Fang Wang

LncRNA LOXL1-AS1 promotes endometrial cancer progression by sponging miR-28-5p to upregulate RAP1B expression

Increasing lncRNAs are found to be involved in the biological process of multiple cancer types. Herein, we aimed to reveal the role of LOXL1-AS1 in endometrial cancer (EC) progression. Tumor and corresponding normal tissues were obtained from EC patients. Si-LOXL1-AS1 and miR-28-5p inhibitor were transfected to downregulate the expressions of LOXL1-AS1 and miR-28-5p, while miR-28-5p mimics were used to upregulate the miR-28-5p expression. CCK-8 and colony assays were applied to estimate the cell proliferation. Flow cytometry was performed to measure the cell apoptosis. Wound healing and transwell assays were conducted to assess the cell migration and invasion abilities. Informatics analysis was used to explore the relationship among LOXL1-AS1, miR-28-5p and RAP1B. LOXL1-AS1 was found markedly up-regulated in EC tissues and cell lines. LOXL1-AS1 knockdown displayed evident suppression in cell proliferation, migration and invasion, as well as promotion in cell apoptosis. Moreover, the LOXL1-AS1 induced regulatory effects on EC cells were partially reversed by miR-28-5p inhibitor. Mechanistically, LOXL1-AS1 competitively bond to miR-28-5p, resulting in upregulation of RAP1B. Additionally, in vivo study confirmed the findings discovered in vitro. In summary, LOXL1-AS1 exerted oncogenic roles in EC progression by sponging miR-28-5p and thereby upregulating RAP1B. This finding might provide potential targets for EC therapy.

Targeting of Tumoral NAC1 Mitigates Myeloid-Derived Suppressor Cell–Mediated Immunosuppression and Potentiates Anti–PD-1 Therapy in Ovarian Cancer

Abstract Epithelial ovarian cancer is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade therapy. In this study, we report that nucleus accumbens–associated protein 1 (NAC1), a putative driver of epithelial ovarian cancer, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression. We further showed that tumoral NAC1 directly enhanced the transcription of CXCL16 by binding to CXCR6, thereby promoting MDSC recruitment to the tumor. Moreover, lipid C20:1T produced by NAC1-expressing tumor cells fueled oxidative metabolism of MDSCs and promoted their immune-suppressive function. We also showed that NIC3, a small-molecule inhibitor of NAC1, was able to sensitize mice bearing NAC1-expressing ovarian tumors to anti–PD-1 therapy. Our study reveals a critical role for NAC1 in controlling tumor infiltration of MDSCs and in modulating the efficacy of immune checkpoint blockade therapy. Thus, targeting of NAC1 may be exploited to sensitize ovarian cancer to immunotherapy.

Xanthohumol Promotes Skp2 Ubiquitination Leading to the Inhibition of Glycolysis and Tumorigenesis in Ovarian Cancer

Ovarian cancer is a common, highly lethal tumor. Herein, we reported that S-phase kinase-associated protein 2 (Skp2) is essential for the growth and aerobic glycolysis of ovarian cancer cells. Skp2 was upregulated in ovarian cancer tissues and associated with poor clinical outcomes. Using a customized natural product library screening, we found that xanthohumol inhibited aerobic glycolysis and cell viability of ovarian cancer cells. Xanthohumol facilitated the interaction between E3 ligase Cdh1 and Skp2 and promoted the Ub-K48-linked polyubiquitination of Skp2 and degradation. Cdh1 depletion reversed xanthohumol-induced Skp2 downregulation, enhancing HK2 expression and glycolysis in ovarian cancer cells. Finally, a xenograft tumor model was employed to examine the antitumor efficacy of xanthohumol in vivo. Collectively, we discovered that xanthohumol promotes the binding between Skp2 and Cdh1 to suppress the Skp2/AKT/HK2 signal pathway and exhibits potential antitumor activity for ovarian cancer cells.

Identifying low muscle mass and monitoring body composition changes in newly diagnosed cancer patients: Agreement between multifrequency bioelectrical impedance analysis and computed tomography

Low muscle mass (MM) is significant in cancer patients, and computed tomography (CT) is considered the reference standard for MM assessment. We investigated the consistency of CT and multifrequency bioelectrical impedance analysis (mBIA) in detecting body composition at baseline and during anticancer treatment and the relationship between MM and malnutrition as well as complications in lung and cervical cancer patients. Abdominal CT and mBIA were conducted to assess body composition at baseline for all patients and repeated for patients with cervical cancer after 4 wk of chemoradiotherapy. Concordance was compared by intraclass correlation coefficient and Bland-Altman plots. Receiver operating characteristic analysis was used to assess the diagnostic efficacy of mBIA for low MM. Correlation analysis was conducted to assess the relationship between MM and Nutritional Risk Screening 2002 and Global Leadership Initiative on Malnutrition. Furthermore, we assessed whether there was a difference in the incidence of chemoradiotherapy side effects in the low MM group derived by CT or mBIA. A total of 77 cervical and 73 lung cancer patients were enrolled. mBIA showed fair discriminative capacity (area under the curve = 0.651) for detecting low MM, the concordance of skeletal MM and visceral fat area between CT and mBIA was good (intraclass correlation coefficient = 0.712 and 0.698, respectively), and mBIA and CT had consistent observations of muscle and fat changes (P = 0.051 and 0.124, respectively). There was no difference in the incidence of chemoradiotherapy side effects in the low MM group compared with controls regardless of whether derived by CT or mBIA (P > 0.05). MM was correlated with Nutritional Risk Screening 2002 and Global Leadership Initiative on Malnutrition but showed unsatisfactory prediction of malnutrition (area under the curve <0.7). mBIA- and CT-derived body composition was highly correlated, and agreement was reached on body composition changes during treatment.

Prognostic Factors and a Predictive Nomogram of Cancer-Specific Survival of Epithelial Ovarian Cancer Patients with Pelvic Exenteration Treatment

Objective. The aim of this study was to explore prognostic factors, develop and internally validate a prognostic nomogram model, and predict the cancer-specific survival (CCS) of epithelial ovarian cancer (EOC) patients with pelvic exenteration (PE) treatment. Methods. A total of 454 EOC patients from the Surveillance, Epidemiology, and End Results (SEER) database were collected according to the inclusion criteria and randomly divided into the training (n = 317) and validation (n = 137) cohorts. Prognostic factors of EOC patients with PE treatment were explored by univariate and multivariate stepwise Cox regression analyses. A predictive nomogram was constructed based on selected risk factors. The predictive power of the constructed nomogram was assessed by the time-dependent receiver operating characteristic (ROC) curve. Kaplan–Meier (KM) curve stratified by patients’ nomoscore was also plotted to assess the risk stratification of the established nomogram. In internal validation, the C index, calibration curve, and decision curve analysis (DCA) were employed to assess the discrimination, calibration, and clinical utility of the models, respectively. Results. In the training cohort, age, histological type, Federation of Gynecology and Obstetrics (FIGO) stage, number of examined lymph nodes, and number of positive lymph nodes were found to be independent prognostic factors of postoperative CSS. A practical nomogram model of EOC patients with PE treatment was constructed based on these selected risk factors. Time-dependent ROC curves and KM curves showed the superior predictive capability and excellent clinical stratification of the nomogram in both training and validation cohorts. In the internal validation, the C index, calibration plots, and DCA in the training and validation cohorts confirmed that the nomogram presents a high level of prediction accuracy and clinical applicability. Conclusion. Our nomogram exhibited satisfactory survival prediction and prognostic discrimination. It is a user-friendly tool with high clinical pragmatism for estimating prognosis and guiding the long-term management of EOC patients with PE treatment.

LRRC75A-AS1 Drives the Epithelial–Mesenchymal Transition in Cervical Cancer by Binding IGF2BP1 and Inhibiting SYVN1-Mediated NLRP3 Ubiquitination

Abstract Cervical cancer severely affects women’s health with increased incidence and poor survival for patients with metastasis. Our study aims to investigate the mechanism by which lncRNA LRRC75A-AS1 regulates the epithelial–mesenchymal transition (EMT) of cervical cancer through modulating m6A and ubiquitination modification. In this study, tumor tissues were collected from patients to analyze the expression of LRRC75A-AS1 and SYVN1. Migratory and invasive capacities of HeLa and CaSki cells were evaluated with wound healing and transwell assays. CCK-8 and EdU incor-poration assays were employed to examine cell proliferation. The interaction between LRRC75A-AS1, IGF2BP1, SYVN1, and NLRP3 was evaluated through RNA immunoprecipitation, RNA pull-down, FISH, and coimmunoprecipitation assays, respectively. MeRIP-qPCR was applied to analyze the m6A modification of SYVN1 mRNA. A subcutaneous tumor model of cervical cancer was established. We showed LRRC75A-AS1 was upregulated in tumor tissues, and LRRC75A-AS1 enhanced EMT through activating NLRP3/IL1β/Smad2/3 signaling in cervical cancer. Furthermore, LRRC75A-AS1 inhibited SYVN1-mediated NLRP3 ubiquitination by destabilizing SYVN1 mRNA. LRRC75A-AS1 competitively bound to IGF2BP1 protein and subsequently impaired the m6A modification of SYVN1 mRNA and its stability. Knockdown of LRRC75A-AS1 repressed EMT and tumor growth via inhibiting NLRP3/IL-1β/Smad2/3 signaling in mice. In conclusion, LRRC75A-AS1 competitively binds to IGF2BP1 protein to destabilize SYVN1 mRNA, subsequently suppresses SYVN1-mediated NLRP3 ubiquitination degradation and activates IL1β/Smad2/3 signaling, thus promoting EMT in cervical cancer. Implication: LRRC75A-AS1 promotes cervical cancer progression, and this study suggests LRRC75A-AS1 as a new therapeutic target for cervical cancer.