Xiao-Jie Lu

Oridonin, a novel lysine acetyltransferases inhibitor, inhibits proliferation and induces apoptosis in gastric cancer cells through p53- and caspase-3-mediated mechanisms

Lysine acetylation has been reported to involve in the pathogenesis of multiple diseases including cancer. In our screening study to identify natural compounds with lysine acetyltransferase inhibitor (KATi) activity, oridonin was found to possess acetyltransferase-inhibitory effects on multiple acetyltransferases including P300, GCN5, Tip60, and pCAF. In gastric cancer cells, oridonin treatment inhibited cell proliferation in a concentration-dependent manner and down-regulated the expression of p53 downstream genes, whereas p53 inhibition by PFT-α reversed the antiproliferative effects of oridonin. Moreover, oridonin treatment induced cell apoptosis, increased the levels of activated caspase-3 and caspase-9, and decreased the mitochondrial membrane potential in gastric cancer cells in a concentration-dependent manner. Caspase-3 inhibition by Ac-DEVD-CHO reversed the proapoptosis effect of oridonin. In conclusion, our study identified oridonin as a novel KATi and demonstrated its tumor suppressive effects in gastric cancer cells at least partially through p53-and caspase-3-mediated mechanisms.

The long noncoding RNA NEAT1 contributes to hepatocellular carcinoma development by sponging miR-485 and enhancing the expression of the STAT3

Accumulating evidence has supported the significance of lncRNAs in tumorigenesis. Recently, some studies indicate the oncogenic role of lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) in hepatocellular carcinoma (HCC). In our present study, we focused on the biological mechanisms through which NEAT1 can regulate HCC development. We found that NEAT1 was greatly upregulated in human HCC cell lines including Huh7, Hep3B, HepG2, Bel‐7404, and SK‐Hep1 cells compared to the normal human liver cell line LO2. In addition, we observed that miR‐485 was significantly downregulated in HCC cells. It was implied that miR‐485 was increased by sh‐NEAT1 and miR‐485 can modulate NEAT1 expression negatively. Meanwhile, NEAT1inhibiton can repress HCC growth, migration, and invasion capacity in HepG2 and Hep3B cells. Through performing bioinformatic analysis, dual‐luciferase reporter test, RNA‐binding protein immunoprecipitation, and RNA pull‐down assay, miR‐485 was confirmed as a interacting target of NEAT1. Additionally, STAT3 was recognized as a direct target of miR‐485 and miR‐485 mimics can inhibit STAT3 expression. It was demonstrated that NEAT1 can increase STAT3 levels while miR‐485 mimics can repress STAT3. Moreover, we found that sh‐STAT3 was able to restrain HCC cell migration and invasion process. NEAT1 can act as a competing endogenous lncRNA (ceRNA) to regulated STAT3 by sponging miR‐485 in HCC. Taken these together, NEAT1 can be used as an important biomarker in HCC diagnosis and treatment.

Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities

Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have been shown to have unprecedented efficacy in B cell malignancies, most notably in B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate using anti-CD19 CAR-T cells. However, CAR T-cell therapy for solid tumors currently is faced with numerous challenges such as physical barriers, the immunosuppressive tumor microenvironment and the specificity and safety. The clinical results in solid tumors have been much less encouraging, with multiple cases of toxicity and a lack of therapeutic response. In this review, we will discuss the current stats and challenges of CAR-T cell therapy for solid tumors, and propose possibl e solutions and future perspectives.Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have been shown to have unprecedented efficacy in B cell malignancies, most notably in B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate using anti-CD19 CAR-T cells. However, CAR T-cell therapy for solid tumors currently is faced with numerous challenges such as physical barriers, the immunosuppressive tumor microenvironment and the specificity and safety. The clinical results in solid tumors have been much less encouraging, with multiple cases of toxicity and a lack of therapeutic response. In this review, we will discuss the current stats and challenges of CAR-T cell therapy for solid tumors, and propose possible solutions and future perspectives.

Decreased levels of serum exosomal miR-638 predict poor prognosis in hepatocellular carcinoma

Currently available studies have implicated that exosome‐delivered microRNAs (miRNAs) play crucial roles in human cancer. However, the association of serum exosomal miR‐638 and hepatocellular carcinoma (HCC) remains largely unknown. We aim to investigate the expression of exosomal miR‐638 in serum of HCC patients and its prognostic role in this deadly disease. Kaplan‐Meier and Cox regression analyses were used to determine the survival of patients histologically diagnosed with HCC. Reduced levels of exosomal miR‐638 in serum samples from patients with HCC were identified by real‐time PCR. Negative association of serum exosomal miR‐638 with tumor size, vascular infiltration, and TNM stage was observed in HCC patients. Besides, the proliferation of Huh7 and SMCC7721 HCC cells were significantly inhibited when miR‐638 was over‐expressed in these cells. In addition, HCC patients with lower levels of serum exosomal miR‐638 had poor overall survival than those with higher levels of exosomal miR‐638 in serum. Our study strongly suggests that serum exosome‐delivered miR‐638 may serve as a novel circulating biomarker for HCC. Downregulation of miR‐638 predicts poor prognosis for patients with HCC.

NEAT1 upregulates TGF-β1 to induce hepatocellular carcinoma progression by sponging hsa-mir-139-5p

Increasing evidence has shown that the lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) play important roles in cell proliferation, migration, and invasion in various tumors. In our current study, we concentrated on the biological mechanisms of NEAT1 in hepatocellular carcinoma (HCC) development. It was found that NEAT1 was significantly increased in human HCC cell lines including Hep3B, LM3, MHCC97L, SK‐hep1, and HepG2 cells compared to the normal human liver cell line LO2. Meanwhile, we observed that hsa‐miR‐139‐5p was greatly decreased in HCC cells, which suggested a negative correlation between NEAT1 and hsa‐mir‐139‐5p. In addition, NEAT1 downregulation can restrain HCC cell growth, migration, and invasion. Consistently, overexpression of hsa‐mir‐139‐5p exerted a similar phenomenon. Dual‐luciferase reporter assay, RIP assay, and RNA pull‐down assay confirmed that NEAT1 can function as a ceRNA by sponging hsa‐mir‐139‐5p. In addition, TGF‐β1 was identified as a downstream target of hsa‐mir‐139‐5p and hsa‐mir‐139‐5p overexpression was able to suppress TGF‐β1 levels. Furthermore, it was indicated that TGF‐β1 inhibition can inhibit HCC cell growth, migration, and invasion ability. Taken these together, we speculated that NEAT1 can modulate TGF‐β1 expression by sponging hsa‐mir‐139‐5p in HCC. These data indicates that targeting the NEAT1/hsa‐mir‐139‐5p/TGF‐β1 axis could be a new strategy for HCC.

Four differentially methylated gene pairs to predict the prognosis for early stage hepatocellular carcinoma patients

Hepatocellular carcinoma (HCC) was the second most common malignant tumor with a poor prognostic condition. We aimed to identify novel methylation signatures to predict HCC patients at their early stages. Differentially expressed methylated genes between HCC patients and normal liver tissues retrieved from TCGA were screened out by SAM. Genes highly related to patients’ survival were figured out by COX. The signatures that could identify relapse HCC patients were identified by the forwarding search algorithm. Besides, functional enrichment analysis was performed on the methylation genes in the signature. A total of 5,392 CPG sites that differentially methylated expressed were found out and 4,294 differentially expressed genes were obtained. A total of 197 genes among were associated with RFS of HCC patients at both stage I and stage II. Signature composed of 21 pairs was obtained to predict the prognostic situation by C‐index forward search method. The function of these genes was figured out by functional enrichment analysis. To summary, the signature composed of 21 gene pairs that can predict the prognostic situation of HCC patients at both stage I and stage II, provided a reference standard for the adjuvant therapy of HCC patients after surgery.

DDX11-AS1 as potential therapy targets for human hepatocellular carcinoma

Hepatocellular Carcinoma (HCC) is one of the most fatal cancers, whose incidence and death rates are still rising. Here, we report the identification of long non-coding RNAs (IncRNAs) that associated with HCC progression and metabolism based on the systematically analysis of large scale RNA-seq data from HCC patients. We identified seven lncRNAs with high confidence which were highly related with prognostic of HCC. Of note, three of them had quite different expression patterns between the control samples and the patients, and their critical roles in cancer progression were validated. We proposed that DDX11-AS1 play important role during HCC oncogenesis and may serve as potential therapy target for HCC.

Applications and advances of CRISPR-Cas9 in cancer immunotherapy

Immunotherapy has emerged as one of the most promising therapeutic strategies in cancer. The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (CRISPR-Cas9) system, as an RNA-guided genome editing technology, is triggering a revolutionary change in cancer immunotherapy. With its versatility and ease of use, CRISPR-Cas9 can be implemented to fuel the production of therapeutic immune cells, such as construction of chimeric antigen receptor T (CAR-T) cells and programmed cell death protein 1 knockout. Therefore, CRISPR-Cas9 technology holds great promise in cancer immunotherapy. In this review, we will introduce the origin, development and mechanism of CRISPR-Cas9. Also, we will focus on its various applications in cancer immunotherapy, especially CAR-T cell-based immunotherapy, and discuss the potential challenges it faces.

Exosomes derived from exhausted CD8+ T cells impaired the anticancer function of normal CD8+ T cells

Background Previous studies suggested that diverse cells in cancer microenvironment can interact with CD8+ T cells via exosomes. We designed this study to explore the potential interaction between exhausted CD8+ T cells and normal CD8+ T cells via exosome. Methods Fluorescence activated cell sorting was used to get PD1+TIM3+/PD1−TIM3−CD8+ T cells. Exosomes from the cell culture medium were collected by ultracentrifugation. Microarrays were performed to analyse the lncRNA expression profile in exosomes. Results Functional exhausted CD8+ T cells could secrete vast exosomes, which can be uptake by normal CD8+ T cells, and impaired their proliferation (Ki67), cell activity (CD69) and the production of cytokines such as interferon-γ and interleukin-2. Microarray detection identified 257 candidate lncRNAs differently expressed in exosomes derived from exhausted CD8+ T cells and non-exhausted CD8+ T cells. Functional enrichment analysis indicated that these lncRNAs actively participated in the regulation of diverse process of CD8+ T cell activity, like metabolism, gene expression, biosynthetic process and so forth. Conclusions The exosomes derived from exhausted CD8+ T cells could be uptake by non-exhausted CD8+ T cells and subsequently impaired the function of receipt cells. Exosomes secreted from exhausted CD8+ T cells have distinct lncRNA expression profiles which are significantly different from those in exosomes secreted by non-exhausted CD8+ T cells.

Identification of TAF1, HNF4A, and CALM2 as potential therapeutic target genes for liver fibrosis: JI et al.

The molecular mechanism of liver fibrosis caused by hepatitis C virus (HCV) is not clear. The aim of this study is to understand the molecular mechanism of liver fibrosis induced by HCV and to identify potential therapeutic targets for hepatic fibrosis. We analyzed gene expression patterns between high liver fibrosis and low liver fibrosis samples, and identified genes related to liver fibrosis. We identified TAF1, HNF4A, and CALM2 were related to the development of liver fibrosis. HNF4A is important for hepatic fibrogenesis, and upregulation of HNF4A is an ideal choice for treating liver fibrosis. The gene expression of CALM2 is significantly lower in liver fibrosis samples than nonfibrotic samples. TAF1 may serve as a biomarker for liver fibrosis. The results were further validated by an independent data set GSE84044. In summary, our study described changes in the gene expression during the occurrence and development of liver fibrosis. The TAF1, HNF4A, and CALM2 may serve as novel targets for the treatment of liver fibrosis.