Ethnic-specific genetic susceptibility loci for endometriosis in Taiwanese-Han population: a genome-wide association study.

Endometriosis is a common gynecological disorder affecting around 10% of reproductive-age women. Although many hypotheses were proposed, genetic alteration has been considered as one of the key factors promoting pathogenesis. Due to racial/ethnic disparities in the process of hormone regulation and nutrition metabolism, a genome-wide association study (GWAS) with 2794 cases and 27,940 controls was conducted in a Taiwanese-Han population. Our study identified five significant susceptibility loci for endometriosis, and three of them, WNT4 (on the 1p36.12), RMND1 (6q25.1), and CCDC170 (6q25.1), have been previously associated with endometriosis across different populations, including European and Japanese descent cohorts. Other two including C5orf66/C5orf66-AS2 (5q31.1) and STN1 (10q24.33) are newly identified ones. Functional network analysis of potent risk genes revealed the involvement of cancer susceptibility and neurodevelopmental disorders in endometriosis development. In addition, long non-coding RNAs (lncRNAs) C5orf66 and C5orf66-AS2 can interact with many RNA-binding proteins (RBPs) which can influence RNA metabolic process, mRNA stabilization, and mRNA splicing, leading to dysregulation in tumor-promoting gene expression. Those findings support clinical observations of differences in the presentation of endometriosis in Taiwanese-Han population with higher risks of developing deeply infiltrating/invasive lesions and the associated malignancies.

Spatial and Single-Cell Investigations Illuminate Theragnostic value and Immune Landscape of Mitochondrial Dynamin-Like GTPase in Breast Cancer.

Background: As we delve into the intricate world of mitochondrial inner membrane proteins, particularly Optic Atrophy types 1 and 3 (OPA1/3), we uncover their pivotal role in maintaining mitochondrial dynamic equilibrium and fusion, crucial for cellular energy production and synthesis. Despite extensive scrutiny, the significance of OPA1/3 in breast cancer (BRCA) and its interplay with the immune microenvironment remain elusive. Materials and Methods: We meticulously sourced BRCA data from renowned repositories such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and the Human Protein Atlas (HPA), leveraging cutting-edge techniques including single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and pharmacogenomics. Through multifaceted data analysis, we endeavored to unravel the intricate role and potential value of OPA1/3 in BRCA tumorigenesis and progression. Results: Our investigation reveals a conspicuous upregulation of OPA1/3 expression in BRCA, correlating with dismal prognoses. Kaplan-Meier plot analysis underscores that heightened OPA1/3 levels are associated with poor survival rates. Both clinical specimens and biobank biopsies corroborate the elevated expression of OPA1/3 in breast cancer patients. Moreover, scRNA-seq unveils a strong correlation between OPA1/3 and macrophage infiltration in the BRCA immune milieu, alongside its association with the cellular communication network involving CXCL, TGFb, VEGF, and IL16. Conclusion: In light of these findings, OPA1/3 emerges as a promising contender for therapeutic targeting and as a potential diagnostic, prognostic, and survival biomarker in BRCA. The implications of our study underscore the pressing need to explore these novel biomarkers to enhance patient outcomes.

Multi-omic profiling of breast tumor microenvironment uncovers a role of mitochondrial calcium gatekeepers.

In this study, we aimed to elucidate the role of mitochondrial calcium uptake 1/2 (MiCU1/2) in breast cancer (BRCA) by employing a comprehensive multi-omics approach. Unlike previous research, we utilized a novel web application tailored for whole tumor tissue, single-cell, and spatial transcriptomics analysis to investigate the association between MiCU1/2 and the tumor immune microenvironment (TIME). Our gene set enrichment analysis (GSEA) provided insights into the primary biological effects of MiCU1/2, while our CRISPR-based drug screening repository identified potential effective drugs. Our study revealed that high MiCU1/2 expression serves as an independent diagnostic biomarker, correlating with advanced clinical status and indicating poorer recurrence-free survival (RFS) rates in BRCA patients. Additionally, spatial transcriptome analysis highlighted the heightened expression of MiCU1/2 in tumors and its relevance in surrounding immune cells. Furthermore, using the CIBERSORT algorithm, we discovered a positive correlation between MiCU1/2 levels and macrophage infiltration, underscoring their potential impact on immune infiltration. We also identified expression patterns of immune-related genes associated with responses against various immune cell types, including CXCL, MIF, GDF, SPP1, and IL16. Finally, our pharmacogenomic screening identified potential small molecule drugs capable of effectively targeting breast cancer cells with elevated MiCU1/2 expression. Overall, our study establishes MiCU1/2 as a promising novel biomarker for BRCA diagnosis and prognostic prediction, as well as a potential therapeutic target, highlighting the importance of exploring these pathways to advance patient care and outcomes in BRCA treatment.

Multi-Omics Reveals the Role of Osteopontin/Secreted Phosphoprotein 1 in Regulating Ovarian Aging.

Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN), is located on chromosome 4q22.1. This multifunctional secreted acidic glycoprotein is expressed intracellularly and extracellularly in various tissues, where it interacts with regulatory proteins and pro-inflammatory immune chemokines, contributing to the pathogenesis of multiple diseases. Nevertheless, the intricate genetic connections between SPP1 and ovarian aging remain largely unexplored. This study aims to bridge this knowledge gap by delving into ovarian aging and its associations with SPP1 using multi-omics data analysis. Our findings indicate that SPP1 is a potential gene related to ovarian aging. To comprehend the role of SPP1, we conducted spatial transcriptomic analyses on young and aged female mouse ovaries, revealing a significant decline in SPP1 expression in the aging group compared to the young group. Similarly, a significantly low level of SPP1 was found in the 73-year-old sample. Additionally, in-depth single-cell RNA-sequencing analysis identified associations between SPP1 and ITGAV, ITGB1, CD44, MMP3, and FN1. Notably, co-expression analysis highlighted a strong correlation between SPP1 and ITGB1. In summary, this study pioneers the identification of SPP1 as a gene implicated in ovarian aging. Further research into the role of SPP1 has the potential to advance precision medicine and improve treatment strategies for ovarian aging-related conditions.

The role of LSM1 in breast cancer: Shaping metabolism and tumor-associated macrophage infiltration.

LSM1 is part of the cytoplasmic protein complex Lsm1-7-Pat1 and is likely involved in pre-mRNA degradation by aiding U4/U6 snRNP formation. More research is needed to uncover LSM1's potential in breast cancer (BRCA) clinical pathology, the tumor immune microenvironment, and precision oncology. We discovered LSM1 as a diagnostic marker for advanced BRCA with poor survival, using a multi-omics approach. We studied LSM1 expression across BRCA regions and its link to immune cells through various methods, including spatial transcriptomics and single-cell RNA-sequencing. We also examined how silencing LSM1 affects mitochondrial function and energy metabolism in the tumor environment. These findings were confirmed using 54 BRCA patient biopsies and tissue microarrays. Immunofluorescence and bioinformatics assessed LSM1's connection to clinicopathological features and prognosis. This study uncovers gene patterns linked to breast cancer, with LSM1 linked to macrophage energy processes. Silencing LSM1 in breast cancer cells disrupts mitochondria and energy metabolism. Spatial analysis aligns with previous results, showing LSM1's connection to macrophages. Biopsies confirm LSM1 elevation in advanced breast cancer with increased macrophage presence. To summarize, LSM1 changes may drive BRCA progression, making it a potential diagnostic and prognostic marker. It also influences energy metabolism and the tumor's immune environment during metastasis, showing promise for precision medicine and drug screening in BRCA.

Unraveling the Clinical Relevance of Ferroptosis-Related Genes in Human Ovarian Aging.

Ferroptosis, a recently discovered form of cell death, has been implicated in various diseases. However, the genetic relationship between ferroptosis and ovarian aging has not been thoroughly investigated through informatics analysis. In this study, we conducted bioinformatics analysis using ovarian aging and ferroptosis datasets to identify potential ferroptosis-related genes using R software. The expression levels of these genes at different ages were analyzed using the GTEx public database. To validate these findings at the genetic level, we performed clinical infertility biopsies. Bioinformatics analysis of a mouse ovary dataset revealed significantly higher expression of Tfrc, Ncoa4, and Slc3a2 in the aging group compared to the young group, while Gpx4 showed the opposite pattern. Consistent results were observed in biopsies from clinically aged infertile patients. This study is the first to identify a ferroptosis-related gene associated with ovarian aging, highlighting its potential as a diagnostic biomarker.

Investigating the Role of Ferroptosis-Related Genes in Ovarian Aging and the Potential for Nutritional Intervention.

With advancing age, women experience irreversible deterioration in the quality of their oocytes, resulting in reduced fertility. To gain a deeper understanding of the influence of ferroptosis-related genes on ovarian aging, we employed a comprehensive approach encompassing spatial transcriptomics, single-cell RNA sequencing, human ovarian pathology, and clinical biopsy. This investigation revealed the intricate interactions between ferroptosis and cellular energy metabolism in aging germ cells, shedding light on the underlying mechanisms. Our study involved 75 patients with ovarian senescence insufficiency, and we utilized multi-histological predictions of ferroptosis-related genes. Following a two-month supplementation period with DHEA, Ubiquinol CoQ10, and Cleo-20 T3, we examined the changes in hub genes. Our results showed that TFRC, NCOA4, and SLC3A2 were significantly reduced and GPX4 was increased in the supplement group, confirming our prediction based on multi-omic analysis. Our hypothesis is that supplementation would enhance the mitochondrial tricarboxylic acid cycle (TCA) or electron transport chain (ETC), resulting in increased levels of the antioxidant enzyme GPX4, reduced lipid peroxide accumulation, and reduced ferroptosis. Overall, our results suggest that supplementation interventions have a notable positive impact on in vitro fertilization (IVF) outcomes in aging cells by improving metal ion and energy metabolism, thereby enhancing oocyte quality in older women.

Boosting mitochondrial function and metabolism in aging female germ cells with dual ROCK/ROS inhibition.

The decline in oocyte quality with age is an irreversible process that results in low fertility. Reproductive aging causes an increase in oocyte aneuploidy leading to a decrease in embryo quality and an increase in the incidence of miscarriage and congenital defects. Here, we show that the dysfunction associated with aging is not limited to the oocyte, as oocyte granulosa cells also show a range of defects related to mitochondrial activity. The addition of Y-27632 and Vitamin C combination drugs to aging germ cells was effective in enhancing the quality of aging cells. We observed that supplement treatment significantly decreased the production of reactive oxygen species (ROS) and restored the balance of mitochondrial membrane potential. Supplementation treatment reduces excessive mitochondrial fragmentation in aging cells by upregulating mitochondrial fusion. Moreover, it regulated the energy metabolism within cells, favoring oxygen respiration and reducing anaerobic respiration, thereby increasing cellular ATP production. In an experiment with aged mice, supplement treatment improved the maturation of oocytes in vitro and prevented the buildup of ROS in aging oocytes in culture. Additionally, this treatment resulted in an increased concentration of anti-mullerian hormone (AMH) in the culture medium. By improving mitochondrial metabolism in aging females, supplement treatment has the potential to increase quality of oocytes during in vitro fertilization.

Alterations of Cytoskeleton Networks in Cell Fate Determination and Cancer Development.

Cytoskeleton proteins have been long recognized as structural proteins that provide the necessary mechanical architecture for cell development and tissue homeostasis. With the completion of the cancer genome project, scientists were surprised to learn that huge numbers of mutated genes are annotated as cytoskeletal or associated proteins. Although most of these mutations are considered as passenger mutations during cancer development and evolution, some genes show high mutation rates that can even determine clinical outcomes. In addition, (phospho)proteomics study confirms that many cytoskeleton-associated proteins, e.g., ß-catenin, PIK3CA, and MB21D2, are important signaling mediators, further suggesting their biofunctional roles in cancer development. With emerging evidence to indicate the involvement of mechanotransduction in stemness formation and cell differentiation, mutations in these key cytoskeleton components may change the physical/mechanical properties of the cells and determine the cell fate during cancer development. In particular, tumor microenvironment remodeling triggered by such alterations has been known to play important roles in autophagy, metabolism, cancer dormancy, and immune evasion. In this review paper, we will highlight the current understanding of how aberrant cytoskeleton networks affect cancer behaviors and cellular functions through mechanotransduction.

A Study on MDA5 Signaling in Splenic B Cells from an Imiquimod-Induced Lupus Mouse Model with Proteomics.

INTRODUCTION: Several environmental stimuli may influence lupus, particularly viral infections. In this study, we used an imiquimod-induced lupus mouse model focused on the TLR7 pathway and proteomics analysis to determine the specific pathway related to viral infection and the related protein expressions in splenic B cells to obtain insight into B-cell responses to viral infection in the lupus model. MATERIALS AND METHODS: We treated FVB/N wild-type mice with imiquimod for 8 weeks to induce lupus symptoms and signs, retrieved splenocytes, selected B cells, and conducted the proteomic analysis. The B cells were co-cultured with CD40L+ feeder cells for another week before performing Western blot analysis. Panther pathway analysis was used to disclose the pathways activated and the protein-protein interactome was analyzed by the STRING database in this lupus murine model. RESULTS: The lupus model was well established and well demonstrated with serology evidence and pathology proof of lupus-mimicking organ damage. Proteomics data of splenic B cells revealed that the most important activated pathways (fold enrichment > 100) demonstrated positive regulation of the MDA5 signaling pathway, negative regulation of IP-10 production, negative regulation of chemokine (C-X-C motif) ligand 2 production, and positive regulation of the RIG-I signaling pathway. A unique protein-protein interactome containing 10 genes was discovered, within which ISG15, IFIH1, IFIT1, DDX60, and DHX58 were demonstrated to be downstream effectors of MDA5 signaling. Finally, we found B-cell intracellular cytosolic proteins via Western blot experiment and continued to observe MDA5-related pathway activation. CONCLUSION: In this experiment, we confirmed that the B cells in the lupus murine model focusing on the TLR7 pathway were activated through the MDA5 signaling pathway, an important RNA sensor implicated in the detection of viral infections and autoimmunity. The MDA5 agonist/antagonist RNAs and the detailed molecular interactions within B cells are worthy of further investigation for lupus therapy.

Subgingival Microbiome in Rheumatoid Arthritis Patients with Periodontitis.

Rheumatoid arthritis (RA) and periodontitis are suggested to be closely linked based on microbial dysbiosis, but limited subgingival bacteria have been proven in the pathogenesis of RA. We enrolled 30 RA patients and 25 controls and divided them into three groups with matched age, gender, and diabetes statuses: group AM (all of the matched participants), group PD (periodontally diseased), and group PH (periodontally healthy). Their subgingival microbial composition was determined by V3-V4 16S rRNA gene sequencing. Significant differences in subgingival microbial clustering between the RA patients and controls were observed in groups AM and PD. Among the taxa enriched in RA, Aminipila butyrica and Peptococcus simiae were the only two species displaying positive correlation to the level of anti-citrullinated protein antibodies (ACPAs) in both of the groups. Surprisingly, the median of relative abundances of A. butyrica and P. simiae were 0% in the controls of group PD. Furthermore, a gene encoding arginine deiminase with the capability to produce citrulline was addressed in the complete genome sequence of A. butyrica. This is the first study to elucidate the important roles of A. butyrica and P. simiae as periodontal bacteria leading to RA possibly through the induction of ACPA production.

Genetic variations in UCA1, a lncRNA functioning as a miRNA sponge, determine endometriosis development and the potential associated infertility via regulating lipogenesis.

Endometriosis is a hormone-associated disease which has been considered as the precursor for certain types of ovarian cancer. In recent years, emerging evidence demonstrated potent roles of lncRNA in regulating cancer development. Since endometriosis shares several features with cancer, we investigated the possible involvement of cancer-related lncRNAs in endometriosis, including UCA1, GAS5 and PTENP1. By using massARRAY system, we investigated certain genetic variations in cancer-related lncRNAs that can change the thermo-stability, leading to up-regulation or down-regulation of those lncRNAs. Our data indicated three risk genetic haplotypes in UCA1 which can stabilize the RNA structure and increase the susceptibility of endometriosis. Of note, such alterations were found to be associated with long-term pain and infertility in patients. It has been known that UCA1 can function as a ceRNA to sponge and inhibit miRNAs, resulting in loss-of-control on downstream target genes. Gene network analyses revealed fatty acid metabolism and mitochondria beta-oxidation as the major pathways associated with altered UCA1 expression in endometriosis patients. Our study thus provides evidence to highlight functional/epigenetic roles of UCA1 in endometriosis development via regulating fatty acid metabolism in women.

Integrated analysis of pivotal biomarker of LSM1, immune cell infiltration and therapeutic drugs in breast cancer.

The discovery of early diagnosis and prognostic markers for breast cancer can significantly improve survival and reduce mortality. LSM1 is known to be involved in the general process of mRNA degradation in complexes containing LSm subunits, but the molecular and biological functions in breast cancer remain unclear. Here, the expression of LSM1 mRNA in breast cancer was estimated using The Cancer Genome Atlas (TCGA), Oncomine, TIMER and bc-GenExMiner databases. We found that functional LSM1 inactivation caused by mutations and profound deletions predicted poor prognosis in breast cancer (BRCA) patients. LSM1 was highly expressed in both BRCA tissues and cells compared to normal breast tissues/cells. High LSM1 expression is associated with poorer overall survival and disease-free survival. The association between LSM1 and immune infiltration of breast cancer was assessed by TIMER and CIBERSORT algorithms. LSM1 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer.

Female Human Papillomavirus Infection Associated with Increased Risk of Ectopic Pregnancy: Early Evidence from Taiwan Population-Based Cohort Study.

BACKGROUND: This is an investigation of the human papillomavirus (HPV) infection and its correlation with the risk of ectopic pregnancy (EP). METHODS: The cohort study includes 11,239 patients with newly diagnosed HPV infections between 2000 and 2012, and by using computer-generated random numbers, patients who do not have HPV infections are selected randomly as the comparison cohort. The HPV infection cohort is matched to comparison individuals at a 1:10 ratio by age and index year. All individuals included in the study were followed up to the point they developed EP, pulled-out from the insurance program, lost to follow-up, or until the end of 2013. A Cox proportional-hazards regression analysis was used to analyze the risk of EP with the hazard ratios (HRs) and 95% confidence intervals (CIs) between the HPV and control cohort. RESULTS: The adjusted hazard ratio (aHR) of EP for HPV patients relative to controls is 1.70 (95% CI = 1.04, 2.78), indicating a positive correlation between EP and HPV in the 13-year follow-up period, after adjusting for age and relevant comorbidities. The sensitivity analyses yield similar results. CONCLUSIONS: A history of HPV infection is a potential risk factor associated with the development of subsequent EP in Taiwanese individuals, especially those diagnosed with an HPV infection within 3 years.

The Efficacy of Thrombin-Gelatin Matrix in Hemostasis for Large Breast Tumor after Vacuum-Assisted Breast Biopsy.

BACKGROUND: Vacuum-assisted breast biopsy (VABB) for benign breast tumor excision is a developing trend in breast surgery. The most common complication of VABB is hematoma. We assessed the efficiency of the thrombin-gelatin matrix (TGM) for hemostasis after VABB. METHODS: From December 2013 to June 2017, 147 patients with breast tumors > 2 cm in size were treated with a 7-gauge ultrasound-guided EnCor EnSpire® breast biopsy system. After VABB, the TGM was applied using an iron-tube device. After injection, brief external compression for 15 min and postoperative bandage compression for approximately 12 h were applied. The medical records were reviewed and analyzed for hematoma and acute bleeding at 1 and 3 months after VABB. RESULTS: A total of 72 patients received hemostasis via TGM, and 75 patients received hemostasis by compression. The rates of postoperative acute bleeding in the TGM group were significantly lower than those in the non-TGM group (5.5% vs. 22.7%, p = 0.003). Among patients with hematoma, there was no statistically significant difference between the two groups (25% vs. 26.7%, p = 0.85). CONCLUSIONS: This is the first cohort study to apply the TGM hemostatic matrix for post-VABB hemostasis. The TGM hemostatic matrix could be an option for patients with large breast tumors.

A More Diverse Cervical Microbiome Associates with Better Clinical Outcomes in Patients with Endometriosis: A Pilot Study.

Infection-induced chronic inflammation is common in patients with endometriosis. Although microbial communities in the reproductive tracts of patients have been reported, little was known about their dynamic profiles during disease progression and complication development. Microbial communities in cervical mucus were collected by cervical swabs from 10 healthy women and 23 patients, and analyzed by 16S rRNA amplicon sequencing. The abundance, ecological relationships and functional networks of microbiota were characterized according to their prevalence, clinical stages, and clinical features including deeply infiltrating endometriosis (DIE), CA125, pain score and infertility. Cervical microbiome can be altered during endometriosis development and progression with a tendency of increased Firmicutes and decreased Actinobacteria and Bacteroidetes. Distinct from vaginal microbiome, upregulation of Lactobacillus, in combination with increased Streptococcus and decreased Dialister, was frequently associated with advanced endometriosis stages, DIE, higher CA125 levels, severe pain, and infertility. Significantly, reduced richness and diversity of cervical microbiome were detected in patients with more severe clinical symptoms. Clinical treatments against infertility can partially reverse the ecological balance of microbes through remodeling nutrition metabolism and transport and cell-cell/cell-matrix interaction. This study provides a new understanding on endometriosis development and a more diverse cervical microbiome may be beneficial for patients to have better clinical outcomes.

Ribosome Biogenesis Serves as a Therapeutic Target for Treating Endometriosis and the Associated Complications.

Ribosome biogenesis is a cellular process critical for protein homeostasis during cell growth and multiplication. Our previous study confirmed up-regulation of ribosome biogenesis during endometriosis progression and malignant transition, thus anti-ribosome biogenesis may be effective for treating endometriosis and the associated complications. A mouse model with human endometriosis features was established and treated with three different drugs that can block ribosome biogenesis, including inhibitors against mTOR/PI3K (GSK2126458) and RNA polymerase I (CX5461 and BMH21). The average lesion numbers and disease frequencies were significantly reduced in treated mice as compared to controls treated with vehicle. Flow cytometry analyses confirmed the reduction of small peritoneal macrophage and neutrophil populations with increased large versus small macrophage ratios, suggesting inflammation suppression by drug treatments. Lesions in treated mice also showed lower nerve fiber density which can support the finding of pain-relief by behavioral studies. Our study therefore suggested ribosome biogenesis as a potential therapeutic target for treating endometriosis.

Acetyl Coenzyme A Synthase 2 Acts as a Prognostic Biomarker Associated with Immune Infiltration in Cervical Squamous Cell Carcinoma.

Cervical squamous cell carcinoma (CESC) is one of the most common malignant tumors in women worldwide with a low survival rate. Acetyl coenzyme A synthase 2 (ACSS2) is a conserved nucleosidase that converts acetate to acetyl-CoA for energy production. Our research intended to identify the correlations of ACSS2 with clinical prognosis and tumor immune infiltration in CESC. ACSS2 is highly expressed in many tumors and is involved in the progression and metastasis of these tumors. However, it is not clear how ACSS2 affects CESC progression and immune infiltration. Analysis of the cBioPortal, GEPIA2, UALCAN, and TCGA databases showed that ACSS2 transcript levels were significantly upregulated in multiple cancer types including CESC. Quantitative RT-PCR analysis confirmed that ACSS2 expression was significantly upregulated in human cervical cancer cells. Here, we performed tissue microarray analysis of paraffin-embedded tissues from 240 cervical cancer patients recorded at FIGO/TNM cancer staging. The results showed that ACSS2 and PDL1 were highly expressed in human CESC tissues, and its expression was associated with the clinical characteristics of CESC patients. TIMER database analysis showed that ACSS2 expression in CESC was associated with tumor infiltration of B cells, CD4+ and CD8+ T cells, and cancer-associated fibroblasts (CAF). Kaplan-Meier survival curve analysis showed that CESC with high ACSS2 expression was associated with shorter overall survival. Collectively, our findings establish ACSS2 as a potential diagnostic and prognostic biomarker for CESC.

Genetic impacts on thermostability of onco-lncRNA HOTAIR during the development and progression of endometriosis.

HOTAIR is a well-known long non-coding RNA (lncRNA) involved in various cellular signaling, whereas its functional impacts on endometriosis development are still largely unknown. To this end, six potential functional single nucleotide polymorphisms (SNPs) in HOTAIR, with minor allele frequencies more than 10% in Han population and altered net energy of RNA structures larger than 0.5 kcal/mol, were selected for genotyping study. The study included 207 endometriosis patients and 200 healthy women. Genetic substitutions at rs1838169 and rs17720428 were frequently found in endometriosis patients, and rs1838169 showed statistical significance (p = 0.0174). The G-G (rs1838169-rs17720428) haplotype showed the most significant association with endometriosis (p < 0.0001) with enhanced HOTAIR stability, and patients who harbor such haplotype tended to show higher CA125. Data mining further revealed higher mRNA HOTAIR levels in the endometria of patients with severe endometriosis which consistently showed reduced HOXD10 and HOXA5 levels. HOTAIR knockdown with specific shRNAs down-regulated cell proliferation and migration with the induction of HOXD10 and HOXA5 expression in human ovarian clear cancer cells. Our study therefore provided evidence to indicate a prominent role of HOTAIR in promoting endometriosis, which could be used as a potential target for clinical applications.