Isthmin 2 is decreased in preeclampsia and highly expressed in choriocarcinoma

Abstract

Introduction: Isthmin 2 (ISM2) is a protein which expression in humans is almost specific to the placenta. There is no previous report in the literature that investigated this protein in preeclampsia or choriocarcinoma.

Methods: We conducted a prospective, cross-sectional study that included women with preeclampsia, gestational hypertension and normotensive pregnancy. We measured serum concentrations of ISM2 protein and performed immunohistochemistry in placenta tissues. We also performed immunohistochemistry of ISM2 in samples from choriocarcinoma and compare with lung, prostate, colon, gastric and breast cancers.

Results: A total of 81 patients were included, 30 with preeclampsia, 21 with gestational hypertension and 30 controls. The ISM2 protein was found to be decreased in patients with preeclampsia compared to the control group (P = 0.036). These results were confirmed by immunohistochemistry. We also found that ISM2 protein was overexpressed in choriocarcinoma.

Discussion: Taken together, our results suggest an angiogenic function for ISM2. Its serum level decreased in our patients with preeclampsia could be reflecting that it is involved in the pathogenesis of the disease; on the other hand its high expression in choriocarcinoma, indicates that ISM2 may play an active role in the angiogenesis of this and other cancers.

Keywords: Angiogenic protein; Biomarkers; Choriocarcinoma; Evidence-based medicine; ISM2; Laboratory medicine; Obstetrics and gynecology; Preeclampsia; Pregnancy; Reproductive system.

Figure 1

ISM1 protein shows no difference in the circulation and placenta in patients with preeclampsia. Circulating ISM1 protein was measured in 30 women with normotensive pregnancy (Control), 21 patients with gestational hypertension (GH) and 30 patients with preeclampsia (PE). In Panel A, ISM1 protein showed no statistically difference in preeclampsia compared with control group and gestational hypertension. We performed immunohistochemistry of ISM1 in placenta tissues from normotensive, gestational hypertension and preeclampsia pregnancies. In Panel B, we observed that 100% of the trophoblastic cells in the normal placentas show diffuse nuclear positivity for ISM1 antibody with accentuated intensity. In Panel C, placentas from gestational hypertension displayed high intensity for ISM1 antibody in about 97% of the trophoblastic cells and finally in preeclamptic placentas ISM1 antibody exhibited strong intensity in 95% of the trophoblastic cells (Panel D). Regarding immunohistochemistry of ISM1, nonrelevant difference between the staining of the ISM1 protein in normal, gestational hypertension and preeclamptic placentas was demonstrated.

Figure 2

ISM2 protein is decreased in the circulation and placenta in patients with preeclampsia. Circulating ISM2 protein was measured in 30 women with normotensive pregnancy (Control), 21 patients with gestational hypertension (GH) and 30 patients with preeclampsia (PE). In Panel A, circulating ISM2 was significantly decreased in women with preeclampsia relative to healthy controls (P = 0.036). We performed immunohistochemistry of ISM2 in placenta tissues from normotensive, gestational hypertension and preeclampsia pregnancies. ISM2 protein expression through immunohistochemistry was also decreased in the preeclampsia group relative to controls. ISM2 showed focal positivity in the cytoplasmic edge in a median of 173 trophoblastic cells per 10 high power fields (HPF) in normal placentas (Panel B), focal positivity in the cytoplasmic edge in a median of 145 trophoblastic cells per 10 HPF in placentas from gestational hypertension (Panel C), and focal positivity in the cytoplasmic edge in a median of 52 trophoblastic cells per 10 HPF in preeclamptic placentas (Panel D).

Figure 3

ISM2 protein is highly expressed in choriocarcinoma compared with lung, prostate, colorectal, gastric and breast cancer tissues. Tissue sections of lung, prostate, colorectal, gastric and breast cancer tissues were compared with choriocarcinoma. We organized the pictures from the higher expression (scored as 3+, 2+) to lesser expression (1+, 0). In Panels A and B, we displayed two magnification of ISM2 protein staining in choriocarcinoma, Panel A x10, Panel B x40. They show a strong (3+) and diffuse positivity expression of ISM2 protein in all the cancer tissue. In Panels C and D, we can notice that ISM2 protein showed less positivity expression than previous, we observed moderate (2+) and diffuse positivity expression in lung adenocarcinoma (x10). Similarly, adenocarcinoma of prostate showed a moderate (2+) and diffuse positivity expression for ISM2 protein which is depicted in Panel E (x4). Panel F displays a mild (1+) and focal positivity expression for ISM2 protein in colorectal adenocarcinoma (x10). Panel G shows a mild (1+) and focal positivity expression for ISM2 protein in poorly cohesive carcinoma gastric (x40). Panel H displays that the immunoreaction of ISM2 protein was negative in invasive ductal carcinoma of the breast (x10).