SPINT2
HGNC:11247 19q13.1 Entrez:10653 MIM.605124
SPINT2 gene encodes a transmembrane protein with two extracellular Kunitz domains that inhibits a variety of serine proteases. The protein inhibits HGF activator which prevents the formation of active hepatocyte growth factor.
This gene is a putative tumor suppressor, and mutations in this gene result in congenital sodium diarrhea. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq] HAI-1 and HAI-2 may possibly be therapeutic target for treatment approaches in ovarian cancer.
Pathology
syndromic congenital sodium diarrhea
- Syndromic congenital sodium diarrhea is a distinct diseas entity cause by SPINT2 loss-of-function mutations.
cancer
- HAI-2 is a candidate tumour suppressor gene that is frequently hypermethylated and underexpressed in human HCCs, and the KD-1 domain of HAI-2 is the key region responsible for its anti-invasive function.
- SPINT2 could be a putative tumor suppressor gene in medulloblastoma and further implicate dysregulation of the HGF/MET signaling pathway in the pathogenesis of medulloblastoma.
- Epigenetic inactivation of HAI-2/SPINT2 causes loss of RCC tumor suppressor activity and implicates abnormalities of the MET pathway in clear cell and papillary sporadic RCC.
- Frequent hypermethylation of SPINT2 gene in human hepatocellular carcinoma.
GeneRIF (February 2010)
HAI-1 and HAI-2 may possibly be therapeutic target for treatment approaches in ovarian cancer
Low HAI-2 expression in cervical cancer may be associated with a poor prognosis.
Unlike HAI-1 and matriptase, HAI-2 expression is detected in non-epithelial cells of brain and lymph nodes, suggesting that HAI-2 may also be involved in inhibition of serine proteases other than matriptase
HAI2 hypermethylation is associated with hepatocellular carcinoma
Hepatocyte growth factor activator inhibitor 2 is regulated by hypoxia in breast cancer
Overexpression of bikunin is associated with suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line
cDNA microarray analysis of gene expression regulated by bikunin in an ovarian cell line, including the pattern of gene expression leading to a block in cell invasion.
Urinary levels provide insight into proteinase/proteinase inhibitor imbalance in patients with inflammatory diseases.
There is a distinct regulation of hepatocyte growth factor activator inhibitor type 2 gene expression in testis and that HAI-2 may play a role in the process of spermatogenesis
Low level of HAI-2 is associated with breast cancer
Bikunin downregulates constitutive & PMA-stimulated uPAR mRNA & protein Through suppression of upstream ERK cascade targets, whether cells were treated with exogenous bikunin or transfected with bikunin gene.
Bikunin was colocalized with tryptase in dermal mast cells, and a small quantity of bikunin was also deposited in the intercellular spaces in FE and ADL.
The use of high hydrostatic pressure (1000-3000 bar) for the refolding of bikunin aggregates was investigated.
There are no significant differences in serum HAI-2 levels among prostate cancer subgroups according to clinical stage.
suppresses lipopolysaccharide-induced lethality through down-regulation of tumor necrosis factor- alpha and interleukin-1 beta in macrophages.
bik-R can physically interact with the CD44v isoforms containing epitope v9 and function as a repressor to down-regulate PMA-stimulated uPA expression, at least in part, by preventing clustering of CD44v isoforms containing epitope v9.
Study demonstrates that the expression of HAI-2/PB is under methylation control to a variable extent in glioma cell lines, in comparison to the other tested neoplasm cell lines (brain, breast, prostate, liver).
The active form of HGFA is specifically complexed with the membrane-form HAI-1 (serine peptidase inhibitor, Kunitz type 1), but not with HAI-2/PB (serine peptidase inhibitor, Kunitz type 2), on the surface of epithelial cells expressing both inhibitors.
See also
SPINTs