Hydatidiform Research Articles

Elucidation of the role of XBP1 in the progression of complete hydatidiform mole to invasive mole through RNA-seq

ObjectiveA complete hydatidiform mole (CHM) is a common disease and is known to develop post-molar gestational trophoblast neoplasia (GTN). However, the molecular mechanisms underlying the progression of CHM to post-molar GTN remain largely unknown. In this study, we investigated the molecular factors associated with the progression using RNA-seq. MethodsWe included 13 patients with CHM and performed RNA-seq using freshly frozen samples. We identified differentially expressed genes between patients who developed GTN (GTN group) and those who achieved spontaneous remission after uterine evacuation (SR group), and performed pathway analysis. Then, functional analyses were performed on choriocarcinoma (JAR and JEG-3) and CHM (Hmol1-3B and Hmol1-2C) cells. Moreover, we evaluated the in vivo tumorigenicity of XBP1-overexpressed Hmol1-3B cells. ResultsThe gene expression profiles were separated into two groups, and an upstream regulator analysis was performed using 281 differentially expressed genes. We focused on transcription factors and identified that 33 transcription factors were activated in the GTN group. Then, excluding those with low expression levels in clinical samples and cell lines, XBP1 was selected for further analysis. Additionally, XBP1 downregulation significantly decreased the migration and invasive abilities of choriocarcinoma cells, whereas XBP1 overexpression significantly increased the migration and invasive abilities of CHM cells. Furthermore, animal experiments showed that tumor weight and blood human chorionic gonadotropin (hCG) levels were significantly higher in the XBP1-overexpressing Hmol1-3B-bearing mice than those in the control mice. ConclusionRNA-seq identified XBP1 as a key factor in post-molar GTN, suggesting it contributes to the development of post-molar GTN.

How long is hCG monitoring required after normalization following evacuation of a complete hydatidiform mole? A national, retrospective population study

How long is hCG monitoring required after normalization following evacuation of a complete hydatidiform mole? A national, retrospective population study

Gestational Trophoblastic Tumours: Experience of the Oncology Department of the Moulay Ismail Military Hospital in Meknes (10 Cases)

Gestational trophoblastic tumors (GTTs) are the malignant forms of gestational trophoblastic diseases. They always follow a pregnancy, most often molar. The diagnosis of GTT is based on an abnormal course of HCG (chorionic gonadotropin hormone) and/or signs of ultrasound invasion and/or histological confirmation. We report a retrospective series of 10 cases of GTT collected at the Medical Oncology Department of the Moulay Ismail Military Hospital in Meknes over an 8-year period from January 2012 to January 2020. The analysis of our series led to the conclusion that: The average age of onsetis 42 years. 90% of our patients were pauciparic. The causal pregnancy was in 90% of the cases a molar pregnancy. The extension assessment was mainly based on the TAP CT identifying the lung as the main metastatic site in 40% of cases. 5 patients (50% of cases) underwent hysterectomy with post operative chemotherapy. 60% of our patients were classified as low risk according to the FIGO score and received methotrexate mono-chemotherapy. 4 patients were classified as high-risk and were treated with poly chemotherapy, the main protocol of which was EMA-CO. All our patients benefited from clinical and biological monitoring, before each chemotherapy session; then weekly and monthly after negativation, up to 12 months in case of good prognosis GTT, and up to 18 months in case of bad prognosis GTT. One case of MTX relapse (the case of IPTT) was reported and for which a 2nd line CMT with a favourable evolution was indicated. This study allowed us to analyze the cure rate, which was 100% for patients who were treated and had completed their monitoring.

Association of gestational trophoblastic disease with subsequent development of non-trophoblastic cancer.

To evaluate the association between gestational trophoblastic disease and the subsequent risk of developing non-trophoblastic cancer. We conducted a retrospective cohort study of 3084 women with gestational trophoblastic disease and 1 415 812 women with obstetric deliveries in Quebec, Canada, between 1989 and 2021. The main exposure was gestational trophoblastic disease, including hydatidiform moles, invasive moles, and gestational choriocarcinoma. The outcome was development of non-trophoblastic cancer during 33 years of follow-up. We measured the association of gestational trophoblastic disease with non-trophoblastic cancer using adjusted hazard ratios (HR) and 95% confidence intervals (CI), and tested whether associations were stronger for certain types of cancer or cancers with later onset. The incidence of non-trophoblastic cancer was greater for women with invasive moles (47.1/10 000 person-years) and gestational choriocarcinoma (59.3/10 000 person-years) than hydatidiform moles (18.4/10 000 person-years) and no gestational trophoblastic disease (22.4/10 000 person-years). Gestational choriocarcinoma (HR 2.33, 95% CI: 1.35-4.01; P = 0.002) and invasive moles (HR 1.97, 95% CI: 1.06-3.65; P = 0.033) were associated with an elevated risk of non-trophoblastic cancer compared with no gestational trophoblastic disease, while hydatidiform moles were not. Gestational choriocarcinoma and invasive moles were mainly associated with gynecologic cancer. However, risk of cancer was limited to the short-term period after pregnancy and became similar to no gestational trophoblastic disease by the end of follow-up. While invasive moles and gestational choriocarcinoma appear to be associated with the subsequent development of non-trophoblastic cancer, the absolute risk is small and limited to the short-term.

7617 Two Cases of Severe Beta-hCG-Mediated Hyperthyroidism with Gestational Trophoblastic Disease

Abstract Disclosure: A. Morvant: None. M. Mashayekhi: None. Introduction: Hyperthyroidism is most commonly caused by Graves’ disease and toxic nodules and affects 2.5% of the world’s population. Hyperthyroidism due to elevations in beta-hCG (b-hCG), which has thyroid-stimulating activity due to homology with TSH, is a rare process that requires high clinical suspicion. We present two cases of hyperthyroidism caused by severely elevated b-hCG due to gestational trophoblastic disease (GTD), with rapid resolution of hyperthyroidism after treatment of the underlying conditions. Clinical Cases Case 1: A 35-year-old at 28-weeks gestation presented with dyspnea, palpitations, and 6-pound weight loss over the prior month. Labs revealed b-hCG 5.2 million (0-5 mIU/mL), TSH <0.015 (0.35-3.6 mcU/mL), and free T4 2.42 (0.7-1.37 ng/dL). Imaging revealed extensive pulmonary lesions concerning for metastatic disease and a 2.4 cm ovarian mass. Due to worsening respiratory distress and the need to start chemotherapy urgently, she underwent Cesarean section to deliver the viable infant and take out the ovarian mass. Pathology confirmed choriocarcinoma. Methimazole was started post-operatively, and she started chemotherapy. Labs after cycle one of chemotherapy showed b-hCG 1.3 million, TSH <0.015, and free T4 1.46. The methimazole dose was decreased and ultimately stopped as free T4 levels decreased with subsequent chemotherapy cycles. After three cycles, labs showed b-hCG 4,652, TSH 1.55, and free T4 0.68. She was discharged without thyroid-targeting therapy. Case 2: A 33-year-old woman at 12-weeks gestation presented with nausea, vomiting, and 10-pound weight loss over 1 month. Labs showed TSH <0.015, free T4 2.39, and total T3 351 (58-160 ng/dL), which were thought to be due to hyperemesis gravidarum. Two months later she presented with vaginal bleeding and imaging showed an enlarged placenta with a moth-eaten appearance and theca lutein cysts concerning for partial molar pregnancy. Beta-hCG level was 3.3 million, TSH <0.015, free T4 1.76, and total T3 289. She underwent dilation and evacuation and pathology confirmed partial hydatidiform mole. Beta-hCG level decreased to 1.8 million and free T4 normalized after surgery, with b-hCG 3,300, normal TSH, and normal total T3 one month later. Conclusion: These cases highlight the importance of considering possible GTD when evaluating a patient with hyperthyroidism, particularly in women of childbearing age and cases of early pregnancy when the degree of hyperthyroidism seems out of proportion to that expected. Clinicians should consider checking a b-hCG level in consultation with an obstetrician when indicated. Treatment is aimed at the GTD and can yield rapid resolution of hyperthyroidism.

A-337 The Utility of Urinary Human Chorionic Gonadotropin Testing in the Emergency Department

Abstract Background Human chorionic gonadotropin (hCG) levels are measured in both urine and blood as an indication of suspected pregnancy, and assessment of progress of conception. It is also measured in the investigation of patients presenting with acute abdomen and suspected of ectopic or molar pregnancy. This study reviewed the utility of urine pregnancy test in a large university teaching hospital. Methods Results of all urinary hCG tests (using hCG Combo Pregnancy kit, MEDLINE, IL) performed as point of care in the emergency department during the year 2023 were obtained. Corresponding plasma hcG levels performed (Total β-HCG Alinity immunoassay, Abbott Diagnostics, IL) were also obtained. Analysis of hCG testing outcomes were assessed. Results A total of 2848 urinary hCG tests were performed during the study period. The majority 2113 (74.2%) of samples were negative for hCG whereas 835 samples (29.3) were positive. Among the positive hCG urine samples, 401 patients (48%) had plasma hCG requested and performed. Plasma hCG values ranged from < 2.4 (26.5) to 219,462.5 mIU/mL (median 16,872.35 mIU/mL). One plasma sample with corresponding positive urinary hCG result had plasma hCG level <2.4 mIU/mL which is below the detection limit of the assay suggesting a false positive urinary hCG result. Among the 13 patients with serial plasma hCG values, only one patient exhibited doubling (48 hours) hCG values when less than 13,000 mIU/mL. One patient had a declining serial hCG plasma values suggesting failing conception. The remaining patients with consecutive plasma hCG values cannot be assessed as either the time gap was excessive or hCG values were markedly elevated (> 30,000 mIU/mL). Conclusions Although the utility of urinary hCG testing in the emergency department appeared appropriate, unnecessary repeat analysis with appropriate plasma request represented 3.2%. An electronic test request duplicate notification may help resolve this unnecessary repeat.

Prevalence and management of ectopic and molar pregnancies in 17 countries in Africa and Latin America and the Caribbean: a secondary analysis of the WHO multi-country cross-sectional survey on abortion

IntroductionThere are limited global data on ectopic pregnancy (EP) and molar pregnancy (MP), making it important to understand their epidemiology and management across different regions. Our study aimed to describe...

Trophoblastic disease and choriocarcinoma

Gestational trophoblastic disease (GTD) is a group of diseases associated with pregnancies that demonstrate abnormal development of trophoblastic cells. GTD includes hydatidiform moles (HM) that may continue to further develop into gestational trophoblastic neoplasms (GTN), such as choriocarcinoma (CC). Gestational CC is a malignant mass development that may arise from HM, from other (normal) pregnancies or from other gestational events (such as ectopic pregnancies). The aim of this review is to outline current understating of the genetics and epigenetics of GTD and gestational CC and the link between the two diseases.

Ultrasonic detective: Solving the mystery of molar pregnancy

Ultrasonic detective: Solving the mystery of molar pregnancy

The causal relationship between hydatidiform mole and nutrients: A two-sample Mendelian randomization study

BackgroundHydatidiform mole (HM), a subset of gestational trophoblastic disease, is considered precancerous and exhibits geographical variation. The incidence of HM is linked to nutritional factors. This study aimed to investigate the causal relationship between nutrients and HM using a bidirectional two-sample Mendelian randomization (MR) approach. MethodsWe utilized publicly available genome-wide association study data to assess the causal associations between levels of specific vitamins (retinol, vitamins B12, B6, C, D, E, folate, and carotene) and minerals (iron, calcium, and magnesium) with HM. The MR analysis was conducted and reported following the STROBE-MR guidelines, employing MR Egger and inverse variance weighted (IVW) methods to estimate associations, with MR-PRESSO for pleiotropy testing. ResultsThe study revealed vitamin B6 as a significant protective factor against HM (MR-Egger OR: 0.094, 95% CI: 0.011-0.0778, P < 0.05; IVW OR: 0.365, 95% CI: 0.142-0.936, P < 0.05). Folate and magnesium showed suggestive associations with HM, whereas most other nutrients did not exhibit a causal relationship. MR-PRESSO analysis supported the absence of horizontal pleiotropy of vitamin B6. Besides, reverse MR analysis did not reveal a significant causal association between HM and serum nutrient levels, suggesting that differences of nutrients in HM patients may not be directly attributed to the mole. ConclusionThis MR study provides evidence that vitamin B6 may protect against HM, and suggests potential roles for folate and magnesium in HM development, while highlighting the need for further research to confirm these findings.

Comprehensive Proteomic Analysis Reveals Distinct Features and a Diagnostic Biomarker Panel for Early Pregnancy Loss in Histological Subtypes

Early pregnancy loss (EPL) is a common event in human reproduction and is classified into histological subtypes such as hydropic abortion (HA) and hydatidiform moles (HMs), including complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs). However, accurate diagnosis and improved patient management remain challenging due to high rates of misdiagnosis and diverse prognostic risks. Therefore, diagnostic biomarkers for EPL are urgently needed. Our study aimed to identify biomarkers for EPL through comprehensive proteomic analysis. Ten CHMs, six PHMs, ten HAs and ten normal control (NC) products of conception (POC) were used to obtain a proteomic portrait. Parallel reaction monitoring (PRM)-targeted proteomic and regression analyses were used to verify and select the diagnostic signatures. Finally, 14 proteins were selected and a panel of diagnostic classifiers (DLK1, SPTB/COL21A1, and SAR1A) was built to represent the CHM, PHM, and NC groups (auROC=0.900, 0.804/0.885, and 0.991, respectively). This high diagnostic power was further validated in another independent cohort (n = 148) by immunohistochemistry (IHC) (n = 120) and western blot (WB) analyses (n = 28). The protein SPTB was selected for further biological behaviour experiments in vitro. Our data suggest that SPTB maintains trophoblast cell proliferation, angiogenesis, cell motility and the cytoskeleton network. This study provides a comprehensive proteomic portrait and identifies potential diagnostic biomarkers. These findings enhance our understanding of EPL pathogenesis and offer novel targets for diagnosis and therapeutic interventions.

Enhanced Extravillous Trophoblast Gene Expression at the Origin of the Pathology of Hydatidiform Moles and their Malignancies.

Enhanced Extravillous Trophoblast Gene Expression at the Origin of the Pathology of Hydatidiform Moles and their Malignancies.

Androgenetic/biparental mosaic/chimeric gestation: A case report

Introduction: Androgenetic/biparental mosaic/chimeric (ABMC) conceptions are a rare group of gestational trophoblastic disease (GTD) that arise as a result of mosaicism or chimerism and are characterized by hydropically enlarged and variably sized villi. Currently, there are very few reports describing ABMC conceptions; there are 13 total in the literature, and even more rare are those with a molar component. Case Report: A 27-year-old female patient at 6+4wga presented to the clinic with a complaint of new vaginal bleeding and was diagnosed with a pregnancy of unknown location. The patient re-presented to the clinic at 8+4wga by last menstrual period (LMP) for a follow-up ultrasound. A serum human chorionic gonadotropin (hCG) was ordered and returned at 424,008 mIU/mL. A transvaginal ultrasound demonstrated a heterogeneous “snowstorm” appearance throughout uterine cavity, with a concern for complete mole in the setting of a significantly elevated beta hCG. The patient underwent a suction dilation and curettage with ultrasound guidance. Pathology returned the following report: The specimen was sent to pathology and DNA ploidy returned as diploid; however, p57 demonstrated a discordant staining pattern characterized by expression in villous cytotrophoblast but the absence in villous stromal cells was characteristic of androgenetic/biparental mosaic/chimeric gestation. No fetal parts were identified in gross examination of the specimen. Conclusion: Androgenetic/biparental mosaic/chimeric (ABMC) conceptions are important to accurately diagnose because the molar form carries an increased risk for persistent gestational trophoblastic diseases. There are few case reports published regarding ABMC cases. We present this case to provide additional data to the field and emphasize the utility for p57 immunohistochemistry and genetic testing to be performed.

Normally Developing Pregnancy and Hydatidiform Mole: A Case Report

Introduction: Hydatidiform mole with a normally developing fetus is a rare case associated with an increased risk of bleeding, preterm birth, preeclampsia, congenital anomalies, and intrauterine fetal death.Case report: We report a case of a twin pregnancy with a hydatidiform mole and a normal fetus. The pregnancy was conceived via in vitro fertilization. The complete hydatidiform mole was diagnosed during the first screening. We extended the pregnancy until 38 weeks’ gestation. Thanks to the control of beta-human chorionic gonadotropin levels and dynamic ultrasound monitoring, the woman successfully gave birth.

Cesarean scar choriocarcinoma following a cesarean scar molar pregnancy: A case report

Gestational choriocarcinoma, a rare variant of gestational trophoblastic disease, typically arises from abnormal trophoblastic cell proliferation post-pregnancy, often associated with a hydatidiform mole. While most choriocarcinoma cases develop within the uterine cavity, an exceedingly rare manifestation occurs within a previous cesarean section scar. In our study, a 31-year-old woman with a history of hydatidiform mole presented with amenorrhea and spotting. Initial assessments revealed elevated beta-human chorionic gonadotropin (βhCG) levels and a heteroechoic mass at her prior cesarean section scar in sonographic examination. Histopathologic findings and the metastatic workup categorized the patient as FIGO stage I, indicating no metastasis. Due to the absence of metastasis, adjuvant chemotherapy was omitted. Total abdominal hysterectomy confirmed choriocarcinoma. Post-surgery, βhCG levels notably decreased, remaining negative during the two-year follow-up with no reported symptoms. Our findings suggest that surgical resection and meticulous βhCG monitoring may be a promising treatment strategy for non-metastatic choriocarcinoma.

Hypermethylated RASAL1’s promotive role in chemoresistance and tumorigenesis of choriocarcinoma was regulated by TET2 but not DNMTs

BackgroundPatients with choriocarcinoma (CC) accompanying chemoresistance conventionally present a poor prognosis. Whether ras protein activator like-1 (RASAL1) functions as a tumor promoter or suppressor depends on tumor types. However, the role of RASAL1 in process of chemoresistance of CC and underlying molecular mechanism remain elusive.MethodsThe expression pattern of RASAL1 in CC cells and tissues was measured using Western blotting, immunohistochemistry and qRT-PCR. Cell viability and proliferative ability were assessed by MTT assay, Tunnel assay and flow cytometric analysis. Additionally, the stemness was evaluated by the colony formation and tumor sphere formation. Methotrexate (MTX) was applied to exam the chemosensitivity of CC cells.ResultsThe expression of RASAL1 was reduced both at the protein and mRNA levels in CC tissues and cells compared to hydatidiform mole (HM) and invasive mole (IM). Loss of RASAL1 was attributed to its promoter hypermethylation and could be restored by 5-Aza. Knock-down of RASAL1 promoted the viability, proliferative potential, stemness and EMT phenotype of JEG-3 cells. However, induced overexpression of RASAL1 by 5-Aza significantly prohibited cell proliferation and stemness potential of the JAR cell. Additionally, the xenograft model indicated that knockdown of RASAL1 led to a remarkable increase of tumor volume and weight in comparison with its counterpart. Moreover, the stimulatory activity brought by decrease of RASAL1 could be deprived by β-catenin inhibitor XAV 939, yet the suppressive activity resulted from its promoter demethylation could be rescued by β-catenin activator BML-284, indicating that function of RASAL1 depends on β-catenin. Besides, the co-immunoprecipitation assay confirmed the physical binding between RASAL1 and β-catenin. Further investigations showed hypermethylated RASAL1 was regulated by TET2 but not DNMTs.ConclusionTaken together, the present data elucidated that reduced RASAL1 through its promoter hypermethylation regulated by TET2 promoted the tumorigenicity and chemoresistance of CC via modulating β-catenin both in vitro and in vivo.

Enhancing Clinicopathological Diagnosis of Hydatidiform Mole Through the Combined Application of Histomorphologic Analysis, Immunohistochemical Analysis of p57 Expression, and Short Tandem Repeat Typing Method

This study aims to assess the early histomorphologic characteristics and investigate the role of the p57kip2 protein combined with STR genotyping for pathological diagnosis and typing of the hydatidiform mole (HM). A total of 73 induced abortion tissues were collected for pathological evaluation, including 14 cases with partial HM (PHM), 7 cases with complete HM (CHM), and 52 cases with non-molar pregnancies. Histopathological examination of moles was conducted using hematoxylin and eosin staining. DNA extraction from paraffin sections was performed using Fe3O4 nano-magnetic beads. Molecular diagnosis was performed using STR genotyping. Immunohistochemical analysis was used to determine the distribution and expression level of p57kip2 protein in HM. Significant differences were observed in the morphological indices of villous edema, cistern formation, trophoblastic inclusions, and trophoblastic hyperplasia between the PHM and CHM groups (P &lt; 0.05). The central cistern formation and the trophoblast inclusion showed a significant difference between the HM and non-molar pregnancy (P &lt; 0.05). Moreover, our findings revealed that p57kip2 expression contributed to distinguishing CHM from PHM. However, it could not distinguish PHM from non-mole pregnancy. Furthermore, the results of STR genotyping were consistent with pathological typing. In conclusion, the integration of pathomorphology, immunohistochemical staining, and molecular diagnostics holds great value for the diagnosis and classification of HM.

Gestational Trophoblastic Neoplasia Rate and Its Related Factors in Women With a Partial Hydatidiform Mole at Tudu Hospital, Vietnam.

Background Minimal studies have been carried out on a partial hydatidiform mole (PHM) in Vietnam, so the treatment outcomes for patients with PHM are unknown. This study aimed to determine the occurrence rate of gestational trophoblastic neoplasia (GTN) and its related factors in women with PHM at Tu Du Hospital, Vietnam. Materials and methods This retrospective cohort study included 370 women with PHM diagnosed through a histopathological assessment following termination of pregnancy at Tu Du Hospital from January 2020 to December 2021. Survival analysis was used for GTN cumulative rate estimationand the Cox regression model for determining GTN-related factors. Results After a 1-year follow-up, 21 patients were found to have GTN, exhibiting a rate of 5.7% (95% confidence interval (CI): 3.5 - 8.4). GTN occurred 4.67±2.23 weeks following curettage with peaks at weeks 3-6.No cases of GTN were recorded eight weeks following termination by curettage. After multivariate analysis, the GTN rate was higher in patients with a history of miscarriage/termination (hazard ratio (HR)=2.84; 95% CI: 1.05-7.69). Conclusion The rate of GTN in PHM patients was 5.7%. Patients who had a history of miscarriage or termination were 2.84 times more likely to develop GTN than patients who did not.

Morphological Diversity of the Endometrium in Choriocarcinoma Specimens and its Role in Differential Diagnosis.

Introduction: The morphological characteristics of the endometrium in patients with choriocarcinoma have not been well described. We described the endometrial morphology patterns in 46 choriocarcinomas and analyzed their relationship with the clinicopathological characteristics of these patients. Methods: Forty-six patients diagnosed with choriocarcinoma that had sufficient endometrial tissues for histopathological diagnosis were selected. Diagnoses of choriocarcinoma and secretory status of endometrium were reviewed. LHCGR expression of endometrium was evaluated by immunostaining. Results: Endometrial morphology was classified as secretory or nonsecretory. The 15 secretory specimens included 2 highly secretory and 13 common secretory specimens. The 31 nonsecretory patterns included 1 hyperplasia without atypia, 7 disordered proliferations, 13 typical proliferations, and 10 resting endometria. Among these, 11 specimens with overall nonsecretory patterns showed focally weak secretory changes surrounding the choriocarcinoma lesion. Secretory patterns were observed in classic choriocarcinomas (8/17) and monomorphic choriocarcinomas (7/21) but not in scanty-trophoblast choriocarcinomas (0/8). Secretory changes appeared significantly less frequently in patients who received multi-agent chemotherapy (4/25) than in those who did not (7/14) or received single-agent chemotherapy (4/7) (P = 0.030). The differences in age, months since the last pregnancy, pregnancy type, recurrence, specimen type, gross diameter, human chorionic gonadotropin (hCG) levels, and expression of hCG receptors were not statistically significant. Conclusions: The endometrial morphologies in choriocarcinoma were diverse, including various proliferative and secretory changes, but rarely hypersecretory changes, compared to the prevailing hypersecretory endometrium in hydatidiform moles. The variety in endometrial morphology was the consequence of ovarian hormonal disturbances of the hypothalamic-pituitary-gonadal axis by hCG from choriocarcinoma. Therefore, the endometrium may serve as a clue for histopathological diagnosis of choriocarcinoma. Our study presents the largest cohort reported to date to describe the diverse spectrum of endometrial changes in choriocarcinoma patients.

HLA-C expression in extravillous trophoblasts is determined by an ELF3–NLRP2/NLRP7 regulatory axis

The distinct human leukocyte antigen (HLA) class I expression pattern of human extravillous trophoblasts (EVT) endows them with unique tolerogenic properties that enable successful pregnancy. Nevertheless, how this process is elaborately regulated remains elusive. Previously, E74 like ETS transcription factor 3 (ELF3) was identified to govern high-level HLA-C expression in EVT. In the present study, ELF3 is found to bind to the enhancer region of two adjacent NOD-like receptor (NLR) genes, NLR family pyrin domain-containing 2 and 7 (NLRP2, NLRP7). Notably, our analysis of ELF3-deficient JEG-3 cells, a human choriocarcinoma cell line widely used to study EVT biology, suggests that ELF3 transactivates NLRP7 while suppressing the expression of NLRP2. Moreover, we find that NLRP2 and NLRP7 have opposing effects on HLA-C expression, thus implicating them in immune evasion at the maternal-fetal interface. We confirmed that NLRP2 suppresses HLA-C levels and described a unique role for NLRP7 in promoting HLA-C expression in JEG-3. These results suggest that these two NLR genes, which arose via gene duplication in primates, are fine-tuned by ELF3 yet have acquired divergent functions to enable proper expression levels of HLA-C in EVT, presumably through modulating the degradation kinetics of IkBα. Targeting the ELF3-NLRP2/NLRP7-HLA-C axis may hold therapeutic potential for managing pregnancy-related disorders, such as recurrent hydatidiform moles and fetal growth restriction, and thus improve placental development and pregnancy outcomes.