Yuxing Zhu

Bio: Yuxing Zhu is an academic researcher from Central South University. The author has contributed to research in topics: Cancer & Immunotherapy. The author has an hindex of 9, co-authored 25 publications receiving 231 citations.

Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy

Abstract: Purpose: Regulated in development and DNA damage response-1 (REDD1) is a stress-related protein and is involved in the progression of cancer. The role and regulatory mechanism of REDD1 in bladder urothelial carcinoma (BUC), however, is yet unidentified.Experimental Design: The expression of REDD1 in BUC was detected by Western blot analysis and immunohistochemistry (IHC). The correlation between REDD1 expression and clinical features in patients with BUC were assessed. The effects of REDD1 on cellular proliferation, apoptosis, autophagy, and paclitaxel sensitivity were determined both in vitro and in vivo Then the targeted-regulating mechanism of REDD1 by miRNAs was explored.Results: Here the significant increase of REDD1 expression is detected in BUC tissue, and REDD1 is first reported as an independent prognostic factor in patients with BUC. Silencing REDD1 expression in T24 and EJ cells decreased cell proliferation, increased apoptosis, and decreased autophagy, whereas the ectopic expression of REDD1 in RT4 and BIU87 cells had the opposite effect. In addition, the REDD1-mediated proliferation, apoptosis, and autophagy are found to be negatively regulated by miR-22 in vitro, which intensify the paclitaxel sensitivity via inhibition of the well-acknowledged REDD1-EEF2K-autophagy axis. AKT/mTOR signaling initially activated or inhibited in response to silencing or enhancing REDD1 expression and then recovered rapidly. Finally, the inhibited REDD1 expression by either RNAi or miR-22 sensitizes BUC tumor cells to paclitaxel in a subcutaneous transplant carcinoma model in vivoConclusions: REDD1 is confirmed as an oncogene in BUC, and antagonizing REDD1 could be a potential therapeutic strategy to sensitize BUC cells to paclitaxel. Clin Cancer Res; 24(2); 445-59. ©2017 AACR.

Turning up the heat on non-immunoreactive tumors: pyroptosis influences the tumor immune microenvironment in bladder cancer

Abstract: The latest research confirms that cytotoxic lymphocytes rely on pyroptosis to kill tumor cells, suggesting that pyroptosis plays a vital role in immune response. However, the influence of pyroptosis on tumor microenvironment (TME) remodeling and immunotherapy is still unclear. We analyzed the variations in the expression of 28 pyroptosis-related molecules in pan-cancer tissues and normal tissues and the influence of genome changes. We investigated 2,214 bladder cancer samples and determined that there are three pyroptosis phenotypes in bladder cancer, and there are significant differences in cell infiltration characteristics in different pyroptosis phenotypes. Phenotypes with high expression of pyroptosis-related molecules are “hot tumors” with better immune function. We used a principal component analysis to measure the level of pyroptosis in patients with PyroScore, and confirmed that the PyroScore can predict the prognosis of bladder cancer patients, the sensitivity of the immune phenotype to chemotherapy, and the response to immunotherapy. Patients with a high PyroScore are more sensitive to chemotherapeutics such as cisplatin and gemcitabine, and have a better prognosis (HR = 0.7; 95%CI = 0.51–0.97, P = 0.041). Our study suggests a significant correlation between the expression imbalance of pyroptosis-related molecules and genome variation in various cancers and suggests pyroptosis plays an important role in modeling the TME. Evaluating pyroptosis modification patterns contributes to enhancing our understanding of TME infiltration and can guide more effective immunotherapy strategies.

Analysis of m6A-Related Signatures in the Tumor Immune Microenvironment and Identification of Clinical Prognostic Regulators in Adrenocortical Carcinoma.

Abstract: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high rate of mortality and recurrence. N6-methyladenosine methylation (m6A) is the most common modification to affect cancer development, but to date, the potential role of m6A regulators in ACC prognosis is not well understood. In this study, we systematically analyzed 21 m6A regulators in ACC samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. We identified three m6A modification patterns with different clinical outcomes and discovered a significant relationship between diverse m6A clusters and the tumor immune microenvironment (immune cell types and ESTIMATE algorithm). Additionally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed that the m6A clusters were strongly associated with immune infiltration in the ACC. Next, to further explore the m6A prognostic signatures in ACC, we implemented Lasso (Least Absolute Shrinkage and Selection Operator) Cox regression to establish an eight-m6A-regulator prognostic model in the TCGA dataset, and the results showed that the model-based high-risk group was closely correlated with poor overall survival (OS) compared with the low-risk group. Subsequently, we validated the key modifications in the GEO datasets and found that high HNRNPA2B1 expression resulted in poor OS and event-free survival (EFS) in ACC. Moreover, to further decipher the molecular mechanisms, we constructed a competing endogenous RNA (ceRNA) network based on HNRNPA2B1, which consists of 12 long noncoding RNAs (lncRNAs) and 1 microRNA (miRNA). In conclusion, our findings indicate the potential role of m6A modification in ACC, providing novel insights into ACC prognosis and guiding effective immunotherapy.

Delivery of RIPK4 small interfering RNA for bladder cancer therapy using natural halloysite nanotubes

Abstract: RNA interference (RNAi) technology can specifically silence the expression of a target gene and has emerged as a promising therapeutic method to treat cancer. In the present study, we showed that natural halloysite nanotube (HNT)–assisted delivery of an active small interfering RNA (siRNA) targeting receptor-interacting protein kinase 4 (RIPK4) efficiently silenced its expression to treat bladder cancer. The HNTs/siRNA complex increased the serum stability of the siRNA, increased its circulation lifetime in blood, and promoted the cellular uptake and tumor accumulation of the siRNA. The siRNA markedly down-regulated RIPK4 expression in bladder cancer cells and bladder tumors, thus inhibiting tumorigenesis and progression in three bladder tumor models (a subcutaneous model, an in situ bladder tumor model, and a lung metastasis model), with no adverse effects. Thus, we revealed a simple but effective method to inhibit bladder cancer using RIPK4 silencing, indicating a promising therapeutic method for bladder cancer.

MicroRNAs: Target Recognition and Regulatory Functions

Abstract: MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling.

Abstract: Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy. In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation. In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N6-methyladenosine (m6A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models. This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.

ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1.

Abstract: N6-methyladenosine (m6A) modification is an emerging layer of epigenetic regulation which is widely implicated in the tumorigenicity of hepatocellular carcinoma (HCC), offering a novel perspective for investigating molecular pathogenesis of this disease. The role of AlkB homolog 5 (ALKBH5), one of the m6A demethylases, has not been fully explored in HCC. Here we clarify the biological profile and potential mechanisms of ALKBH5 in HCC. Expression of ALKBH5 and its correlation with clinicopathological characteristics of HCC were evaluated using tissue microarrays and online datasets. And biological effects of ALKBH5 in HCC were determined in vitro and in vivo. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq), and following m6A dot blot, MeRIP-qPCR, RIP-qPCR or dual luciferase reporter assays were employed to screen and validate the candidate targets of ALKBH5. We demonstrated that ALKBH5 was down-regulated in HCC, and decreased ALKBH5 expression was an independent prognostic factor of worse survival in HCC patients. Functionally, ALKBH5 suppressed the proliferation and invasion capabilities of HCC cells in vitro and in vivo. Mechanistically, ALKBH5-mediated m6A demethylation led to a post-transcriptional inhibition of LY6/PLAUR Domain Containing 1 (LYPD1), which could be recognized and stabilized by the m6A effector IGF2BP1. In addition, we identified that LYPD1 induced oncogenic behaviors of tumors in contrast to ALKBH5. Dysregulation of ALKBH5/LYPD1 axis impelled the progression of HCC. Our study reveals that ALKBH5, characterized as a tumor suppressor, attenuates the expression of LYPD1 via an m6A-dependent manner in HCC cells. Our findings enrich the landscape of m6A-modulated tumor malignancy, and provide new insights into potential biomarkers and therapeutic targets of HCC treatment.

Novel insights into the interplay between m6A modification and noncoding RNAs in cancer.

Abstract: N6-methyladenosine (m6A) is one of the most common RNA modifications in eukaryotes, mainly in messenger RNA (mRNA). Increasing evidence shows that m6A methylation modification acts an essential role in various physiological and pathological bioprocesses. Noncoding RNAs (ncRNAs), including miRNAs, lncRNAs and circRNAs, are known to participate in regulating cell differentiation, angiogenesis, immune response, inflammatory response and carcinogenesis. m6A regulators, such as METTL3, ALKBH5 and IGF2BP1 have been reported to execute a m6A-dependent modification of ncRNAs involved in carcinogenesis. Meanwhile, ncRNAs can target or modulate m6A regulators to influence cancer development. In this review, we provide an insight into the interplay between m6A modification and ncRNAs in cancer.