Xinya Gao

Bio: Xinya Gao is an academic researcher from Sun Yat-sen University. The author has contributed to research in topics: Medicine & Biology. The author has an hindex of 5, co-authored 6 publications receiving 942 citations.

Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis

Abstract: Background Circular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported.

A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis.

Abstract: Circular RNAs (circRNAs) are recognized as functional non-coding transcripts in eukaryotic cells. Recent evidence has indicated that even though circRNAs are generally expressed at low levels, they may be involved in many physiological or pathological processes, such as gene regulation, tissue development and carcinogenesis. Although the ‘microRNA sponge’ function is well characterized, most circRNAs do not contain perfect trapping sites for microRNAs, which suggests the possibility that circRNAs have functions that have not yet been defined. In this study, we show that a circRNA containing an open reading frame (ORF) driven by the internal ribosome entry site (IRES) can translate a functional protein. The circular form of the SNF2 histone linker PHD RING helicase (SHPRH) gene encodes a novel protein that we termed SHPRH-146aa. Circular SHPRH (circ-SHPRH) uses overlapping genetic codes to generate a ‘UGA’ stop codon, which results in the translation of the 17 kDa SHPRH-146aa. Both circ-SHPRH and SHPRH-146aa are abundantly expressed in normal human brains and are down-regulated in glioblastoma. The overexpression of SHPRH-146aa in U251 and U373 glioblastoma cells reduces their malignant behavior and tumorigenicity in vitro and in vivo. Mechanistically, SHPRH-146aa protects full-length SHPRH from degradation by the ubiquitin proteasome. Stabilized SHPRH sequentially ubiquitinates proliferating cell nuclear antigen (PCNA) as an E3 ligase, leading to inhibited cell proliferation and tumorigenicity. Our findings provide a novel perspective regarding circRNA function in physiological and pathological processes. Specifically, SHPRH-146aa generated from overlapping genetic codes of circ-SHPRH is a tumor suppressor in human glioblastoma.

Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling.

Abstract: Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.

Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer

Abstract: Metastasis is the chief cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. We used a proteomics approach to screen for metastasis-associated proteins and found that collapsin response mediator protein-4 (CRMP4) expression was inversely associated with the lymph node metastasis of prostate cancer (PCa). Subsequent in vitro and in vivo studies revealed that overexpression of CRMP4 not only suppressed the invasion ability of PCa cells, but also strongly inhibited tumor metastasis in an animal model. Furthermore, methylation of a CpG island within the promoter region of the CRMP4 gene is responsible for downregulation of CRMP4 expression. Thus, in this study, we show new function of CRMP4 as a metastasis-suppressor in PCa. The findings provide new mechanistic insights into metastasis and therapeutic potential for this most common male cancer.

Metadherin/Astrocyte elevated gene-1 positively regulates the stability and function of forkhead box M1 during tumorigenesis.

Abstract: Background Forkhead box M1 (FOXM1) is overexpressed and activates numerous oncoproteins in tumors. However, the mechanism by which the FOXM1 protein aberrantly accumulates in human cancer remains uncertain. This study was designed to clarify the upstream signaling pathway(s) that regulate FOXM1 protein stability and transcriptional activity. Methods Mass spectrometry and immunoprecipitation were performed to identify the FOXM-metadherin (MTDH) interaction. In vivo and in vitro ubiquitination assays were conducted to test the effect of MTDH on FOXM1 stability. Chromatin immunoprecipitation assays were used to determine the involvement of MTDH in FOXM1 transcriptional activity. Cell invasion assays, tube formation assays, and in vivo tumor formation assays were performed to evaluate the cooperative activities of FOXM1 and MTDH during tumorigenesis. Results MTDH directly interacts with FOXM1 via the N-terminal inhibitory domain of MTDH, and this interaction disrupted the binding of cadherin-1 to FOXM1, thus protecting FOXM1 from subsequent proteasomal degradation. Deleting the MTDH-binding sites of FOXM1 abolished the MTDH overexpression-mediated stabilization of FOXM1. MTDH also bound to FOXM1 target gene promoters and enhanced FOXM1 transcriptional activity. MTDH knockdown destabilized FOXM1 and attenuated its transcriptional activity, consequently inhibiting cell cycle progression, angiogenesis, and cancer cell invasion in vitro and in vivo; these effects were abolished via forced overexpression of a stabilized mutant form of FOXM1. Thus, MTDH stabilized FOXM1 and supported the sustained activation of FOXM1 target genes. Conclusion These findings highlight a novel MTDH-regulated mechanism of FOXM1 stabilization and provide profound insight into the tumorigenic events simultaneously mediated by FOXM1 and MTDH.

The biogenesis, biology and characterization of circular RNAs.

Abstract: Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.

Circular RNAs function as ceRNAs to regulate and control human cancer progression.

Abstract: Circular RNAs (circRNAs) are connected at the 3′ and 5′ ends by exon or intron cyclization, forming a complete ring structure. circRNA is more stable and conservative than linear RNA and abounds in various organisms. In recent years, increasing numbers of reports have found that circRNA plays a major role in the biological functions of a network of competing endogenous RNA (ceRNA). circRNAs can compete together with microRNAs (miRNAs) to influence the stability of target RNAs or their translation, thus, regulating gene expression at the transcriptional level. circRNAs are involved in biological processes such as tumor cell proliferation, apoptosis, invasion, and migration as ceRNAs. circRNAs, therefore, represent promising candidates for clinical diagnosis and treatment. Here, we review the progress in studying the role of circRNAs as ceRNAs in tumors and highlight the participation of circRNAs in signal transduction pathways to regulate cellular functions.

Past, present, and future of circRNAs.

Abstract: Exonic circular RNAs (circRNAs) are covalently closed RNA molecules generated by a process named back-splicing. circRNAs are highly abundant in eukaryotes, and many of them are evolutionary conserved. In metazoans, circular RNAs are expressed in a tissue-specific manner, are highly stable, and accumulate with age in neural tissues. circRNA biogenesis can regulate the production of the linear RNA counterpart in cis as back-splicing competes with linear splicing. Recent reports also demonstrate functions for some circRNAs in trans: Certain circRNAs interact with microRNAs, some are translated, and circRNAs have been shown to regulate immune responses and behavior. Here, we review current knowledge about animal circRNAs and summarize new insights into potential circRNA functions, concepts of their origin, and possible future directions in the field.