5 of 11 renal cell carcinoma (RCC) cell lines showed increased expression of hepatocyte growth factor (HGF) activator inhibitor type 2 (HAI-2/SPINT2/Bikunin), a Kunitz-type protease inhibitor that regulates HGF activity [1].
• We found that transcriptional silencing of HAI-2 in RCC cell lines was associated with promoter region methylation and HAI-2/SPINT2 protein expression was down-regulated in 30% of sporadic RCC [1].
• The primary translation product of HAI-2 has a hydrophobic sequence in the COOH-terminal region, suggesting that, like HAI-1, HAI-2 is produced in a membrane-associated form and secreted in a proteolytically truncated form [7].
• The cDNA sequence revealed that HAI-2 is derived from a precursor protein of 252 amino acids and contains two Kunitz domains, indicating that HAI-2 is also a member of the Kunitz family of serine protease inhibitors [7].

Chemical compound and disease context of SPINT2

• During the course of acetic acid-induced murine experimental colitis, HAI-1, but not HAI-2, was indeed upregulated in the recovery phase [8].
• Previous microarray analysis demonstrated that 14 genes, including hepatocyte growth factor activator inhibitor 2/placental bikunin (HAI2/PB) gene, showed particularly high inductions after 5-aza-2'deoxycytidine (5Aza-dC) treatment in multiple hepatoma cell lines [9].
• Purification and characterization of protein PB of betaine reductase and its relationship to the corresponding proteins glycine reductase and sarcosine reductase from Eubacterium acidaminophilum [10].
• The influence of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), caffeic acid oxidation product (KOP), and trisodiumphosphonoformate (TPF) on the course of the primary cutaneous herpes simplex virus infection was investigated by means of a guinea pig test model [11].
• Pneumonias were polymicrobial in the absence of antibiotics, due to PCN-sensitive organisms in the topical PB group, and due to gram-negative bacilli in the IV PCN/GM group [12].

Biological context of SPINT2

• The genes were mapped to chromosome 15q15 (HAI-1) and 19q13.11 (HAI-2) [13].
• 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].
• 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 [3].
• Subsequent experiments revealed that there are two major transcription start sites of the HAI-2 gene, which are -30 bp and -360 bp upstream from the translation initiation ATG codon [14].
• These results suggest a distinct regulation of HAI-2 gene expression in testis and that HAI-2 may play a role in the process of spermatogenesis [14].

Anatomical context of SPINT2

• Hepatocyte growth factor activation inhibitors (HAI-1 and HAI-2) regulate HGF-induced invasion of human breast cancer cells [3].
• An immunohistochemical study using a specific monoclonal antibody raised against human HAI-2 protein indicated that HAI-2 is expressed exclusively in primary spermatocytes [14].
• In IPF fibroblasts, HGFA expression was lower and HAI-1 and HAI-2 expression was higher compared with control fibroblasts [15].
• Immunohistochemical studies revealed that HAI-1 but not HAI-2 was detected more strongly in regenerative epithelium than in normal epithelium, although both proteins were detected throughout the human gastrointestinal tract [16].
• CONCLUSIONS: HAI-1 and HAI-2 were expressed in renal tubular epithelial cells [17].

Associations of SPINT2 with chemical compounds

• A point mutation in the COOH-terminal Kunitz domain did not affect the activity of HAI-2, whereas a point mutation in the NH2-terminal Kunitz domain markedly reduced the activity [18].
• Diffusion coefficients of PY and PB, of their complexes, and of rhodamine 110 are given and compared to those of similar molecules [19].
• Additionally, high levels of HAI-2 were a significant predictor for poor clinical complete response to preoperative epirubicin in univariate (P = 0.01) and multivariate analyses (P = 0.016) [20].
• We found that this peptide can also fold into a helix H1 conformation when dissolved in a TFE/PB mixture [21].
• The latter subunits cross-reacted with antibodies raised against PB betaine and showed high sequence similarity to the 45-kDa and 48-kDa subunits of PB betaine, respectively [10].

Regulatory relationships of SPINT2

• In human testis, HAI-2 was strongly expressed whereas HAI-1 mRNA was hardly detectable [14].

Other interactions of SPINT2

• Purification and cloning of hepatocyte growth factor activator inhibitor type 2, a Kunitz-type serine protease inhibitor [7].
• HGFA, HAI-1, and HAI-2 expression was evaluated by immunohistochemistry, RNA protection assay, and Western blot [15].
• Identification and cloning of human placental bikunin, a novel serine protease inhibitor containing two Kunitz domains [22].
• The effect of HIF-1alpha RNAi on HAI-2 expression was evaluated in these cells [20].
• HAI-2 also correlated with hypoxia markers such as carbonic anhydrase IX expression (P = 0.01) and HIF-1alpha [20].

Analytical, diagnostic and therapeutic context of SPINT2

• 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 [4].
• After treatment with 5-Aza-CdR, re-expression and demethylation of HAI-2/PB gene were detected in these cells [23].
• Methylation-specific PCR analysis demonstrated that HAI-2/PB hypermethylation occurred in 21 of 26 HCC tumors (80.8%), whereas in the corresponding nontumorous liver tissues, it was found in 7 of 26 samples (26.9%) [23].
• An endogenous soluble form of this protein, which was designated as placental bikunin, was highly purified from human placenta by sequential kallikrein-Sepharose affinity, gel filtration, and C18 reverse-phase chromatography [22].
• In the present study, we studied all of these genes except for the HAI2/PB gene and examined DNA methylation status and levels of acetylated histones using bisulphite genomic sequencing and the chromatin immunoprecipitation (ChIP) assay, respectively [9].

References