Siglec-6 is expressed in gestational trophoblastic disease and affects proliferation, apoptosis and invasion

Abstract

Sialic acid immunoglobulin-like lectin (Siglec)-6 is a transmembrane receptor that binds leptin. Leptin is an obesity-associated peptide hormone overexpressed in gestational trophoblastic disease (GTD). GTD encompasses several placental abnormalities that range from benign to malignant. Among GTD, molar placentas are characterized by excess proliferation, whereas gestational trophoblastic neoplasias (GTN) have characteristically aggressive invasion. We hypothesized that in GTD, Siglec-6 expression would increase with disease severity and that Siglec-6 and leptin would promote proliferation, inhibit apoptosis and/or promote invasion. Siglec-6 expression patterns were evaluated with particular attention to the diagnostic utility of Siglec-6 in GTD (controls: normal placentas (n=32), hydropic abortus placentas (n=7), non-GTD reproductive tract cancers (n=2); GTD: partial moles (PM; n=11), complete moles (n=24), GTN (n=6)). In normal placentas, Siglec-6 expression dramatically decreased after 8 weeks gestation. Complete molar placentas had significantly higher Siglec-6 expression than controls, but expression was not significantly different from PM. In GTN, Siglec-6 expression was low. These data suggest that Siglec-6 may have diagnostic utility for distinguishing complete moles from normal and hydropic abortus placentas. Functional studies in choriocarcinoma-derived BeWO cells demonstrated a complex interplay between Siglec-6 expression and leptin exposure. In cells lacking Siglec-6, leptin treatment promoted invasion, likely through interaction with LepR leptin receptor, without affecting proliferation or apoptosis. Siglec-6 expression promoted proliferation in a leptin-dependent manner, but protected cells from apoptosis and promoted invasion in a leptin-independent manner. We propose that Siglec-6 and leptin play a role in the aberrant properties characteristic of GTD, namely excess proliferation and invasion.

The maternal plasma proteome changes as a function of gestational age in normal pregnancy: a longitudinal study

“…A recent report has documented an increase in Siglec-6 expression in the placenta following spontaneous labor and delivery in comparison to those following elective cesarean section without labor; therefore, it has been proposed that this molecule may play a role in the process of parturition (270,271). In addition, increased Siglec-6 trophoblast expression was reported in women with gestational trophoblastic disease and those with preterm preeclampsia (124, 269,[272][273][274]. The findings in Siglec-6 reported herein provide further support that an increase in abundance of this protein, detected with current technology in the maternal circulation, may have biological and clinical implications.…”

“…In addition, this molecule can also serve as a leptin receptor (OB-BP1), which has high specificity and affinity to this molecule. Importantly, Siglec-6 is expressed only in cyto-and syncytiotrophoblasts of the human placenta (268)(269)(270), and this may explain how it gains access to the maternal circulation and increases with gestational age as the volume of the villous tree increases (270). A recent report has documented an increase in Siglec-6 expression in the placenta following spontaneous labor and delivery in comparison to those following elective cesarean section without labor; therefore, it has been proposed that this molecule may play a role in the process of parturition (270,271).…”

Expression patterns of maspin and mutant p53 are associated with the development of gestational trophoblastic neoplasia

“…At present, there is a relative lack of predictive markers for GTN. Novel markers include telomerase activity, apoptotic activity and expression of Siglec-6, all of which have been associated with the development of GTN from HMs (20–22); however, these correlations have yet to be conclusively demonstrated.…”

Daidzein inhibits choriocarcinoma proliferation by arresting cell cycle at G1 phase through suppressing ERK pathway in vitro and in vivo

“…However, ~25% of gestational trophoblastic tumors will be resistant to, or will relapse after initial chemotherapy (3,4). Also, in development of gestational trophoblastic disease, excess proliferation is an important clue and is related with outcome of treatment (5,6). Therefore, we are wondering if there is an alternative medicine which may inhibit trophoblastic cell proliferation and improve the curative rate of choriocarcinoma.…”