• 생명과학회지
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• 제33권1호
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• pp.102-113
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• 2023

본 총설에서는 지난 수년 동안 자궁내막 염증 관련 새롭게 밝혀진 에스트로겐과 프로게스테론 수용체의 기능 중 지엽적 에스트로겐의 합성, 특이적 에스트로겐 수용체의 조절, 프로게스테론 저항성 그리고 스테로이드 호르몬의 작용에 의한 자궁내막 조직세포의 염증반응, 분화 및 생존에 대한 세포 및 분자적 조절기전들을 고찰한다. 자궁내막 조직 기질세포의 비정상적인 후성유전체적 변화는 자궁내막증의 발병과 진행에 중요한 요인으로 작용한다. 특히, 에스트로겐 수용체 유전자들의 차별적 메틸화는 기질세포내 ERα로부터 ERβ로의 발현 우세도 전환을 유도하여, ERβ-매개 염증반응, 프로게스테론 저항성 및 레티노이드 합성장애 등의 비정상적인 에스트로겐 반응을 초래한다. 이 기질세포는 또한 PGE2 및 SF-1 매개에 의한 스테로이드 합성효소의 발현유도를 통하여 지엽적 에스트로겐의 생성을 촉진하며, 증가된 에스트라디올은 다시 ERβ에 피드백으로 작용하여 COX-2 촉진을 통한 염증반응의 악순환을 야기한다. 높은 ERβ의 발현은 중간엽 줄기세포의 염색질 구조변화릉 야기하여 프로게스테론 저항성을 획득하고, 이는 반복적 생리에 따른 지속적 노출로 자궁내막 조직의 염증을 형성하며, 이후에는 ERβ-매개 에스트로겐과 TNF-α 및 TGF-β1을 포함한 염증 유발 인자들이 작용하여 염증 조직세포의 부착, 혈관생성 및 생존과 기질세포의 분화조절장애를 유도한다. 따라서, 생리주기의 역동적인 호르몬 변화와 이에 따르는 자궁내막 조직의 핵수용체 신호전달 조절기전에 대한 구체적인 이해는 정상적인 생식기능을 유지하면서 자궁내막증과 같은 비정상적 염증질환을 치료하기 위한 새로운 안목을 제공할 수 있을 것으로 기대된다.

• Asian Pacific Journal of Cancer Prevention
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• 제14권10호
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• pp.5589-5597
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• 2013

The aim of this review article was to evaluate the relationship and the possible etiological mechanisms between endometriosis, leiomyoma (LM) and adenomyosis and gynecological cancers, such as ovarian and endometrial cancer and leiomyosarcoma (LMS). MEDLINE was searched for all articles written in the English literature from July 1966 to May 2013. Reports were collected systematically and all the references were also reviewed. Malignant transformation of gynecologic benign diseases such as endometriosis, adenomyosis and LM to ovarian and endometrial cancer remains unclear. Hormonal factors, inflammation, familial predisposition, genetic alterations, growth factors, diet, altered immune system, environmental factors and oxidative stress may be causative factors in carcinogenesis. Early menarche, low parity, late menopause and infertility have also been implicated in the pathogenesis of these cancers. Ovarian cancers and endometriosis have been shown to have common genetic alterations such as loss of heterozygosity (LOH), PTEN, p53, ARID1A mutations. MicroRNAs have also been implicated in malignant transformation. Inflammation releases proinflammatory cytokines, and activates tumor associated macrophages (TAMS) and nuclear factor kappa b (NF-KB) signaling pathways that promote genetic mutations and carcinogenesis. MED12 mutations in LM and smooth muscle tumors of undetermined malignant potential (STUMP) may contribute to malignant transformation to LMS. A hyperestrogenic state may be shared in common with pathogenesis of adenomyosis, LM and endometrial cancer. However, the effect of these benign gynecologic diseases on endometrial cancer should be studied in detail. This review study indicates that endometriosis, LM, adenomyosis may be associated with increased risk of gynecological cancers such as endometrial and ovarian cancers. The patients who have these gynecological benign diseases should be counseled about the future risks of developing cancer. Further studies are needed to investigate the relationship between STUMPs, LMS and LM and characteristics and outcome endometrial carcinoma in adenomyotic patients.

• 한국동물생명공학회지
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• 제35권1호
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• pp.35-41
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• 2020

In this study, we investigated whether infusion of colorectal cancer cell line and PMSG could increase endometrial cancer. As a result, our study confirmed that the injection of colorectal cancer can cause inflammation and cancer in the uterus and increase the VEGF gene in the uterus. The study also found that endometrial cancer was associated with PMSG.

• Asian Pacific Journal of Cancer Prevention
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• 제15권2호
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• pp.713-716
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• 2014

Objective: Connections between chronic inflammation and tumor development and progression are now generally accepted. Recent evidence indicates that hepatitis B is associated with several types of cancer, but whether endometrial carcinoma (EC) is included has not been reported. Methods: We analyzed HBV serum marker status in 398 patients with endometrial cancer, comparing them to 788 control women undergoing health examination. Results: The total prevalence of HBsAg tested positive in cancer group was significantly higher than the control group (12.8% vs 6.0%, P=0.001), while positive HBsAb was significantly lower (41.2% vs 68.5%, P=0.001). Hepatitis B carriers in endometrial cancer group were also more frequent than in the control group (9.3% vs 5.5%, P=0.013). Interestingly, in the endometrial cancer group, 147 cases were HBV serum marker negative, which was also higher than in the control group (36.9% vs 15.6%, P=0.001). Conclusion: There may be a correlation between HBV infection and endometrial carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• 제15권4호
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• pp.1689-1692
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• 2014

Background: An easy, reproducible and simple marker is needed to estimate phase of endometrial pathologic lesions such as hyperplasia and endometrial cancer and distinguish from pathologically normal results. We here aimed to clarify associations among neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), endometrial hyperplasia and cancer in patients with abnormal uterine bleeding. Materials and Methods: Patients (n=161) who were admitted with abnormal uterine bleeding and the presence of endometrial cells on cervical cytology or thick endometrium were investigated. The study constituted of three groups according to pathologic diagnosis. Group 1 included endometrial precancerous lesions like hyperplasia (n=63), group 2 included endometrial cancerous lesions (n=38) and group 3 was a pathologically normal group (n=60). Blood samples were obtained just before the curettage procedure and the NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count; similarly, PLR was defined as the absolute platelet count divided by the absolute lymphocyte count. Results: The white blood cell count was significantly higher in patients with cancer than in those with hyperplasia (p=0.005). The platelet count and neutrophil to lymphocyte ratio were significantly higher in patients with cancer than in control patients, but there was significantly no difference between patients with hyperplasia and other groups (p=0.001 and p=0.025 respectively). PLR was significantly lower in control subjects than in other groups (p<0.001), but there was no significant difference between patients with hyperplasia and those with cancer. Conclusions: PLR was significantly lower in control subjects than in other groups. Thus both hyperplasia and cancer may be differentiated from pathologically normal patients by using PLR. White blood cell count was significantly higher in patients with cancer than in those with hyperplasia and pathologically normal patients. Therefore white blood cell count may be used for discriminate hyperplasia to cancer. By using multiple inflammation parameters, discrimination may be possible among endometrial cancer, endometrial precancerous lesions and pathologically normal patients.

• Journal of Ginseng Research
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• 제46권4호
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• pp.592-600
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• 2022

Background: Di-(2-ethylhexyl) phthalate (DEHP) is the most common endocrine disrupting chemical used as a plasticizer. DEHP is associated with the development of endometrium-related diseases through the induction of inflammation. The major therapeutic approaches against endometrial cancer and endometriosis involve the suppression of inflammatory response. Korean Red Ginseng (KRG) is a natural product with anti-inflammatory and anti-carcinogenic properties. Thus, the purpose of this study is to investigate the effects of KRG on DEHP-induced inflammatory response in endometrial cancer Ishikawa cells and a mouse model of endometriosis. Methods: RNA-sequencing was performed and analyzed on DEHP-treated Ishikawa cells in the presence and absence of KRG. The effects of KRG on DEHP-induced cyclooxygenase-2 (COX-2) mRNA levels in Ishikawa cells were determined by RT-qPCR. Furthermore, the effects of KRG on the extracellular signal-regulated kinases (ERKs) pathway, COX-2, and nuclear factor-kappa B (NF-kB) p65 after DEHP treatment of Ishikawa cells were evaluated by western blotting. In the mouse model, the severity of endometriosis induced by DEHP and changes in immunohistochemistry were used to assess the protective effect of KRG. Results: According to the RNA-sequencing data, DEHP-induced inflammatory response-related gene expression was downregulated by KRG. Moreover, KRG significantly inhibited DEHP-induced ERK1/2/NF-κB/COX-2 levels in Ishikawa cells. In the mouse model, KRG administration significantly inhibited ectopic endometriosis growth after DEHP-induced endometriosis. Conclusions: Overall, these results suggest that KRG may be a promising lead for the treatment of endometrial cancer and endometriosis via suppression of the inflammatory response.

• Clinical and Experimental Reproductive Medicine
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• 제48권2호
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• pp.132-141
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• 2021

Objective: Lipopolysaccharide (LPS) from Gram-negative bacteria causes poor uterine receptivity by inducing excessive inflammation at the maternal-fetal interface. This study aimed to investigate the detrimental effects of LPS on the attachment and outgrowth of various types of trophoblastic spheroids on endometrial epithelial cells (ECC-1 cells) in an in vitro model of implantation. Methods: Three types of spheroids with JAr, JEG-3, and JAr mixed JEG-3 (JmJ) cells were used to evaluate the effect of LPS on early implantation events. ECC-1 cells were treated with LPS to mimic endometrial infection, and the expression of inflammatory cytokines and adhesion molecules was analyzed by quantitative real-time polymerase chain reaction and western blotting. The attachment rates and outgrowth areas were evaluated in the various trophoblastic spheroids and ECC-1 cells treated with LPS. Results: LPS treatment significantly increased the mRNA expression of inflammatory cytokines (CXCL1, IL-8, and IL-33) and decreased the protein expression of adhesion molecules (ITGβ3 and ITGβ5) in ECC-1 cells. The attachment rates of JAr and JmJ spheroids on ECC-1 cells significantly decreased after treating the ECC-1 cells with 1 and 10 ㎍/mL LPS. In the outgrowth assay, JAr spheroids did not show any outgrowth areas. However, the outgrowth areas of JEG-3 spheroids were similar regardless of LPS treatment. LPS treatment of JmJ spheroids significantly decreased the outgrowth area after 72 hours of coincubation. Conclusion: An in vitro implantation model using novel JmJ spheroids was established, and the inhibitory effects of LPS on ECC-1 endometrial epithelial cells were confirmed in the early implantation process.

• Clinical and Experimental Reproductive Medicine
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• 제38권4호
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• pp.179-185
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• 2011

The ultimate function of the endometrium is to allow the implantation of a blastocyst and to support pregnancy. Cycles of tissue remodeling ensure that the endometrium is in a receptive state during the putative 'implantation window', the few days of each menstrual cycle when an appropriately developed blastocyst may be available to implant in the uterus. A successful pregnancy requires strict temporal regulation of maternal immune function to accommodate a semi-allogeneic embryo. To preparing immunological tolerance at the onset of implantation, tight temporal regulations are required between the immune and endocrine networks. This review will discuss about the action of steroid hormones on the human endometrium and particularly their role in regulating the inflammatory processes associated with endometrial receptivity.

• Biomolecules & Therapeutics
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• 제29권6호
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• pp.678-684
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• 2021

Luteolin, a flavonoid present in several fruits, vegetables, nuts, and herbs reportedly exhibits anti-cancer and anti-inflammatory properties. However, the effect of luteolin on endometriosis, a painful condition characterized by the ectopic growth of endometrial tissue and pelvic inflammation, remains elusive. Herein, we observed that luteolin inhibited cell growth and induced apoptosis of 12Z human endometriotic cells by activating caspase-3, -8, and -9. Additionally, luteolin significantly inhibited the expression of key chemokines, C-C motif chemokine ligand 2 (CCL2) and CCL5, required for monocyte/macrophage influx at endometriotic sites. In macrophages stimulated by endometriotic cells, luteolin treatment suppressed the intracellular expression of M2 markers and endometriosis-promoting factors. Collectively, our data suggest that luteolin exerts anti-endometriotic effects by stimulating endometriotic cell apoptosis and hindering the alternative activation of macrophages.

• Genomics & Informatics
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• 제16권4호
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• pp.21.1-21.7
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• 2018

Metritis, the inflammation of the uterus caused by polymicrobial infections, is a prevalent and costly disease to the dairy industry as it decreases milk yield, survival, and the welfare of dairy cows. Although affected cows are treated with broad-spectrum antibiotics such as ceftiofur, endometrial and ovarian function are not fully recovered, which results in subfertility and infertility. According to culture-dependent studies, uterine pathogens include Escherichia coli, Trueperella pyogenes, Fusobacterium necrophorum, and Prevotella melaninogenica. Recent studies using high-throughput sequencing observed very low relative abundance of Escherichia coli, Trueperella pyogenes, and Prevotella melaninogenica in cows with metritis. Herein, we propose that metritis is associated with a dysbiosis of the uterine microbiota, which is characterized by high abundance of Bacteroides, Porphyromonas, and Fusobacterium.