Genetic Profiling of Sebaceous Carcinoma Arising from an Ovarian Mature Teratoma: A Case Report.

Ovarian mature teratomas (OMTs) originate from post-meiotic germ cells. Malignant transformation occurs in approximately 1-2% of OMTs; however, sebaceous carcinoma arising from OMTs is rare. This is the first report of a detailed genomic analysis of sebaceous carcinoma arising from an OMT. A 36-year-old woman underwent evaluation for abdominal tumors and subsequent hysterectomy and salpingo-oophorectomy. Pathologically, a diagnosis of stage IA sebaceous carcinoma arising from an OMT was established. Eight months post-surgery, the patient was alive without recurrence. Immunohistochemically, the tumor was negative for mismatch repair proteins. A nonsense mutation in TP53 (p.R306*) and a deletion in PIK3R1 were identified. Single nucleotide polymorphisms across all chromosomes displayed a high degree of homozygosity, suggestive of uniparental disomy. Herein, the OMT resulting from the endoreduplication of oocytes underwent a malignant transformation to sebaceous carcinoma via TP53 as an early event and PIK3R1 as a late event.

Multiple Somatic Mutations of SMARCA4 in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: A Case Report.

Small-cell carcinoma of the ovary, the hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young females. It is a monogenic disorder caused by germline and/or somatic SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) mutations. Here, we report a case of SCCOHT harboring multiple previously unreported somatic mutations in SMARCA4 (c.2866_2867delC>T; c.3543del). A 28-year-old breastfeeding Japanese female presented to a previous hospital with nausea and vomiting. She had no family history of relevant malignancies, including ovarian cancer. Based on an evaluation performed at another institution, she was referred to a gynecologist for suspected ovarian cancer. Imaging studies revealed a 16×15 cm heterogenous enhancing mass within the right ovary without lymph node or distant metastasis. She had mild ascites without peritoneal dissemination, but there was an elevation in the serum calcium level (15.1 mg/dL). The patient underwent cytoreductive surgery and was pathologically diagnosed with SCCOHT. Auxiliary immunohistochemical staining confirmed the loss of SMARCA4 protein expression. The patient was diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) 2014 stage IA (pT1a pN0 M0). The serum calcium levels returned to normal post-surgery. Matched-pair analysis using tumor tissue and peripheral blood revealed multiple somatic mutations in SMARCA4, but no deleterious germline mutations were present. Microsatellite instability was not significant, and the patients had a heterozygous mutation of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1)*6. She underwent six cycles of irinotecan hydrochloride plus cisplatin chemotherapy and achieved complete remission. The patient was finally examined and evaluated 45 months postoperatively; there was no evidence of the disease. Overall, the genetic findings will not aid in the SCCOHT diagnosis and relevant genetic counseling; however, they may have implications for the treatment of this disease in the future.

Coexistence of Ovarian Endometrioma and Ovarian Pregnancy: A Case Report.

Both ovarian pregnancy and endometrioma can rupture and cause life-threatening hemoperitoneum. However, little is known about their coexistence. We report the case of a 34-year-old Japanese woman with a life-threatening hemoperitoneum in the first trimester coexisting with ovarian endometrioma and ovarian pregnancy. The patient was hospitalized in our department for acute hypogastric pain and massive hemoperitoneum during pregnancy. She had a history of miscarriage at eight weeks of gestation one year prior. Her serum beta-human chorionic gonadotropin (hCG) level was >2,000 mIU/mL. Also, a transvaginal ultrasound showed an empty uterus, an intact right ovary, an inhomogeneous left ovary, and a massive hemoperitoneum. An exploratory laparoscopy revealed a rupture of the left ovarian endometrioma, a left corpus luteal cyst, and intraperitoneal bleeding of approximately 1,200 mL. However, no ectopic lesions were observed. Microscopic examination revealed an endometriotic cyst with decidual changes in the stroma, a corpus luteal cyst, and chorionic villi with hemorrhage. Serum beta-hCG levels became negative on the 27th postoperative day. The postoperative course was uneventful. This case shows that, in addition to the differential diagnosis of ovarian pregnancy from ovarian endometrioma, clinicians should consider the coexistence of both conditions.

Promising therapeutic targets of endometriosis obtained from microRNA studies.

Endometriosis is a benign tumor that affect 6-10% women of reproductive age. To date, it is suggested that the aberrant microRNA (miRNA) expressions play important roles in the pathogenesis of endometriosis. Reviewing the literature, we found nine overexpressed miRNAs, which were thoroughly investigated in the context of endometriotic tissues and cells. Most of the overexpressed miRNAs induced endometriosis-specific characteristics including inhibition of apoptosis and decidualization, upregulation of fibrogenesis, invasion, migration, cell proliferation, attachment to extracellular matrix, inflammation, and angiogenesis in the endometriotic cells. Then, we found that the downstream target molecules of these miRNAs, such as early growth response protein-1, extracellular signal-regulated kinase, matrix metallopeptidase 1, signal transducer and activator of transcription 3, cyclooxygenase-2, phosphoinositide 3-kinase, AKT, mammalian target of rapamycin, and vascular endothelial growth factor-A are promising for the therapeutic targets of endometriosis. Recent findings suggest that complex molecular mechanisms leading to development and progression of endometriosis by miRNAs may exist in endometriosis. The meticulous balance between tumorigenic miRNAs and tumoristatic miRNAs may destine the natural course and response to the surgical, medical, and hormonal treatments of this disease. Further investigations into endometriosis-associated miRNAs may elucidate the pathogenesis of endometriosis and help to develop novel therapeutics.

Role of repressed microRNAs in endometriosis.

Endometriosis is a common, estrogen-dependent benign tumor that affect 3-10% women of reproductive age, and is characterized by the ectopic growth of endometrial tissue, which is found primarily in the rectovaginal septum, ovaries, and pelvic peritoneum. To date, accumulating evidence suggests that various epigenetic aberrations, including the expression of aberrant microRNAs (miRNAs), play definite roles in the pathogenesis of endometriosis. This review summarizes the recent findings on the aberrantly repressed miRNAs, as well as their potential roles regarding the pathogenesis of endometriosis.

Report from "International Workshop for Junior Fellows 2: Tocolytic treatment for prevention of preterm birth" at the 73rd Annual Congress of the Japan Society of Obstetrics and Gynecology.

At the 73rd Annual Congress of the Japan Society of Obstetrics and Gynecology, we discussed recent tocolytic treatments for the prevention of preterm birth with obstetricians from Korea and Taiwan. The rate of preterm birth in our countries has been increasing, and optimal tocolytic treatments are of great concern. Ritodrine hydrochloride was the first available drug for tocolysis in our countries and is often administered for over 48 h, although it is not recommended for maintenance therapy in Western countries. Meanwhile, there are differences in the use of other tocolytic drugs, based on approval of the drugs and the health insurance systems. Nifedipine and atosiban have not been considered first-line agents in Japan. The long-term use of unnecessary tocolysis should be avoided, and the introduction of other tocolytic drugs, including nifedipine or atosiban, should be discussed.

hsa-miR-199a-3p Inhibits Motility, Invasiveness, and Contractility of Ovarian Endometriotic Stromal Cells.

It is suggested that aberrantly expressed microRNAs are involved in the pathogenesis of endometriosis. Our previous study demonstrated that expression of the microRNA hsa-miR-199a-3p is attenuated in human endometriotic cyst stromal cells (ECSCs). The current study aimed to define the roles of hsa-miR-199a-3p in the development of endometriosis. ECSCs and normal endometrial stromal cells (NESCs) were isolated from ovarian endometrioma and normal endometrial tissues, respectively. We evaluated the effect of transfected hsa-miR-199a-3p on the migration, invasion, and contractility of ECSCs using Transwell migration assays, in vitro wound healing assays, Transwell invasion assays, and collagen gel contraction assays. We also examined the downstream target of hsa-miR-199a-3p with an online public database search and luciferase reporter assay. Expression of hsa-miR-199a-3p in ECSCs was significantly lower than that in NESCs, whereas the expression of p21-activated kinase 4 (PAK4) mRNA was significantly higher. Transfection of hsa-miR-199a-3p inhibited the migration, invasion, and contractility of ECSCs via inhibition of PAK4 mRNA expression. PAK4 was confirmed to be the direct target of hsa-miR-199a-3p. Transfection of PAK4 small interfering RNA and the PAK4 inhibitor PF-3758309 also inhibited ECSC migration, invasion, and contractility. These findings suggest that hsa-miR-199a-3p may act as a tumor suppressor in endometriosis development. Attenuation of hsa-miR-199a-3p expression was favorable for ECSCs to acquire the highly invasive, motile, and contractile characteristics of endometriotic cells and is involved in the development of endometriosis. Accordingly, PAK4 inhibitors may be promising for the treatment of endometriosis.

Uterine torsion in non-gravid women: A case report and review of cases reported in the last 20 years.

Uterine torsion is defined as a rotation of >45° around the long axis of the uterus. Uterine torsion is an uncommon event but is even rarer in non-gravid women, with only 25 cases reported in the last 20 years. Here, we report a case of uterine torsion associated with multiple pedunculated subserosal uterine leiomyomas in an 83-year-old woman. She presented at the hospital with lower abdominal pain, and a computed tomography scan revealed multiple uterine leiomyomas with calcifications. Subsequent magnetic resonance imaging raised suspicion for torsion of pedunculated subserosal uterine leiomyomas. Emergency laparotomy was performed, and the patient was diagnosed with uterine torsion with multiple pedunculated subserosal uterine leiomyomas. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. The patient's postoperative course was uneventful. Although difficult to diagnose due to its rarity, uterine torsion can be life-threatening and may cause infertility. Therefore, early diagnosis with imaging and surgical intervention are crucial to avoid serious complications.

Port-site implantation of parasitic leiomyoma after laparoscopic myomectomy and its histopathology.

Although parasitic leiomyoma could be spontaneous or iatrogenic in origin, port-site implantation of parasitic leiomyoma is an iatrogenic benign sequela of laparoscopic surgery. A 30-year-old, primigravida Japanese woman was referred after unresponsiveness to preoperative gonadotropin-releasing hormone for intramural fibroids. Magnetic resonance imaging showed multiple intramural fibroids and left ovarian endometrioma with no malignant features. Laparoscopic myomectomy with power morcellation and ovarian cystectomy were performed, followed by treatment with a combined oral contraceptive. Seven years after the primary surgery, she underwent abdominal myomectomy for a port-site, and peritoneal recurrence of the leiomyoma and intramural leiomyomas was detected. Microscopic examination revealed that resected specimens from the port-site demonstrated leiomyoma with lesser cell density and more prominent hyalinization than those from the uterus. Therefore, clinicians should counsel patients regarding the risks and benefits of laparoscopy with morcellation versus laparotomy. Further development of techniques for uterine tissues extraction is warranted.

Pembrolizumab and Radiotherapy for Platinum-refractory Recurrent Uterine Carcinosarcoma With an Abscopal Effect: A Case Report.

BACKGROUND: Immune responses due to radiotherapy and immune checkpoint inhibitors potentially have synergistic effects. CASE REPORT: Here, we report a 65-year-old Japanese woman presenting with high-grade endometrial cancer. She was diagnosed with carcinosarcoma, stage IB. A month post-surgery, lung, and mediastinal lymph node metastasis/recurrence was detected. Progressive disease (with high microsatellite instability) with local recurrence and bone metastasis was detected after six chemotherapy cycles with paclitaxel and carboplatin. After combination therapy with pembrolizumab (2 mg/kg, tri-weekly, 10 cycles) and pelvic radiotherapy (30 Gy/10 fractions), enhanced computed tomography revealed a complete response. The patient survived for 14 months with the residual tumour post-relapse. This is the first case of a complete response of recurrent endometrial carcinosarcoma upon combinatorial pembrolizumab and radiotherapy. CONCLUSION: Combinatorial immune checkpoint inhibitors and local radiotherapy cause the abscopal effect and may be a promising treatment strategy for advanced or recurrent carcinosarcomas refractory to traditional chemotherapy.

hsa-miR-100-5p, an overexpressed miRNA in human ovarian endometriotic stromal cells, promotes invasion through attenuation of SMARCD1 expression.

BACKGROUND: A number of microRNAs are aberrantly expressed in endometriosis and are involved in its pathogenesis. Our previous study demonstrated that has-miR-100-5p expression is enhanced in human endometriotic cyst stromal cells (ECSCs). The present study aimed to elucidate the roles of has-miR-100-5p in the pathogenesis of endometriosis. METHODS: Normal endometrial stromal cells (NESCs) were isolated from normal eutopic endometrium without endometriosis. Using hsa-miR-100-5p-transfected NESCs, we evaluated the effect of hsa-miR-100-5p on the invasiveness of these cells by Transwell invasion assay and in-vitro wound repair assay. We also investigated the downstream signal pathways of hsa-miR-100-5p by microarray analysis and Ingenuity pathways analysis. RESULTS: hsa-miR-100-5p transfection enhanced the invasion and motility of NESCs. After hsa-miR-100-5p transfection, mRNA expression of SWItch/sucrose non-fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 (SMARCD1) was significantly attenuated. Whereas, the expression of matrix metallopeptidase 1 (MMP1) mRNA and active MMP1 protein levels was upregulated. CONCLUSION: We found that SMARCD1/MMP-1 is a downstream pathway of hsa-miR-100-5p. hsa-miR-100-5p transfection enhanced the motility of NESCs by inhibiting SMARCD1 expression and MMP1 activation. These findings suggest that enhanced hsa-miR-100-5p expression in endometriosis is involved in promoting the acquisition of endometriosis-specific characteristics during endometriosis development. Our present findings on the roles of hsa-miR-100-5p may thus contribute to understand the epigenetic mechanisms involved in the pathogenesis of endometriosis.

Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) with sarcomatous features without recurrence after extended radical surgery: A case report.

RATIONALE: The malignant potential and the appropriate treatment of uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is controversial. Although these tumors generally have benign outcomes, several reports have described recurrences, metastases, and deaths associated with this disease. PATIENT CONCERNS: A 57-year-old Japanese woman (gravida 2, para 2) was referred to our hospital for the evaluation and treatment of uterine fibroids. Magnetic resonance imaging revealed a right ovarian mass and multiple fibroids in the uterine myometrium. DIAGNOSES: The patient was diagnosed with UTROSCT with sarcomatous features. INTERVENTIONS: She initially underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by second-stage surgery comprising pelvic and para-aortic lymphadenectomy and subtotal omentectomy. OUTCOMES: No postoperative recurrence was observed in the patient in 36 months. LESSONS: In this case, extended radical surgery prevented the development of recurrent disease in a patient with UTROSCT with sarcomatous features. These clinicopathological findings suggest that UTROSCT is associated with several risk factors, including older age, presence of necrosis, lymphovascular invasion, significant nuclear atypia, and significant mitotic activity. This lesion type should be considered malignant and treated with curative intent.

Chemokine expression profiles of ovarian endometriotic stromal cells in three-dimensional culture.

Endometriosis is a chronic inflammatory disease which is associated with aberrant chemokine expression. We have established a three-dimensional (3D) floating collagen gel culture of human endometriotic cyst stromal cells (ECSCs) as an in vitro model of early-stage fibrosis formation in endometriosis. We evaluated the gene expression profiles of 3D-cultured ECSCs using a gene expression microarray. We identified and confirmed with reverse transcription-polymerase chain reaction that mRNA levels of CXCL1, CXCL2, CXCL3, CXCL8, and CCL20 in 3D-cultured ECSCs were significantly higher than in 2D-cultured ECSCs. The protein levels of CXCL1, CXCL2, CXCL8, and CCL20 in the supernatant of 3D-cultured ECSCs were significantly higher than in 2D-cultured ECSCs. It has been suggested that the 3D-culture model of ECSCs is more suitable for in vitro endometriosis research than 2D-culture. This microarray data provides a new platform to identify the candidate genes involved in the pathogenesis of endometriosis which could be masked in conventional 2D-culture.

ATM expression is attenuated by promoter hypermethylation in human ovarian endometriotic stromal cells.

A number of genes involved in the pathogenesis of endometriosis are silenced by the hypermethylation of their promoter regions. We assessed the effect and mechanism of the DNA demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) (10 µM) on the cell cycle in human endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) by flow cytometry. The DNA methylation status of G2/M checkpoint regulators were investigated by methylation-specific PCR. The expression of ataxia telangiectasia mutated (ATM) and the effect of 5-aza-dC on its expression were also evaluated by quantitative RT-PCR and western blotting analysis. 5-aza-dC treatment resulted in the cell cycle arrest of ECSCs at the G2/M phase. In contrast, 5-aza-dC did not affect the cell cycle of NESCs. The promoter region of the ATM gene was hypermethylated in ECSCs, but not in NESCs. ATM mRNA expression was attenuated in ECSCs compared to that in NESCs. Further, 5-aza-dC was found to restore ATM expression in ECSCs by its promoter demethylation. Our findings indicate that ATM promoter hypermethylation occurs in endometriosis, and that ATM silencing is involved in tumorigenesis during this disease; moreover, selective DNA demethylating agents and molecular target drugs against ATM silencing are promising for the treatment of endometriosis.

Therapeutic dilemma in twin reversed arterial perfusion sequence.

The dissemination of minimally invasive in utero surgery reduced the mortality of twin reversed arterial perfusion sequence, but the mortality of expectantly treated surgical candidates remains high. A 26-year-old, non-parous, Japanese woman at 13 weeks of gestation had been diagnosed with twin reversed arterial perfusion sequence and was judged as a surgical candidate for radiofrequency ablation. However, she did not undergo surgery because of the anatomical location of the acardiac twin. At 18 weeks of gestation, the blood flow to the acardiac twin disappeared spontaneously. The pump twin began to demonstrate fetal growth retardation during the third trimester. The patient delivered a 1891 g female at term. We macroscopically identified the cause of the fetal growth retardation as velamentous insertion of the umbilical cord and microscopically diagnosed the acardiac twin with acardiac acephalus. We should give the same attention to the management of post-twin reversed arterial perfusion sequence as twin reversed arterial perfusion sequence itself.

Arcyriaflavin a, a cyclin D1-cyclin-dependent kinase4 inhibitor, induces apoptosis and inhibits proliferation of human endometriotic stromal cells: a potential therapeutic agent in endometriosis.

BACKGROUND: We previously showed that microRNA-503 (miR-503) transfection into endometriotic cyst stromal cells (ECSCs) induced cell cycle arrest at the G0/G1 phase by suppressing cyclin D1. This finding prompted us to evaluate the potential therapeutic effects of cyclin D1 inhibitors in endometriotic cells. This study aimed to determine whether arcyriaflavin A, a representative inhibitor of cyclin D1-cyclin-dependent kinase 4 (CDK4), is beneficial in the treatment of endometriosis. METHODS: ECSCs were isolated from the ovarian endometriotic tissues of 32 women. The effects of arcyriaflavin A on cell viability and proliferation, vascular endothelial growth factor A expression, apoptosis, and cell cycle progression were evaluated using a modified methylthiazoletetrazolium assay, enzyme-linked immunosorbent assay (ELISA), Caspase-Glo® 3/7 assay, and flow cytometry. RESULTS: Arcyriaflavin A significantly inhibited cell viability, proliferation, and angiogenesis of ECSCs as assessed using the 5-bromo-2-deoxyuridine (BrdU) and methylthiazoletetrazolium bromide (MTT) assays, and vascular endothelial growth factor (VEGF) ELISA. Arcyriaflavin A induced apoptosis as shown in the Caspase-Glo® 3/7 assay and cell death detection ELISA whilethe cell cycle was arrested at the G0/G1 phase. CONCLUSION: The findings indicate that cyclin D1-CDK4 inhibitors may be promising candidates for the treatment of endometriosis. This is the first study to demonstrate the potential usefulness of arcyriaflavin A as a therapeutic agent for endometriosis. Further studies of the effects of cyclin D1-CDK4 inhibitors on endometriosis may provide useful information on pathogenesis and treatment.

Decidualization Differentially Regulates microRNA Expression in Eutopic and Ectopic Endometrial Stromal Cells.

Decidualization of the endometrium and endometriosis involves the morphological and biochemical reprogramming of the estrogen-primed proliferative stromal compartment under the continuing influence of progesterone. Here, we evaluated the involvement of microRNA in the decidualization processes of normal endometrial stromal cells (NESCs) and endometriotic cyst stromal cells (ECSCs). In vitro decidualization of NESCs and ECSCs was induced by long-term culture with a combination of 0.5 mmol/L of dibutyryl cyclic adenosine monophosphate and 100 nmol/L of dienogest. We investigated the effect of in vitro decidualization on the microRNA and messenger RNA (mRNA) expression profiles of the NESCs and ECSCs using global microarray techniques and an Ingenuity Pathways Analysis. Decidualization differentially enhanced the miR-30a-5p expression in the NESCs and the miR-210 expression in the ECSCs. The enhanced miR-30a-5p expression in the NESCs correlated with the increased mRNA expression of Krüppel-like factor 9 and period circadian clock 3 as well as the decreased mRNA expression of tolloid-like 1, tolloid-like 2, and paired-like homeodomain 1. The enhanced expression of miR-210 in the ECSCs correlated with the decreased mRNA expression of growth hormone receptor and thymidine kinase 1. Although there is no direct evidence, we speculate that the loss of miR-30a-5p-mediated mechanisms of decidualization and the acquisition of miR-210-mediated mechanisms of decidualization may be involved in the progesterone resistance in endometriosis. Further investigations are necessary to test this speculation.

miR-503, a microRNA epigenetically repressed in endometriosis, induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells.

STUDY QUESTION: Is the micro-RNA (miRNA) miR-503, downregulated in endometriotic cyst stromal cells (ECSCs) and does this affect the cell cycle, cell proliferation, angiogenesis and contractility of these cells? SUMMARY ANSWER: miR-503 expression is downregulated in ECSCs by DNA hypermethylation and this contributes to their proliferation, resistance to apoptosis, extracellular matrix (ECM) contractility and angiogenesis through effects on cyclin D1, B-cell lymphoma/leukemia (Bcl)-2, Ras homology A  and vascular endothelial growth factor A (VEGF-A). WHAT IS KNOWN ALREADY: A variety of miRNAs are demonstrated to involve in the pathogenesis of endometriosis. miR-503 is a miRNA with tumor-suppressor functions, whose expression is suppressed in ECSCs. STUDY DESIGN, SIZE, DURATION: We isolated ECSCs and normal endometrial stromal cells (NESCs) from ovarian endometriotic tissues (n = 32) and eutopic endometrial tissues without endometriosis (n = 8), respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: We investigated the functions of miR-503 by using miR-503-transfected ECSCs and the DNA methylation status of miR-503 gene in ECSCs and NESCs by combined bisulfite restriction analysis. MAIN RESULTS AND THE ROLE OF CHANCE: In ECSCs, miR-503 is downregulated by the DNA hypermethylation of its gene. The transfection of miR-503 into ECSCs resulted in the inhibition of cell proliferation and induction of cell-cycle arrest at G0/G1 phase through the suppression of cyclin D1, the induction of apoptosis through Bcl-2 suppression, the inhibition of VEGF-A production and the attenuation of ECM contractility via the suppression of Rho/Rho-associated coiled-coil-forming protein kinase-pathways. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: The present experiments were carried out only with the stromal component of endometriosis and eutopic endometrium. The experiments with the eutopic endometrial stromal cells from women with endometriosis are not performed. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that epigenetically repressed miR-503 in ECSCs is involved in the acquisition of endometriosis-specific cellular functions. STUDY FUNDING/COMPETING INTERESTS: This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 13237327 to K.N., no. 26861335 to K.K. and no. 23592407 to H.N.) and the Kanzawa Medical Research Foundation (to K.K.). There are no conflicts of interest to declare.

Wisteria floribunda agglutinin-binding glycan expression is decreased in endometriomata.

BACKGROUND: Glycosylation is one of the most common post-translational modifications of eukaryotic proteins and is known to undergo dynamic changes in a wide range of biological processes. To date, however, the glycan expression profiles in endometriosis are largely unknown. The objective of the study was to identify the panel of glycans that were aberrantly expressed in endometriosis, a hormone-dependent disease. METHODS: The glycan expression profiles in primary cultured human endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) were determined by lectin microarray analysis. Distribution of Wisteria floribunda agglutinin (WFA)-binding glycans in ovarian endometriotic cysts and eutopic proliferative phase endometrium were assessed by lectin histochemistry. The expressions of N-acetylgalactosaminyl transferases that synthesize WFA-binding glycans were evaluated in ECSCs and NESCs. RESULTS: We found that the levels of WFA-binding glycans were decreased in ECSCs. Lectin histochemistry revealed that WFA-binding glycans were decreased only in the stromal components of the ovarian endometriotic cysts, but not in the epithelial components, compared to the eutopic proliferative phase endometrium. The expressions of N-acetylgalactosaminyl transferases that synthesize WFA-binding glycans were downregulated in ECSCs. CONCLUSIONS: Utilizing lectin microarray analysis and lectin histochemistry, we found that WFA-binding glycans were decreased in endometriosis. The synthetic enzymes of WFA-binding glycans were significantly downregulated in ECSCs. It is suggested that reduced expression of N-glycans with WFA-binding properties on ECSCs is a novel characteristics of endometriosis.

Aberrant histone modification in endometriosis.

Accumulating evidence suggests that epigenetic aberrations play definite roles in the pathogenesis of endometriosis. These include aberrations in genomic DNA methylation, microRNA expression, and histone modification. The aberrant histone modification status and the aberrant expression of histone deacetylases, which regulate histone acetylation, in endometriosis are the focus of this review. Herein, we summarize the recent studies in the following areas: (i) hyperacetylation of histones located in the promoter lesions of G-protein-coupled estrogen receptor 1, steroidogenic factor-1, and hypoxia-inducible factor-1 alpha genes and (ii) hypoacetylation of histones located in the promoter lesions of estrogen receptor alpha, homeobox A10, CCAAT/enhancer-binding protein alpha, p16(INK4a), p21(Waf1/Cip1), p27(Kip1), checkpoint kinase 2, death receptor 6, and E-cadherin genes. Further research from the viewpoint of epigenetics may lead to the identification of the candidate molecules that are aberrantly expressed in endometriosis and may help elucidate the pathogenesis of this disease. In addition, epigenetic drugs (including histone deacetylase inhibitors) show promise for the treatment of endometriosis by amending the expression of these epigenetically dysregulated genes.