SNORA73B promotes endometrial cancer progression through targeting MIB1 and regulating host gene RCC1 alternative splicing.

Endometrial cancer (EC) is a common gynaecological malignant tumour with unclear pathogenesis. Small nucleolar RNA (snoRNA) is involved in many biological processes, including those of cancers. Using the Cancer Genome Atlas (TCGA) database, the expression pattern of a snoRNA, SNORA73B, was analysed. The biological functions of SNORA73B were assessed by in vitro proliferation, apoptosis, migration, and invasion assays and in vivo by the xenograft model. RNA sequencing (RNA-seq) and RNA immunoprecipitation assays were performed to determine the relationship between SNORA73B and its target genes. High-performance liquid chromatography (HPLC) was performed to detect the pseudouridine content of the mindbomb E3 ubiquitin protein ligase 1 gene (MIB1). The stability of MIB1 mRNA was evaluated using a transcription inhibitor, actinomycin D. By performing co-immunoprecipitation assays, the change in the ubiquitin levels of the Jagged canonical Notch ligand 1 (Jag 1), caused by SNORA73B and MIB1, was identified. RNA-seq and qRT-PCR were performed to detect the alternative splicing of the regulator of the chromosome condensation 1 gene (RCC1). The TCGA database analysis showed that SNORA73B was highly expressed in EC. SNORA73B promoted cell proliferation, migration, and invasion and inhibited apoptosis. SNORA73B modified the pseudouridine content in MIB1 and increased the stability of MIB1 mRNA and protein; thus, it affected Jag 1 ubiquitination and further activated the Notch pathway. SNORA73B also affected the alternative splicing of RCC1, increasing the number of transcripts, RCC1-T2 and RCC1-T3, which promoted cell proliferation, migration, and invasion. SNORA73B can be a potential target for EC.

Enhancer RNAs: mechanisms in transcriptional regulation and functions in diseases.

In recent years, increasingly more non-coding RNAs have been detected with the development of high-throughput sequencing technology, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), small nucleolar RNAs (snoRNAs), and piwi-interacting RNA (piRNAs). The discovery of enhancer RNAs (eRNAs) in 2010 has further broadened the range of non-coding RNAs revealed. eRNAs are non-coding RNA molecules produced by the transcription of DNA cis-acting elements, enhancer fragments. Recent studies revealed that the transcription of eRNAs may be a biological marker responding to enhancer activity that can participate in the regulation of coding gene transcription. In this review, we discussed the biological characteristics of eRNAs, their functions in transcriptional regulation, the regulation factors of eRNAs production, and the research progress of eRNAs in different diseases. Video Abstract.

LncRNA linc01194 promotes the progress of endometrial carcinoma by up-regulating SOX2 through binding to IGF2BP1.

OBJECTIVE: Endometrial carcinoma (EC) is one of the most common gynecological malignant tumors. Our study showed that long non-coding RNA (lncRNA) linc01194 plays an important role in EC. We explored the mechanism of lncRNA linc01194 in EC. METHODS: The expression of lncRNA linc01194 was detected in The Cancer Genome Atlas database and starBase database. The potential targeted protein of linc01194 was predicted through the starBase database. To determine the role of linc01194 in EC, we downregulated or upregulated the level of linc01194 in EC cell lines and analyzed the cell behaviors and the changes of its potential target proteins. RESULTS: The expression of linc01194 in EC tissues is higher than that in normal endometrial tissues. The knockdown of linc01194 inhibited the cell proliferation, invasion and migration and promoted the apoptosis of EC cells, while overexpression of linc01194 promoted cell proliferation, invasion and migration and inhibited the apoptosis of EC cells. The starBase database revealed that linc01194 could bind to insulin-like growth factor 2 binding protein 1 (IGF2BP1). Previous results showed that in EC, IGF2BP1 could promote the expression of sex-determining region Y-box 2 (SOX2) by promoting the stability of SOX2 mRNA. Our results showed that linc01194 regulate the expression of IGF2BP1 and SOX2. CONCLUSION: Linc01194 can promote the expression of downstream protein SOX2 through binding to IGF2BP1, thus promoting the occurrence and development of EC.

SNORD6 promotes cervical cancer progression by accelerating E6-mediated p53 degradation.

Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs widely distributed in eukaryotic nucleoli. In recent years, studies have revealed that snoRNAs can also participate in the occurrence and development of malignant tumors through different pathways. Cervical cancer is one of the most common malignant tumors of the female reproductive system, and the high-risk HPV virus infection is its main pathogenic mechanism. However, the outcomes in different patients with malignant tumors vary, indicating that other factors might affect the pathogenic process of cervical cancer. In this study, we screened the poor prognosis indicator SNORD6 from the TCGA database to find the snoRNA that affects the disease outcome during the pathogenesis of cervical cancer. We discovered that SNORD6 expression in cervical cancer tissues was higher than that in normal cervical tissues. Cell phenotype experiments revealed that the knockdown of SNORD6 retarded cell proliferation and plate clone formation. Furthermore, G1-S phase cell cycle arrest was induced, DNA synthesis was decreased, cell migration and invasion were reduced, while the level of apoptosis increased, whereas the opposite results were obtained after SNORD6 overexpression. Moreover, after intratumoral injection of ASO-SNORD6, the tumor growth rate slowed down, and the tumor volume decreased compared with the control group. In the mechanism study, we found that SNORD6 concurrently acted as a binding "hub" to promote the formation of the tumor suppressor protein p53 degradation complex E6-E6AP-p53. This reaction enhanced the ubiquitination and degradation of p53, thus influenced the regulation of p53 activities in the cell cycle and apoptosis. This study preliminarily clarified the biological role and specific mechanism of SNORD6 in the occurrence of cervical cancer, broadening the basic theoretical research of ovarian cancer and may provide a new perspective on the diagnosis and treatment of cervical cancer.

A patient-derived organoid-based study identified an ASO targeting SNORD14E for endometrial cancer through reducing aberrant FOXM1 Expression and ß-catenin nuclear accumulation.

BACKGROUND: Most of the endometrial cancer (EC) patients are diagnosis in early stage with a good prognosis while the patients with locally advanced recurrent or metastatic result in a poor prognosis. Adjuvant therapy could benefit the prognosis of patients with high-risk factors. Unfortunately, the molecular classification of great prognostic value has not yet reached an agreement and need to be further refined. The present study aims to identify new targets that have prognostic value in EC based on the method of EC patient-derived organ-like organs (PDOs), and further investigate their efficacy and mechanism. METHODS: The Cancer Genome Atlas (TCGA) database was used to determine SNORD14E expression. The effects of SNORD14E were investigated using CCK8, Transwell, wound-healing assays, and a xenograft model experiment; apoptosis was measured by flow cytometry. Antisense oligonucleotide (ASO) targeting SNORD14E was designed and patient-derived organoids (PDO) models in EC patients was established. A xenograft mouse and PDO model were employed to evaluate the effects of ASO targeting SNORD14E. RNA-seq, Nm-seq, and RNA immunoprecipitation (RIP) experiments were employed to confirm the alternative splicing (AS) and modification induced by SNORD14E. A minigene reporter gene assay was conducted to confirm AS and splicing factors on a variable exon. Actinomycin-d (Act-D) and Reverse Transcription at Low deoxy-ribonucleoside triphosphate concentrations followed by PCR (RTL-P) were utilized to confirm the effects of 2'-O methylation modification on FOXM1. RESULTS: We found that SNORD14E was overexpressed in EC tissues and patients with high expressed SNORD14E were distributed in the TCGA biomolecular classification subgroups without difference. Further, SNORD14E could reduce disease-free survival (DFS) and recurrence free survival (RFS) of EC patients. SNORD14E promoted proliferation, migration, and invasion and inhibited the apoptosis of EC cells in vitro. ASOs targeting SNORD14E inhibited cell proliferation, migration, invasion while promoted cell apoptosis. ASOs targeting SNORD14E inhibited tumor growth in the xenograft mouse model. TCGA-UCEC database showed that the proportion of patients with high expression of SNORD14E in middle-high risk and high-risk patients recommended by EMSO-ESGO-ESTRO guidelines for adjuvant therapy is more than 50%. Next, we enrolled 8 cases of high-risk and high-risk EC patients according to EMSO-ESGO-ESTRO guidelines and successfully constructed EC-PDOs. ASOs targeting SNORD14E inhibited the EC-PDO growth. Mechanistically, SNORD14E could recognize the mRNA of FOXM1 and recruit SRSF1 to promote the shearing of the variable exon VIIa of FOXM1, resulting in the overexpression of the FOXM1 malignant subtypes FOXM1b and FOXM1c. In addition, SNORD14E modified FOXM1 mRNA with 2`-O-methylation, which prolonged the half-life of FOXM1 mRNA. The nucleus accumulation of ß-catenin caused by aberrant FOXM1 expression led to EC progression. CONCLUSIONS: ASO targeting SNORD14E can be an effective treatment for EC.

Small Nucleolar RNA and C/D Box 15B Regulate the TRIM25/P53 Complex to Promote the Development of Endometrial Cancer.

Background: Endometrial cancer is associated with a high mortality rate, which warrants the identification of novel diagnostic markers and therapeutic targets. The aim of this study is to evaluate the role of SNORD15B in the development of endometrial cancer and explore the potential underlying mechanisms. Methods: Bioinformatics was used to analyze the expression level and prognostic relevance of SNORD15B in endometrial cancer. The Ishikawa and HEC-1B cells were respectively transfected with SNORD15B expression plasmid and an antisense oligonucleotide, or the corresponding empty vector and a nonspecific sequence. The malignant phenotype of the suitably transfected cells was assessed by standard in vitro functional assays and the establishment of in vivo xenografts. The expression levels of the specific markers were analyzed with RT-qPCR and western blotting. The subcellular localization of P53 was determined by analyzing the nuclear and cytoplasmic fractions. RIP, Co-IP, and immunohistochemistry were performed as per standard protocols. Results: SNORD15B was overexpressed in the endometrial cancer tissues and correlated to a poor prognosis. Ectopic expression of SNORD15B in Ishikawa cells inhibited apoptosis, increased the proliferation, invasion, and migration in vitro, and enhanced their tumorigenicity in vivo. SNORD15B overexpression also upregulated TRIM25 and accelerated P53 accumulation in the cytoplasm of the endometrial cancer cells. Conclusion: SNORD15B functions as an oncogene in endometrial cancer by targeting the TRIM25/P53 complex and blocking the nuclear translocation of P53.

Molecular mechanism of cell ferroptosis and research progress in regulation of ferroptosis by noncoding RNAs in tumor cells.

Ferroptosis is a newly identified form of nonapoptotic regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species. Morphologically and biochemically different from known types of cell death and apoptosis, ferroptosis promotes nervous system diseases, renal failure, ischemia-reperfusion injury, and the treatment of tumors. It could be induced by several mechanisms, including inhibition of glutathione peroxidase 4, lack of cysteine, and peroxidation of polyunsaturated fatty acids, but could be inhibited by iron chelators, lipophilic antioxidants, and some specific inhibitors. Ferroptosis is found to be closely related to the tumorigenesis, invasion, and metastasis of tumors. Noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), microRNAs, and circular RNAs, do not encode proteins. NcRNAs are found to be capable of regulating the molecular mechanism of ferroptosis in tumor cells post transcription. Ferroptosis provides a new method for cancer treatment. Although several studies have confirmed the important role of ferroptosis in cancer treatment, its specific affecting mechanism is unclear. Here we reviewed the molecular mechanism of ferroptosis in tumor cells and the relationship between ferroptosis and the three important ncRNAs.

Fusion genes in gynecologic tumors: the occurrence, molecular mechanism and prospect for therapy.

Gene fusions are thought to be driver mutations in multiple cancers and are an important factor for poor patient prognosis. Most of them appear in specific cancers, thus satisfactory strategies can be developed for the precise treatment of these types of cancer. Currently, there are few targeted drugs to treat gynecologic tumors, and patients with gynecologic cancer often have a poor prognosis because of tumor progression or recurrence. With the application of massively parallel sequencing, a large number of fusion genes have been discovered in gynecologic tumors, and some fusions have been confirmed to be involved in the biological process of tumor progression. To this end, the present article reviews the current research status of all confirmed fusion genes in gynecologic tumors, including their rearrangement mechanism and frequency in ovarian cancer, endometrial cancer, endometrial stromal sarcoma, and other types of uterine tumors. We also describe the mechanisms by which fusion genes are generated and their oncogenic mechanism. Finally, we discuss the prospect of fusion genes as therapeutic targets in gynecologic tumors.

Esculetin inhibits endometrial cancer proliferation and promotes apoptosis via hnRNPA1 to downregulate BCLXL and XIAP.

Endometrial cancer represents one of the most common gynecological tumors in the world. Advanced and relapsed patients rely on drug therapy. Therefore, it is extremely important to seek more effective targeted drugs. This study found that esculetin has an anti-tumor effect on endometrial cancer through cellular proliferation and apoptosis. At the same time, its anti-tumor effect has also been verified in human endometrial cancer xenograft models in nude mice. Western blot results showed that BCLXL, XIAP, and pAKT protein expression level were down-regulated. A pulldown experiment and LC-MS/MS analysis technology revealed that esculetin targets the hnRNPA1 protein. Cellular proliferation experiments following si-hnRNPA1 transfection verified the tumor-promoting effect of hnRNPA1 in endometrial cancer cells. Nuclear and cytoplasmic separation experiment demonstrated esculetin affecting the export of the hnRNPA1/mRNA complex from the nucleus into the cytoplasm. Thus, esculetin targets hnRNPA1, thereby downregulates BCLXL and XIAP mRNA transcription and translation, resulting in apoptosis and an arrest in proliferation.

Circ-NOLC1 promotes epithelial ovarian cancer tumorigenesis and progression by binding ESRP1 and modulating CDK1 and RhoA expression.

Circular RNAs (circRNAs) play important roles in cancer tumorigenesis and progression, representing prognostic biomarkers and therapeutic targets. In this case, we demonstrated the role of circ-NOLC1 in epithelial ovarian cancer (EOC). Our results have shown that Circ-NOLC1 expression was higher in EOC tissues than in normal tissues, and was positively associated with FIGO stage, differentiation. Among ovarian cancer cell lines, circ-NOLC1 expression was the highest in A2780, and lowest in CAOV3. Overexpression of circ-NOLC1 in CAOV3 cells increased cell proliferation, migration, and invasion ability, whereas silencing of circ-NOLC1 in A2780 cells had the opposite effect: however, neither circ-NOLC1 downregulation nor overexpression influenced NOLC1 mRNA expression. In nude mice with subcutaneous tumors, circ-NOLC1 downregulation decreased tumor growth. Bioinformatic analysis and RNA-binding protein immunoprecipitation showed that circ-NOLC1 could bind to ESRP1. In addition, the overexpression of circ-NOLC1 significantly increased ESRP1, RhoA, and CDK1 protein and mRNA expression level; circ-NOLC1 downregulation had the opposite effects. The tumor-promoting effect of circ-NOLC1 was inhibited by knockdown of ESRP1, CDK1, or RhoA expression in circ-NOLC1-overexpressing cells, which might act by modulating RhoA and CDK1 expression. In conclusion, our study demonstrated that Circ-NOLC1 might promote EOC tumorigenesis and development by binding ESRP1 and modulating CDK1 and RhoA expression.

Efficacy of amiodarone in the prevention of atrial fibrillation after coronary artery bypass grafting: A systematic review and meta-analysis / 中国胸心血管外科临床杂志

@#Objective     To evaluate efficacy of amiodarone in the prevention of atrial fibrillation after coronary artery bypass grafting. Methods     CBM (from January 1978 to August 2017), CNKI (from January 1987 to August 2017), VIP (from January 1989 to August 2017), Wanfang (from January 1998 to August 2017) and PubMed (from January 1989 to August 2017) databases were searched. The articles were selected based on the inclusion and exclusion criteria. Quality of articles was assessed by improved Jadad scale. Statistical analysis was performed using RevMan 5.3. Results     There were 19 articles meeting inclusion criteria including 2 817 patients and all were randomized controlled trial (RCT). There were 16 articles with high quality and 3 articles with low quality by improved Jadad scale. Compared with the placebo, amiodarone had a significant effect on reducing the incidence of atrial fibrillation after coronary artery bypass grafting (RR=0.37, 95% CI 0.28 to 0.50, P<0.000 01) and different administration models and time of amiodarone had effect on the atrial fibrillation after aterial bypass grafting (P<0.05). Conclusion    Compared with the placebo, amiodarone is effective in reducing the incidence of atrial fibrillation after coronary artery bypass grafting.