Reduced expression of hepatocyte growth factor activator inhibitor type-2/placental bikunin (HAI-2/PB) in human glioblastomas: Implication for anti-invasive role of HAI-2/PB in glioblastoma cells

Abstract

Hepatocyte growth factor activator inhibitor type-2/placental bikunin (HAI-2/PB) is a serine proteinase inhibitor that contains 2 Kunitz-domains and a presumed transmembrane domain. It has broad inhibitory spectra against various serine proteinases showing potent inhibitory activities not only to hepatocyte growth factor activator but also to plasmin, trypsin and kallikreins. In this study, we investigated the expression of HAI-2/PB in human gliomas in viv o and the effects of HAI-2/PB on the fibrinolytic and invasive capabilities of human glioblastoma cells in vitr o. With RNA blot analysis, HAI-2/PB mRNA was expressed in normal brain and in low-grade astrocytomas, but was hardly detectable in anaplastic astrocytomas and glioblastomas, indicating that its expression levels were inversely correlated with the histological grade of human gliomas. To further explore the possible role of HAI-2/PB in glioma progression, cultured human glioblastoma cell lines (U251 and YKG-1) were transiently transfected with an expression vector harboring human HAI-2/PB cDNA. Subsequent analysis indicated that the expression of HAI-2/PB suppressed the fibrinolytic activities of both glioblastoma cell lines. Moreover, HAI-2/PB inhibited Matrigel invasion of U251 and YKG-1 cells by 30% and 64%, respectively. This anti-invasive effect appeared to be mediated primarily by the inhibitory activity of HAI-2/PB against the serine proteinasedependent matrix degradation. These findings suggest that the reduced expression of HAI-2/PB is possibly involved in the progression of human gliomas.

Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells

“…7C and D). Similar to a previous report (Hamasuna et al, 2001), forced re-expression of SPINT2 also reduced cell mobility in U87G cells as accessed by artificial wound healing analysis (data not shown).…”

Aberrant Methylation of Promoter Region of SPINT2/HAI-2 Gene: An Epigenetic Mechanism in Hepatitis C Virus-Induced Hepatocarcinogenesis

“…The disturbed methylation status in the promoter region of the SPINT2/HAI-2 gene highlighted its potential use as an emerging anticancer agent (Hamasuna et al, 2001). Kobayashi et al (2004) reported that oral SPINT2/HAI-2 therapy reduced tumor load in a nude mouse model and in human ovarian cancer.…”

“…In addition, it inhibits the formation of active HGF by inhibiting the action of the HGF activator (Tung et al, 2009). It is recognized as a tumor suppressor gene and its underexpression has been reported in cancers, such as breast cancer (Parr et al, 2004) and glioblastoma (Hamasuna et al, 2001;Schuster et al, 2003). Morris et al (2005) have demonstrated promoter region hypermethylation of SPINT2/HAI-2 in renal cell carcinoma cell lines and primary tumors; however, the role in HCC is still under research.…”

Hepatocyte Growth Factor, a Key Tumor-Promoting Factor in the Tumor Microenvironment

“…Intestinal deletion of endogenous HAI-1 augments Wnt signaling in Apc Min/+ mice, both in tumors and in normal mucosa, and enhances intestinal tumor formation [72], confirming that HAI-1 has tumor suppressor properties. Accordingly, reduced expression of HAIs is associated with advanced disease and poor outcome in cancer patients [72,73,74,75,76,77,78]. Small molecule inhibitors of HGFA and antibodies neutralizing HGFA and matriptase have been developed [79] as potential therapeutic agents.…”