Ming Li

Bioinformatic analysis of differentially expressed profiles of lncRNAs and miRNAs with their related ceRNA network in endometrial cancer

Increasing evidence suggests that long non-coding riboneucleic acids (lncRNAs), as competing endogenous RNA (ceRNA), play a key role in the initiation, invasion, and metastasis of cancer. As a new hypothesis, the lncRNA-micro RNA (miRNA)-messenger RNA (mRNA), ceRNA regulatory network has been successfully constructed in a variety of cancers. However, lncRNA, which plays a ceRNA function in endometrial cancer (EC), is still poorly understood. In this study, we downloaded EC expression profiling from The Cancer Genome Atlas database and used the R software “edgeR” package to analyze the differentially expressed genes between EC and normal endometrium samples. Then, differentially expressed (DE) lncRNAs, miRNAs and mRNAs were selected to construct a lncRNA-miRNA-mRNA prognosis-related regulatory network based on interaction information. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed on the genes in the network to predict the potential underlying mechanisms and functions of lncRNAs in EC. Kaplan–Meier method and the log-rank test were used for survival analysis. Based on the “ceRNA hypothesis,” we constructed a co-expression network of mRNA and lncRNA genes mediated by miRNA in the process of tumor genesis. Furthermore, we successfully constructed a dysregulated lncRNA-associated ceRNA network containing 96 DElncRNAs, 27 DEmiRNAs, and 74 DEmRNAs. Through Kaplan–Meier curve analysis, we found that 9 lncRNAs, 3 miRNAs, and 12 mRNAs were significantly correlated with the overall survival rate of patients among all lncRNAs, miRNAs, and mRNAs involved in ceRNA (P < .05). Our research provides a new perspective for the interaction among lncRNAs, miRNAs, and mRNA and lays the foundation for further research on the mechanism of lncRNAs in the occurrence of EC.

A NOTCH1 Mutation Found in a Newly Established Ovarian Cancer Cell Line (FDOVL) Promotes Lymph Node Metastasis in Ovarian Cancer

Peritoneal implantation and lymph node metastasis have different driving mechanisms in ovarian cancer. Elucidating the underlying mechanism of lymph node metastasis is important for treatment outcomes. A new cell line, FDOVL, was established from a metastatic lymph node of a patient with primary platinum-resistant ovarian cancer and was then characterized. The effect of NOTCH1-p.C702fs mutation and NOTCH1 inhibitor on migration was evaluated in vitro and in vivo. Ten paired primary sites and metastatic lymph nodes were analyzed by RNA sequencing. The FDOVL cell line with serious karyotype abnormalities could be stably passaged and could be used to generated xenografts. NOTCH1-p.C702fs mutation was found exclusively in the FDOVL cell line and the metastatic lymph node. The mutation promoted migration and invasion in cell and animal models, and these effects were markedly repressed by the NOTCH inhibitor LY3039478. RNA sequencing confirmed CSF3 as the downstream effector of NOTCH1 mutation. Furthermore, the mutation was significantly more common in metastatic lymph nodes than in other peritoneal metastases in 10 paired samples (60% vs. 20%). The study revealed that NOTCH1 mutation is probably a driver of lymph node metastasis in ovarian cancer, which offers new ideas for the treatment of ovarian cancer lymph node metastasis with NOTCH inhibitors.

m6A-Related lncRNA Signature Is Involved in Immunosuppression and Predicts the Patient Prognosis of the Age-Associated Ovarian Cancer

Background. Epithelial ovarian cancers are age-associated diseases, usually diagnosed at an advanced stage. lncRNA has been discovered to interplay with N6-methyladenosine (m6A), working in tandem to promote cancer progression and worsening patient outcomes. This study is aimed at investigating the roles and mechanism of m6A-related lncRNA signature on ovarian cancers. Methods. We retrieved TCGA and CGGA sequencing data to identify m6A-related lncRNA signature and constructed an m6A score (MS) using the LASSO algorithm. A clinical nomogram was then established to predict the overall survival of patients. Subsequently, GSEA analyses were conducted to obtain pathways involved. Expression of HLA genes, 28 tumor-infiltrating lymphocyte infiltration, and anticancer cycle were analyzed the immunological differences between high-MS and low-MS groups. Finally, immune checkpoint gene expressions and IC50 of chemotherapeutic drugs were calculated, and CMap was run to identify the potential compounds and their corresponding mechanisms. Results. We identified 16 m6A-related lncRNAs and constructed an MS model. The high-MS group showed a poor prognosis. A clinical nomogram consists of MS, and age was constructed and predicted the 1-, 3-, and 5-year survival with high accuracy. GSEA analyses presented downregulated antigen processing and presentation pathways. Immunocyte infiltrating analyses demonstrated that high-MS was associated with high infiltration of Treg cells, macrophages, and low Th1/Th2 rate. Also, high expression of immune checkpoint genes NRP1, TNFSF9, and VSIR was observed in the high-MS group. Finally, the high-MS group also predicted low IC50 of vinorelbine and vorinostat. Conclusion. This study constructed a robust prediction model for prognostic management and revealed the cross-talk between m6A and immunosuppression. Besides, the m6A lncRNA signature can predict the chemotherapeutic drug response. These will shed light on the development of novel therapeutic strategies and render survival benefits for ovarian patients.

Lactobacillus spp. create a protective micro-ecological environment through regulating the core fucosylation of vaginal epithelial cells against cervical cancer

AbstractVaginal dysbiosis often occurs in patients with cervical cancer. The fucosylation of mucosal epithelial cells is closely related to microbial colonization, and play an important role in protecting the vaginal mucosal epithelial cells. However, no reports on the relationship between vaginal dysbiosis and abnormal mucosal epithelial cell fucosylation, and their roles in the occurrence and development of cervical cancer are unavailable. Here we report that core fucosylation levels were significantly lower in the serum, exfoliated cervical cells and tumor tissue of cervical cancer patients. Core fucosyltransferase gene (Fut8) knockout promoted the proliferation and migration of cervical cancer cells. In patients with cervical cancer, the vaginal dysbiosis, and the abundance ofLactobacillus, especiallyL. iners, was significantly reduced. Meanwhile, the abundance ofL.inerswas positively correlated with core fucosylation levels. TheL. inersmetabolite lactate can activate the Wnt pathway through the lactate-Gpr81 complex, which increases the level of core fucosylation in epidermal cells, inhibiting the proliferation and migration of cervical cancer cells, and have application prospects in regulating the vaginal microecology and preventing cervical cancer.

Resveratrol Induces Apoptosis, Suppresses Migration, and Invasion of Cervical Cancer Cells by Inhibiting the Hedgehog Signaling Pathway

To investigate the effect and mechanism of resveratrol on the biological behavior of cervical cancer cells (HeLa cells), the apoptosis, migration, and invasion of HeLa cells were detected by flow cytometry, wound healing, and transwell assays. The expression levels of Hedgehog signal pathway proteins (smoothened (SMO), zinc finger transcription factors (Gli1), and sonic hedgehog homolog (Shh)) were detected by quantitative real‐time PCR (qPCR) and western blotting. Compared with that control group, resveratrol (RES) significantly induced apoptosis, inhibited the migration and invasion of the HeLa cells. The expression of SMO, Gli1, and Shh were downregulated in the HeLa cells treated with RES. The Hedgehog agonist purmorphamine (PUR) reversed the RES‐induced increase of apoptosis and reduction of migration and invasion in the HeLa cells. In conclusion, RES induced the apoptosis and suppressed the migration and invasion of HeLa cells by inhibiting Hedgehog signal pathway.

Von Willebrand factor promotes radiation-induced intestinal injury (RIII) development and its cleavage enzyme rhADAMTS13 protects against RIII by reducing inflammation and oxidative stress

Patients with abdominopelvic cancer undergoing radiotherapy commonly develop radiation-induced intestinal injury (RIII); however, its underlying pathogenesis remains elusive. The von Willebrand factor (vWF)/a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) axis has been implicated in thrombosis, inflammation, and oxidative stress. However, its role in RIII remains unclear. In this study, the effect of radiation on vWF and ADAMTS13 expression was firstly evaluated in patients with cervical cancer undergoing radiotherapy and C57BL/6J mice exposed to different doses of total abdominal irradiation. Then, mice with the specific deletion of vWF in the platelets and endothelium were established to demonstrate the contribution of vWF to RIII. Additionally, the radioprotective effect of recombinant human (rh) ADAMTS13 against RIII was assessed. Results showed that both the patients with cervical cancer undergoing radiotherapy and RIII mouse model exhibited increased vWF levels and decreased ADAMTS13 levels. The knockout of platelet- and endothelium-derived vWF rectified the vWF/ADAMTS13 axis imbalance; improved intestinal structural damage; increased crypt epithelial cell proliferation; and reduced radiation-induced apoptosis, inflammation, and oxidative stress, thereby alleviating RIII. Administration of rhADAMTS13 could equally alleviate RIII. Our results demonstrated that abdominal irradiation affected the balance of the vWF/ADAMTS13 axis. vWF exerted a deleterious role and ADAMTS13 exhibited a protective role in RIII progression. rhADAMTS13 has the potential to be developed into a radioprotective agent.

Preclinical Combination Targeting VEGF and PI3K in a Rare, Aggressive Mixed Endometrial Carcinoma: An Applied Case Report

Abstract We report a rare case of a young patient (VENUS 167) initially diagnosed with grade 1 endometrioid endometrial cancer, which, following endocrine treatment, presented with mixed aggressive carcinoma with three distinct histologic patterns: grade 1 endometrioid, large cell neuroendocrine, and undifferentiated carcinoma. The surgical specimen at the time of disease progression was used to establish OPTO.85, a patient-derived organoid (PDO), followed by a corresponding organoid-derived xenograft (ODX). Multi-omic analyses confirmed that OPTO.85 accurately reflected the patient’s tumor characteristics. Whole-exome sequencing analysis identified oncogenic alterations in PIK3CA, ARID1A, and CTNNB1. Further RNA sequencing and assay for transposase-accessible chromatin using sequencing analyses revealed enrichment in VEGF and Wnt signaling pathways, suggesting therapeutic vulnerabilities. A high-throughput drug screen was conducted using ApexBio-approved and epigenetic drug libraries, along with kinase inhibitor and tool compound libraries developed at the Ontario Institute of Cancer Research. The OPTO.85 PDO exhibited sensitivity to PI3K inhibitors and responsiveness to VEGF inhibition. Cediranib demonstrated synergy with BKM120, significantly reducing organoid growth. This combination also showed in vivo efficacy in the ODX model, in which dual inhibitors significantly suppressed tumor growth compared with single compounds. This case exemplifies the impact of genomic profiling and patient-derived models in identifying actionable molecular changes in rare cancers with limited therapeutic options and poor prognosis. It highlights that high-throughput sequencing for individual patient tumors and generation of patient-derived models are feasible in endometrial cancer. This preclinical model may assist clinical decision and personalized therapy requiring validation in prospective studies. Significance: This study characterizes a rare aggressive mixed endometrial carcinoma that developed after hormonal therapy. Patient-derived organoid and xenograft models revealed actionable targets in the VEGF and PI3K pathways. Combined cediranib and BKM120 treatment showed synergistic antitumor effects in vitro and in vivo. These findings highlight the potential of integrating molecular profiling and drug testing to guide personalized therapies in rare and recurrent endometrial cancers.