Expression of Placental Leucine Aminopeptidase and Adipocyte-Derived Leucine Aminopeptidase in Human Normal and Malignant Invasive Trophoblastic Cells

Abstract

SUMMARY:We recently identified two novel aminopeptidases, placental leucine aminopeptidase (P-LAP) and adipocytederived leucine aminopeptidase (A-LAP). Enzymatically, P-LAP degrades oxytocin, vasopressin, and angiotensin III, while A-LAP degrades angiotensin II and kallidin. In this study we investigated the expression and localization of P-LAP and A-LAP in human trophoblastic cells in the normal placenta (n ϭ 26), gestational choriocarcinoma (n ϭ 8), and placental site trophoblastic tumor (n ϭ 3). On immunoblot analysis both P-LAP and A-LAP proteins were detected in normal placenta and five choriocarcinoma tissues, as well as in two choriocarcinoma cell lines. Immunohistochemical staining of normal placental tissues demonstrated that P-LAP was not only localized in villous syncytiotrophoblasts but also highly expressed in extravillous trophoblasts (EVTs) invading the decidua or maternal spiral arteries. The expression level of P-LAP on these invasive EVTs reached a maximum during the late first to second trimesters of pregnancy, and it decreased in the third trimester. Similarly, A-LAP was strongly expressed in EVTs invading the decidua or spiral arteries in the second trimester of pregnancy, while it was weakly or moderately expressed in villous cytotrophoblasts or EVTs located in the cell columns. These two aminopeptidases were more strongly expressed in all eight choriocarcinomas and three placental site trophoblastic tumors and mainly localized to the intermediate-type trophoblastic tumor cells invading the uterine myometrium or stromal vessels. In summary P-LAP and A-LAP were predominantly expressed in the invasive phenotype of EVTs during placentation, as well as in the invasive tumor cells of trophoblastic neoplasms. These results suggest the involvement of these aminopeptidases in invasiveness of both normal and malignant intermediate-type trophoblasts possibly through degradation of specific peptide substrates. (Lab Invest 2003, 83:1799 -1809.

LAP3 promotes glioma progression by regulating proliferation, migration and invasion of glioma cells

“…Because of the resistance of glioma cells to conventional therapies, it is very difficult to cure; however, the identification of genes or proteins that effectively promote or inhibit tumor growth, migration and invasion is imperative [25]. The dysregulation expression of LAPs (leucine aminopeptidases) could result in changes in tumor cell proliferation, invasion and/or angiogenesis, such as endometrial carcinoma, endothelial cells, breast cancer, trophoblastic neoplasms, ovarian cancer [11][12][13][14][15]. But the study of LAP3 in neoplasms is less, the latest research reported LAP3 is upregulateed in human esophageal squamous cell carcinoma [21].…”

“…In addtion, P-LAP also promotes the progression of breast cancer [14]. P-LAP and A-LAP were predominantly expressed in the invasive phenotype of EVTs during placentation, as well as in the invasive tumor cells of trophoblastic neoplasms [15]. PT-PCR and Western blot showed that the expression of LAP3 was increased in high-grade glioma tissues (grade III and grade IV) compared with in low-grade glioma tissues (grade II) and in normal brain.…”

Distribution of Adipocyte-derived Leucine Aminopeptidase (A-LAP)/ER-aminopeptidase (ERAP)-1 in Human Uterine Endometrium

“…Enzymatically, aminopeptidases hydrolyze N-terminal amino acids of peptide substrates with their own specificity. Recently, our group identified A-LAP in human invasive trophoblastic cells (Ino et al 2003). Among the bioactive peptides, it appears that angiotensin II may play important roles in such processes as angiogenesis, vasoconstriction, and trophoblast invasion in the cyclic endometrium (Li and Ahmed 1996;Ando et al 2002;Xia et al 2002).…”

Endocrine aspects of pre-eclampsia

“…Angiotensin (3-8) (Ang IV) has been shown to influence blood flow through a mechanism mediated by its specific receptor (AT4 receptor) and nitric oxide. Ino et al [41] have previously described AT4 receptors in extravillous trophoblasts and suggested they may play a role in placentation. AT4 receptors are known to be upregulated in healthy placentae, possibly as a control mechanism to prevent Ang IV binding to the AT1 receptor.…”