Yun Liu

METTL3‐induced FGD5‐AS1 contributes to the tumorigenesis and PD‐1/PD‐L1 checkpoint to enhance the resistance to paclitaxel of endometrial carcinoma

AbstractEndometrial cancer (EC), a widely occurring cancer in the uterus, is among the top four most frequent malignancies in women. To improve approaches for combating this disease, it is essential to gain a more comprehensive comprehension of the intricate causes of EC. Accumulating evidence highlight the essential role of long non‐coding RNA (LncRNA) in EC progression, while its biological and mechanical function has not been fully revealed. In this study, a LncRNA microarray analysis was performed using four pairs of paclitaxel (PTX) resistant EC cells, FGD5‐AS1 was identified as a significantly upregulated gene. Biologically, it was found that FGD5‐AS1 enhances chemoresistance of EC cells to PTX treatment and blocking immune escape via PD‐1/PD‐L1 checkpoint. Furthermore, FGD5‐AS1 exerted an oncogene role in EC cells via promoting cell proliferation and migration. Mechanically, METTL3 could upregulate FGD5‐AS1 expression via N6‐methyladenosine (m6A) modification. The biological roles of METTL3 were exerted via modulating FGD5‐AS1 expression in EC. Collectively, our research has shed light on the involvement of the METTL3/FGD5‐AS1 axis in the development of PTX resistance in EC. This finding offers a new avenue for further exploration of the underlying mechanisms of chemoresistance in EC and provides valuable insights for the development of potential therapeutic targets in the treatment of EC.

Circ_0067835 sponges miR‐324‐5p to induce HMGA1 expression in endometrial carcinoma cells

AbstractEndometrial cancer is a common gynaecological malignant tumour among women across the world. Circular RNAs (circRNAs) are a novel kind of non‐coding RNAs, and they can play a crucial role in multiple cancers. Nevertheless, the mechanisms of circRNAs in regulating gene expression in endometrial cancer are still unclear. Here, our work sought to focus on the role that circ_0067835 exert in progression and development of endometrial cancer cells. We observed circ_0067835 was markedly elevated in endometrial cancer. Then, changes in endometrial cancer cell (RL95‐2 and HEC‐1B) function were determined after circ_0067835 knockdown. Loss‐of‐functional assays revealed that circ_0067835 down‐regulation significantly repressed RL95‐1 and HEC‐1B cell proliferation, migration and invasion. Bioinformatics analysis, luciferase reporter experiment and RNA pull‐down assay were employed to predict and validate circ_0067835 can bind to miR‐324‐5p. Increase in miR‐324‐5p remarkably depressed the proliferation, migration and invasion of endometrial cancer cells via inhibiting high mobility group A1 (HMGA1). HMGA1 is identified as a vital prognostic biomarker in endometrial cancer. Currently, we reported circ_0067835 was positively correlated with HMGA1 in endometrial cancer. We implied that circ_0067835 was capable of sponging miR‐324‐5p and inducing its downstream target HMGA1 in vitro and in vivo. In conclusion, circ_0067835 can compete with miR‐324‐5p, resulting in HMGA1 up‐regulation, and therefore induce the development of endometrial cancer.

lncRNA OIP5-AS1 Suppresses Cell Proliferation and Invasion of Endometrial Cancer by Regulating PTEN/AKT via Sponging miR-200c-3p

Background. Endometrial carcinoma (EC) is one of the major gynecologic malignancy cancers affecting females with dismal prognosis and high mortality around the world. Numerous studies have proven that an aberrant level of long noncoding RNAs is present in many endometrial cancer patients, while the underlying molecular mechanism remains unclear. Method. The expression levels of lncRNA OIP5-AS1, miR200c-3p, and PTEN were measured by a quantitative real-time polymerase chain reaction in endometrial cancer tissue and endometrial cancer cells. CCK8 assay, wound-healing assay, and cell colony formation were applied to evaluate cell proliferation, cell migration, and cell colony formation ability. Cell cycle and cell apoptosis were detected by flow cytometry. The interactions between OIP5-AS1, miR200c-3p, and PTEN were explored by luciferase activity. Results. In the present study, we demonstrated that long noncoding RNA OIP5-AS1 was significantly reduced in EC tissue compared with normal tissue. The lower expression level of OIP5-AS1 was also confirmed in four kinds of EC cell lines compared with the normal endometrial cell line. Gain- and loss-of-function of experiments indicated that upregulation of OIP5-AS1 could inhibit the proliferation, migration, and invasion of EC cells in vitro. Meanwhile, overexpression of OIP5-AS1 could also suppress the growth of tumor in the xenograft model. Moreover, further study revealed that miR-200c-3p could bind to OIP5-AS1, and the loss function of miR-200c-3p could reverse the elevated OIP5-AS1’s inhibitory effect on the progression of EC. Furthermore, we found that downregulation of miR-200c-3p was inversely correlated with PTEN expression in EC cells. Reduced OIP5-AS1 could lead to the accumulation of miR-200c-3p, which could induce the upregulation of PTEN indirectly. Conclusion. Our study demonstrated a novel molecular mechanism that lncRNA OIP5-AS1 could modulate the progression of EC by combining competitively with miR-200c-3p to control the PTEN/AKT pathway in EC cells, which might supply important information for developing novel therapeutic strategies for EC patients.

Comprehensive Analysis of the Control of Cancer Stem Cell Characteristics in Endometrial Cancer by Network Analysis

Background. Cancer stem cells play an important role in endometrial cancer (EC). It is closely related to self-renewal and therapeutic resistance of EC. Methods. In this study, WGCNA (weighted gene coexpression network analysis) was used to analyze the relationship between genes and clinical features. We also performed immune cell infiltration analysis of a key module by using ImmuCellAI (Immune Cell Abundance Identifier). Then, key genes were verified in the GEO database. Finally, causal relationship analysis and protein-protein interaction analysis were performed in DisNor tool and STRING. Result. The mRNA expression-based stemness index (mRNAsi) is significantly lower in normal tissues and is significantly higher in individuals with stage IV or high-grade cancer and those who are obese or postmenopausal. Nineteen key genes (ORC6, C1orf112, RAD54L, SGO2, BUB1, PLK4, KIF18B, BUB1B, TTK, NCAPG, XRCC2, CENPF, KIF15, RACGAP1, ARHGAP11A, TPX2, KIF14, KIF4A, and NCAPH) that were enriched mainly in terms related to the cell cycle and DNA replication were selected by weighted gene coexpression network analysis (WGCNA). Based on the key modules, the numbers of NKT cells, NK cells, and neutrophils in the normal group were significantly higher than those in the cancer group. PLK1, CDK1, and MAD2L1, which were correlated with upstream genes, may be an regulated upstream of key genes. Conclusion. PLK1, CDK1, and MAD2L1 which were strongly correlated with upstream genes may be a regulated upstream of key genes.

A novel lncRNA-mRNA-miRNA signature predicts recurrence and disease-free survival in cervical cancer

Cervical cancer (CC) patients have a poor prognosis due to the high recurrence rate. However, there are still no effective molecular signatures to predict the recurrence and survival rates for CC patients. Here, we aimed to identify a novel signature based on three types of RNAs [messenger RNA (mRNAs), microRNA (miRNAs), and long non-coding RNAs (lncRNAs)]. A total of 763 differentially expressed mRNAs (DEMs), 46 lncRNAs (DELs), and 22 miRNAs (DEMis) were identified between recurrent and non-recurrent CC patients using the datasets collected from the Gene Expression Omnibus (GSE44001; training) and The Cancer Genome Atlas (RNA- and miRNA-sequencing; testing) databases. A competing endogenous RNA network was constructed based on 23 DELs, 15 DEMis, and 426 DEMs, in which 15 DELs, 13 DEMis, and 390 DEMs were significantly associated with disease-free survival (DFS). A prognostic signature, containing two DELs (CD27-AS1, LINC00683), three DEMis (hsa-miR-146b, hsa-miR-1238, hsa-miR-4648), and seven DEMs (ARMC7, ATRX, FBLN5, GHR, MYLIP, OXCT1, RAB39A), was developed after LASSO analysis. The built risk score could effectively separate the recurrence rate and DFS of patients in the high- and low-risk groups. The accuracy of this risk score model for DFS prediction was better than that of the FIGO (International Federation of Gynecology and Obstetrics) staging (the area under receiver operating characteristic curve: training, 0.954 vs 0.501; testing, 0.882 vs 0.656; and C-index: training, 0.855 vs 0.539; testing, 0.711 vs 0.508). In conclusion, the high predictive accuracy of our signature for DFS indicated its potential clinical application value for CC patients.

Bufogarlides A-C, three new bufadienolides with Δ 14,15 double bond from the skins of Bufo bufo gargarizans

Three new bufadienolides with a