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Abstract Background Fibrogenesis within ovarian endometrioma (endometrioma), mainly induced by transforming growth factor-β (TGF-β), is characterized by myofibroblast over-activation and excessive extracellular matrix (ECM) deposition, contributing to endometrioma-associated symptoms such as infertility by impairing ovarian reserve and oocyte quality. However, the precise molecular mechanisms that underpin the endometrioma- associated fibrosis progression induced by TGF-β remain poorly understood. Methods The expression level of lysine acetyltransferase 14 (KAT14) was validated in endometrium biopsies from patients with endometrioma and healthy controls, and the transcription level of KAT14 was further confirmed by analyzing a published single-cell transcriptome (scRNA-seq) dataset of endometriosis. We used overexpression, knockout, and knockdown approaches in immortalized human endometrial stromal cells (HESCs) or human primary ectopic endometrial stromal cells (EcESCs) to determine the role of KAT14 in TGF-β-induced fibrosis. Furthermore, an adeno-associated virus (AAV) carrying KAT14-shRNA was used in an endometriosis mice model to assess the role of KAT14 in vivo. Results KAT14 was upregulated in ectopic lesions from endometrioma patients and predominantly expressed in activated fibroblasts. In vitro studies showed that KAT14 overexpression significantly promoted a TGF-β-induced profibrotic response in endometrial stromal cells, while KAT14 silencing showed adverse effects that could be rescued by KAT14 re-enhancement. In vivo, Kat14 knockdown ameliorated fibrosis in the ectopic lesions of the endometriosis mouse model. Mechanistically, we showed that KAT14 directly interacted with serum response factor (SRF) to promote the expression of α-smooth muscle actin (α-SMA) by increasing histone H4 acetylation at promoter regions; this is necessary for TGF-β-induced ECM production and myofibroblast differentiation. In addition, the knockdown or pharmacological inhibition of SRF significantly attenuated KAT14-mediating profibrotic effects under TGF-β treatment. Notably, the KAT14/SRF complex was abundant in endometrioma samples and positively correlated with α-SMA expression, further supporting the key role of KAT14/SRF complex in the progression of endometrioma-associated fibrogenesis. Conclusion Our results shed light on KAT14 as a key effector of TGF-β–induced ECM production and myofibroblast differentiation in EcESCs by promoting histone H4 acetylation via co-operating with SRF, representing a potential therapeutic target for endometrioma-associated fibrosis.

Abstract Objective This study assessed the impacts of in vitro culture times of cleavage embryos on clinical pregnancy outcomes. Methods This retrospective cohort study was performed at the Reproductive Medicine Department of Hainan Modern Women and Children’s Hospital in China between January 2018 and December 2022. Patients who first underwent frozen embryo transfer with in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles on day 3 were included. According to the time of embryo culture after thawing, the embryos were divided into long-term culture group(18-20 h) and short-term culture group (2-4 h). The clinical pregnancy rate was regarded as he primary outcome. To minimize confounding factors and reduce selection bias, the propensity score matching was used to balance the effects of known confounding factors and to reduce selection bias. Stratified analyses and multiple logistic regression analyses were used to evaluate the risk factors affecting the clinical pregnancy outcomes after matching. Results General characteristics between two groups were comparable after matching. In the long-term culture group, 266/381 (69.81%) embryos had more than 10 blastomeres, and 75/381 (19.68%) reached the morula stage. After overnight culture, the implantation rate (27.97% vs. 14.28%, P = 0.018) and clinical pregnancy rate (38.46% vs. 22.5%, P = 0.05) were increased in the group with proliferating blastomeres. The long-term culture group trended to have a higher clinical pregnancy rate compared with the short-term culture group (35.74% vs. 29.79%). No statistical differences in clinical pregnancy outcomes between the two groups were observed after matching, including the rates of implantation (25.46% vs23.98%), miscarriages (25% vs. 22.85%), ongoing pregnancy rate (76.2% vs. 77.15%) and live birth rate (26.8% vs. 22.98%). Stratified analyses were performed according to the age of the patients. After matching, there were no significant differences in the clinical pregnancy, implantation and miscarriage rates between the two groups for patients > 35 or ≤ 35 years of age. Subgroup analyses were performed according to the quality of the transferred embryos. There were no significant differences in the clinical outcomes, between two groups after embryos transferred with the same quality. Multivariate Logistic regression analysis was used to evaluate the influencing factors of clinical pregnancy outcomes after matching. Culture time was not found to be an independent predictor for clinical pregnancy [OR 0.742, 95%CI 0.487 ~ 1.13; P = 0.165]. The age of oocyte retrieval [OR 0.906, 95%CI 0.865 ~ 0.949; P

Abstract Background Dysregulated epithelial–mesenchymal transition (EMT) is involved in cervical cancer metastasis and associated with histone acetylation. However, the underlying molecular mechanisms of histone acetylation in cervical cancer EMT and metastasis are still elusive. Methods We systematically investigated the expression patterns of histone acetylation genes and their correlations with the EMT pathway in cervical cancer. The expression of CSRP2BP among cervical cancer tissues and cell lines was detected using Western blotting and immunohistochemistry analyses. The effects of CSRP2BP on cervical cancer cell proliferation and tumorigenicity were examined by cell growth curve, EdU assay, flow cytometry and xenotransplantation assays. Wound healing assays, transwell migration assays and pulmonary metastasis model were used to evaluate the effects of CSRP2BP on cell invasion and metastasis of cervical cancer cells in vivo and in vitro. RNA-seq, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and luciferase reporter assays were used to uncover the molecular mechanisms of CSRP2BP in promoting cervical cancer EMT and metastasis. Results We prioritized a top candidate histone acetyltransferase, CSRP2BP, as a key player in cervical cancer EMT and metastasis. The expression of CSRP2BP was significantly increased in cervical cancer tissues and high CSRP2BP expression was associated with poor prognosis. Overexpression of CSRP2BP promoted cervical cancer cell proliferation and metastasis both in vitro and in vivo, while knockdown of CSRP2BP obtained the opposite effects. In addition, CSRP2BP promoted resistance to cisplatin chemotherapy. Mechanistically, CSRP2BP mediated histone 4 acetylation at lysine sites 5 and 12, cooperated with the transcription factor SMAD4 to bind to the SEB2 sequence in the N-cadherin gene promotor and upregulated N-cadherin transcription. Consequently, CSRP2BP promoted cervical cancer cell EMT and metastasis through activating N-cadherin. Conclusions This study demonstrates that the histone acetyltransferase CSRP2BP promotes cervical cancer metastasis partially through increasing the EMT and suggests that CSRP2BP could be a prognostic marker and a potential therapeutic target for combating cervical cancer metastasis.

Abstract Background Gastric cancer has a high incidence and mortality rate. Angiogenesis is necessary for tumor infiltration and metastasis and affects patient prognosis. YKL-39 has monocyte chemotactic activity and pro-angiogenic activity in some tumors. In this study, we investigated the relationship between YKL-39 and tumor-associated macrophages and microangiogenesis in gastric cancer to determine its potential as a prognostic biomarker. Materials and methods A total of 119 patients with gastric cancer who had undergone gastrectomy at the 940th Hospital of the Joint Security Force between 2014 and 2018 were included in this study. We assayed the protein expression of YKL-39, CD68, and CD34 by immunohistochemistry in tissues of 119 patients with gastric cancer, as well as the intracellular expression of YKL-39 and CD68 by immunofluorescence. Data were analyzed with SPSS Statistics 25.0 to explore the impact of expression of YKL-39, CD68, and CD34 in gastric cancer patients and the relationship among them. Results Our results show that YKL-39 was expressed in both the nucleus and cytoplasm of gastric cancer cells and tumor mesenchyme. YKL-39 protein expression was associated with the depth of tumor infiltration, lymph node metastasis, and TNM stage; CD68 protein expression was associated with lymph node metastasis and TNM stage; CD34 protein expression was not associated with clinicopathological characteristics. Expression of YKL-39 was positively correlated with CD68 and CD34 (p

Abstract Background Studies have shown that abnormalities in the decidualization process were closely related to recurrent implantation failure (RIF). Prokineticin 2 (PK2) is a secreted protein with angiogenic and tissue remodeling functions but its role in the endometrium is unknown. Methods PK2 levels and its receptor PKR1 mRNA and protein levels in mid-secretory endometrium from normal and RIF women were examined by real-time PCR and western blotting, respectively. The effects of PK2 were evaluated by overexpressed PK2 in immortalized endometrial T-HESC cells using lentivirus vector and found different expression of Matrix metalloproteinase 9(MMP9) and lncRNA LUCAT1 by RNA-sequencing. The ability of PK2 to regulate LUCAT1 and MMP9 was verified in endometrial cells by real-time PCR and western blotting. Results Using endometrial biopsies from normal and RIF patients, we found increased expression of PK2, together with its receptor PKR1 in RIF patients. We then overexpressed PK2 in immortalized endometrial T-HESC cells using lentivirus vector and found decreased expression of Matrix metalloproteinase 9(MMP9), and increased expression of lncRNA LUCAT1. We verified the ability of PK2 to stimulate LUCAT1 and decrease MMP9 in endometrial cells. We further demonstrated that increased expression of a long noncoding RNA LUCAT1 and decreased expression of MMP9 in endometrial biopsies of patients with RIF. Thus, we highlighted the important role of PK2 and its receptor PKR1 in decidualization and RIF. Conclusion Prokineticin 2 and its receptor are important in endometrium decidualization. PK2 may affect endometrial decidualization through the LUCAT1- MMP9 pathway, thereby affecting embryo implantation.