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Genetic Causal Relationship Between Systemic Lupus Erythematosus and Malignant Tumors of the Female Reproductive System: A GWAS Analysis in European Populations
Background: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women of reproductive age. Existing studies have demonstrated complex associations between SLE and various diseases, but its genetic relationship with malignant tumors of the female reproductive system has not been fully elucidated. This study is aimed at exploring the potential genetic associations and shared molecular basis between SLE and female reproductive system malignancies using genome‐wide association studies (GWASs) and cross‐trait analysis. Methods: We selected genetic variants significantly associated with SLE ( p < 5 × 10 −8 ) from large‐scale GWAS databases as genetic instruments and applied various statistical methods to analyze the associations between SLE and cervical cancer, endometrial cancer, ovarian cancer, vulvar cancer, vaginal cancer, and uterine cancer. The primary analysis was conducted using inverse variance weighting (IVW), supplemented by Egger regression, weighted median, and weighted mode methods. To control for potential confounders, we performed multivariable analysis while including BMI, estradiol, and CRP as covariates. Additionally, cross‐trait analysis using the association analysis based on subset (ASSET) method was employed to identify shared genetic variants and their effect directions between SLE and uterine cancer. Results: Genetic association analysis showed a significant negative association between SLE and endometrial cancer (OR = 0.972, 95% CI [0.946–0.998], p = 0.038), suggesting that SLE may be associated with a reduced risk of endometrial cancer. For uterine cancer, the weighted median method also indicated a marginally significant negative association (OR = 0.955, 95% CI [0.912–1.000], p = 0.049). Multivariable analysis further confirmed that the protective association between SLE and endometrial cancer remained significant after controlling for BMI, estradiol, and CRP (OR = 0.96, 95% CI [0.93–0.99], p = 0.014). However, no significant association was observed between SLE and cervical cancer, ovarian cancer, vulvar cancer, or vaginal cancer. Cross‐trait analysis identified 193 shared genetic variants between SLE and endometrial cancer and 71 shared variants between SLE and uterine cancer, with rs2442719 and rs3131004 showing consistent effect directions in both comparisons. Conclusion: This study provides genetic epidemiological evidence suggesting that SLE may have a protective effect against endometrial and uterine cancers and identifies potential shared genetic bases. These findings offer new insights into the relationship between SLE and gynecological tumors and may provide references for the prevention and treatment of related diseases.
Journal Article
Biogenesis and functions of circular RNAs and their role in diseases of the female reproductive system
A member of the newly discovered RNA family, circular RNA (circRNA) is considered as the intermediate product of by-product splicing or abnormal RNA splicing. With the development of RNA sequencing, circRNA has recently drawn research interest. CircRNA exhibits stability, species conservatism, and tissue cell specificity. It acts as a miRNA sponge in the circRNA-microRNA (miRNA-mRNA axis, which can regulate gene transcription and protein translation. Studies have confirmed that circRNA is ubiquitous in eukaryotic cells, which play an important role in the regulation of human gene expression and participate in the occurrence and development of various human diseases. CircRNA may be closely related to the occurrence and development of female reproductive system diseases. By analyzing the biological functions and mechanism of circRNA, we find that circRNA has certain development prospects as biomarkers of the female reproductive system diseases. The production and degradation of circRNA, biological functions, and their association with the occurrence of diseases of female reproductive system are reviewed in this article.
Journal Article
Body Mass Index and Risk of Female Reproductive System Tumors Subtypes: A Meta-Analysis Using Mendelian Randomization
Introduction: A strong association was previously established between body mass index (BMI) and female reproductive system tumors; however, the causal relationship is unclear. We conducted a Mendelian randomization (MR) study to further explore this association. Methods: Genetic information for BMI was retrieved from a published genome-wide association study involving 339,224 participants. Genetic associations with five common female reproductive system tumors were obtained from the FinnGen, UK Biobank studies, and other large consortia. Results: Genetic predisposition towards BMI exhibits a significant association with multiple tumors of the female reproductive system. Specifically, for every 1-unit increase in BMI log-transformed odds ratio (OR). The OR fluctuations overall for patients with breast cancer ranged from 0.661 to 0.996 (95% confidence interval [CI],0.544-1.000, P < 0.05). When stratified by estrogen receptor (ER) status, the OR for patients with ER (+) breast cancer ranged from 0.782 to 0.844 (95% CI, 0.616-0.994, P < 0.05) and that for those with ER (-) breast cancer ranged from 0.663 to 0.789 (95% CI, 0.498-0.991, P < 0.05). Additionally, ORs were as follows for cancer types: 1.577–1.908 (95% CI, 1.049-2.371, P < 0.05) for endometrial carcinoma; 1.216–1.303 (95% CI, 1.021-1.591, P < 0.05) for high-grade serous ovarian cancer; 1.217 (95% CI, 1.034-1.432, P < 0.05) for low-grade malignant serous ovarian cancer; and 1.502 (95% CI, 1.112-2.029, P < 0.05) for endometrioid ovarian carcinoma. Furthermore, our findings indicated that genetic predisposition towards BMI did not exhibit a causal association with uterine fibroids, cervical precancerous lesions, or cervical cancer itself. Conclusion: A genetic association was established between a high BMI and high risk of developing multiple tumors of the female reproductive system and their associated subtypes. This underscores the significance of taking measures to prevent reproductive system tumors in women who have a high BMI.
Journal Article
Coicis Semen for the treatment of malignant tumors of the female reproductive system: A review of traditional Chinese medicinal uses, phytochemistry, pharmacokinetics, and pharmacodynamics
Coicis Semen is an important food product and traditional Chinese medicine (TCM) derived from the dried and mature seeds of Coix lacryma-jobi L. var. ma-yuen (Roman.) Stapf. An increasing number of studies have investigated its use, either alone or in combination with other botanical drugs, to treat female reproductive system malignancies, and its pharmacological effects have been confirmed clinically. This review aims to provide an overview of Coicis Semen ’s historical role in treating female reproductive system malignancies based on TCM theory, to summarize clinical trials results, and to analyze information pertaining to the main phytochemical components, pharmacokinetics, related anti-cancer pharmacological effects, and toxicology of Coicis Semen . Information on Coicis Semen was collected from internationally accepted scientific databases. Seventy-four clinical trials were identified that used Coicis Semen in combination with other Chinese medicine to treat female reproductive system malignancies, most of which demonstrated good anti-tumor efficacy and few adverse reactions. To date, more than 80 individual compounds have been isolated from this botanical drug. In terms of anti-tumor effects, Coix seed oil has been studied the most. Pharmacokinetic data suggest that the active ingredients in Coicis Semen are widely distributed after administration, and Coicis Semen and its active compounds play a beneficial role in treating female reproductive system malignancies. Mechanistically, the anti-cancer effects may be related to inhibition of tumor cell proliferation and promotion of apoptosis, inhibition of tumor angiogenesis, suppression of the chronic inflammatory microenvironment of tumors, modulation of immune function, and regulation of the female reproductive system. Most acute toxicity and genotoxicity studies have shown that Coicis Semen is non-toxic. However, the existing studies have many limitations, and the future research direction should emphasize 1) the relationship between drug concentration and pharmacological action as well as toxicity; 2) the structural modification or the synthesis of analogues led by the active ingredients of Coicis Semen to enhance pharmacological activities and bioavailability; 3) accurately revealing the anti-cancer pharmacological effects of Coicis Semen and its compounds through multi-omics technology. We hope that this review can determine future directions and inform novel drug development for treating female reproductive malignancies.
Journal Article
HMGB1: a double-edged sword and therapeutic target in the female reproductive system
HMGB1 that belongs to the High Mobility Group-box superfamily, is a nonhistone chromatin associated transcription factor. It is present in the nucleus of eukaryotes and can be actively secreted or passively released by kinds of cells. HMGB1 is important for maintaining DNA structure by binding to DNA and histones, protecting it from damage. It also regulates the interaction between histones and DNA, affecting chromatin packaging, and can influence gene expression by promoting nucleosome sliding. And as a DAMP, HMGB1 binding to RAGE and TLRs activates NF-κB, which triggers the expression of downstream genes like IL-18, IL-1β, and TNF-α. HMGB1 is known to be involved in numerous physiological and pathological processes. Recent studies have demonstrated the significance of HMGB1 as DAMPs in the female reproductive system. These findings have shed light on the potential role of HMGB1 in the pathogenesis of diseases in female reproductive system and the possibilities of HMGB1-targeted therapies for treating them. Such therapies can help reduce inflammation and metabolic dysfunction and alleviate the symptoms of reproductive system diseases. Overall, the identification of HMGB1 as a key player in disease of the female reproductive system represents a significant breakthrough in our understanding of these conditions and presents exciting opportunities for the development of novel therapies.
Journal Article
Investigating the role of exosomal long non-coding RNAs in drug resistance within female reproductive system cancers
Exosomes, as key mediators of intercellular communication, have been increasingly recognized for their role in the oncogenic processes, particularly in facilitating drug resistance. This article delves into the emerging evidence linking exosomal lncRNAs to the modulation of drug resistance mechanisms in cancers such as ovarian, cervical, and endometrial cancer. It synthesizes current research findings on how these lncRNAs influence cancer cell survival, tumor microenvironment, and chemotherapy efficacy. Additionally, the review highlights potential therapeutic strategies targeting exosomal lncRNAs, proposing a new frontier in overcoming drug resistance. By mapping the interface of exosomal lncRNAs and drug resistance, this article aims to provide a comprehensive understanding that could pave the way for innovative treatments and improved patient outcomes in female reproductive system cancers.
Journal Article
Diagnostic Value of Preoperative CA125, LDH and HE4 for Leiomyosarcoma of the Female Reproductive System
Leiomyosarcoma (LMS) is a rare and extremely aggressive malignancy that is derived from or shows evidence of differentiation toward smooth muscle. If LMS occurs in the female reproductive system, preoperative diagnosis can be difficult, as LMS is easily mistaken for a uterine leiomyoma, especially a degenerated uterine fibroid (DUF). Thus, we assessed the diagnostic value of the preoperative serum concentrations of cancer antigen 125 (CA125), lactate dehydrogenase (LDH) and human epididymis protein 4 (HE4) for differentiating LMS from DUF.
We enrolled patients with LMS or DUF who were receiving treatment in The First Affiliated Hospital of Chongqing Medical University between 2009 and 2020. If the preoperative serum concentrations of CA125, LDH and HE4 of our study participants had been tested, these data were analyzed. The preoperative serum concentrations of CA125, LDH and HE4 in participants with LMS (n = 37) were compared with those of participants with pathologically diagnosed DUF (n = 102), who served as the control group.
The preoperative serum concentrations of CA125, LDH and HE4 of participants with LMS of the female reproductive system were significantly higher than those of participants with DUF (
= 0.009,
< 0.001,
= 0.001, respectively). The cut-off preoperative serum concentrations of CA125, LDH and HE4 were 30.85 U/mL, 186.50 U/L and 50.50 pmol/L, respectively. When these three parameters were used for an analysis of their combined diagnostic utility, the area under the curve (AUC) was 0.892, the sensitivity was 68.4% and the specificity was 95.1% (
< 0.001).
A combined analysis of the preoperative serum concentrations of CA125, LDH and HE4 could be a promising method for diagnostically differentiating LMS of the female reproductive system from DUF.
Journal Article
Role of m6A modification in female infertility and reproductive system diseases
Gamete abnormalities and reproductive system tumors have become a dominant cause of infertility, troubling people globally. In recent years, increasing evidence emerged and found that N6-methyladenosine (m6A) played a leading role in reproduction. The biological effects of m6A modification are dynamically and reversibly regulated by methyltransferases (writers), WTAP, METTL3, METTL14 and KIAA1429, demethylases (erasers), FTO and ALKBH5, and m6A binding proteins (readers), including YTH domain. In this review, we highlight the change of m6A modification in abnormal oogenesis, female reproductive system diseases including reproductive system tumors, adenomyosis, endometriosis, premature ovarian failure and polycystic ovary syndrome. Moreover, we review some of the mechanisms and the specific modified genes that have been identified. Especially, with the underlying mechanisms being uncovered, m6A and its protein machineries are expected to be the markers and targets for the diagnosis and treatment of female reproductive dysfunction.
Journal Article
Developmental programming of the female reproductive system—a review
Exposures to adverse conditions in utero can lead to permanent changes in the structure and function of key physiological systems in the developing fetus, increasing the risk of disease and premature aging in later postnatal life. When considering the systems that could be affected by an adverse gestational environment, the reproductive system of developing female offspring may be particularly important, as changes have the potential to alter both reproductive capacity of the first generation, as well as health of the second generation through changes in the oocyte. The aim of this review is to examine the impact of different adverse intrauterine conditions on the reproductive system of the female offspring. It focuses on the effects of exposure to maternal undernutrition, overnutrition/obesity, hypoxia, smoking, steroid excess, endocrine-disrupting chemicals, and pollutants during gestation and draws on data from human and animal studies to illuminate underlying mechanisms. The available data indeed indicate that adverse gestational environments alter the reproductive physiology of female offspring with consequences for future reproductive capacity. These alterations are mediated via programmed changes in the hypothalamic–pituitary–gonadal axis and the structure and function of reproductive tissues, particularly the ovaries. Reproductive programming may be observed as a change in the timing of puberty onset and menopause/reproductive decline, altered menstrual/estrous cycles, polycystic ovaries, and elevated risk of reproductive tissue cancers. These reproductive outcomes can affect the fertility and fecundity of the female offspring; however, further work is needed to better define the possible impact of these programmed changes on subsequent generations. Summary sentence Explores the extent to which different environmental exposures during gestation impact the reproductive physiology of female offspring by drawing on data from human and experimental animal studies to illuminate underlying mechanisms.
Journal Article