lncRNA FGD5-AS1 is required for gastric cancer proliferation by inhibiting cell senescence and ROS production via stabilizing YBX1.

BACKGROUND: The vast majority of lncRNAs have low expression abundance, which greatly limits their functional range and impact. As a high expression abundance lncRNA, FGD5-AS1's non-ceRNA biological function in cancer is unclear. METHODS: RNA-seq studies and chromatin immunoprecipitation (Chip) assays were performed to identify ZEB1-regulated lncRNAs. RNA sequencing, RNA pulldown, RNA Immunoprecipitation assays, and rescue assays were conducted to explore the molecular mechanisms of FGD5-AS1 in GC. RESULTS: As one of the most abundant lncRNAs in cells, FGD5-AS1 has been shown to be transcriptionally activated by ZEB1, thus closely related to epithelial-mesenchymal transition (EMT) signaling. Clinical analysis showed that FGD5-AS1 overexpression was clinically associated with lymph node metastasis, and predicted poor survival in GC. Loss-of-function studies confirmed that FGD5-AS1 knockdown inhibited GC proliferation and induced cisplatin chemosensibility, cell senescence, and DNA damage in GC cells. Mechanismically, FGD5-AS1 is a YBX1-binding lncRNA due to its mRNA contains three adjacent structural motifs (UAAUCCCA, ACCAGCCU, and CAGUGAGC) that can be recognized and bound by YBX1. And this RNA-protein interaction prolonged the half-life of the YBX1 protein in GC. Additionally, a rescue assay showed that FGD5-AS1 promotes GC by repressing cell senescence and ROS production via YBX1. CONCLUSION: FGD5-AS1 is a cellular high-abundant lncRNA that is transcriptionally regulated by ZEB1. FGD5-AS1 overexpression promoted GC progression by inhibiting cell senescence and ROS production through binding and stabilizing the YBX1 protein.

A novel TGFbeta/TGILR axis mediates crosstalk between cancer-associated fibroblasts and tumor cells to drive gastric cancer progression.

Transforming growth factor beta (TGFß) signaling plays a critical role in tumorigenesis and metastasis. However, little is known about the biological function of TGFbeta-induced lncRNA in cancer. In this study, we discovered a novel TGFbeta-induced lncRNA, termed TGILR, whose function in cancer remains unknown to date. TGILR expression was directly activated by the canonical TGFbeta/SMAD3 signaling axis, and this activation is highly conserved in cancer. Clinical analysis showed that TGILR overexpression showed a significant correlation with lymph node metastasis and poor survival and was an independent prognostic factor in gastric cancer (GC). Depletion of TGILR caused an obvious inhibitory effect on GC cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. More importantly, we demonstrated that TGFbeta signaling in GC was overactivated due to cancer-associated fibroblast (CAF) infiltration. Mechanistically, increased level of CAF-secreted TGFbeta activates TGFbeta signaling, leading to TGILR overexpression in GC cells. Meanwhile, TGILR overexpression inhibited the microRNA biogenesis of miR-1306 and miR-33a by interacting with TARBP2 and reducing its protein stability, thereby promoting GC progression via TCF4-mediated EMT signaling. In conclusion, CAF infiltration drives GC metastasis and EMT signaling through activating TGFbeta/TGILR axis. Targeted blocking of CAF-derived TGFbeta should be a promising anticancer strategy in GC.

A new high-throughput screening methodology for the discovery of cancer-testis antigen using multi-omics data.

BACKGROUND: Cancer/testis antigens (CTAs), also known as tumor-specific antigens (TSAs) are specifically expressed in cancer cells and exhibit high immunogenicity, making them promising targets for immunotherapy and cancer vaccines. METHODS: A new integrated high-throughput screening methodology for CTAs was proposed in this study through combining DNA methylation and RNA sequencing data. Briefly, the genes with increased transcript level and decreased DNA methylation were identified by multi-omics analysis. RNA sequencing studies in cell lines exposed to DNA methyltransferase (DNMT) inhibitors were performed to validate the inherent causal relationship between DNA hypomethylation and gene expression upregulation. RESULTS: We proposed a new integrated high-throughput screening methodology for identification of CTAs using multi-omics analysis. In addition, we tested the feasibility of this method using gastric cancer (GC) as an example. In GC, we identified over 2000 primary candidate CTAs and ultimately identified 20 CTAs with significant tissue-specificity, including a testis-specific serine protease TESSP1/PRSS41. Integrated analysis confirmed that PRSS41 expression was reactivated in gastrointestinal cancers by promoter DNA hypomethylation at the CpG site (cg08104780). Additionally, DNA hypomethylation of PRSS41 predicted a poor prognosis in GC. CONCLUSION: We propose a new high-throughput screening method for the identification of CTAs in cancer and validate its effectiveness. Our work emphasizes that serine protease PRSS41 is a novel TSA that is reactivated in GC due to promoter DNA hypomethylation.