Ecdysoneless Protein Regulates Viral and Cellular mRNA Splicing to Promote Cervical Oncogenesis

Mirza, Sameer; Kalluchi, Achyuth; Raza, Mohsin Ali; Saleem, Irfana; Mohapatra, Bhopal; Pal, Dhananjaya; Ouellette, Michel; Qiu, Fang; Yu, Lulu; Lobanov, Alexei V.; Zheng, Zhi-Ming; Zhang, Ying; Alsaleem, Mansour; Rakha, Emad A.; Band, Hamid; Rowley, M. Jordan; Band, Vimla

doi:10.1158/1541-7786.mcr-21-0567

Cited by 6 publications

(11 citation statements)

References 58 publications

(93 reference statements)

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“…CTCF mutation increases the synthesis of unspliced E6 and spliced E6*I (35). Mirza S et al reported that knockdown ECD lead to aberrations in E6/E7 RNA splicing, as well as RNA splicing of several HPV oncogenesis-linked cellular genes (36).…”

Section: Discussionmentioning

confidence: 99%

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Construction of an immune-related ceRNA network in cervical cancer based on HPV E6 splicing

Jiang

Zhou

et al. 2022

Front. Oncol.

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BackgroundCervical cancer is one of the leading causes of cancer-related deaths worldwide. The unspliced human papillomavirus (HPV) E6 plays an important role in tumor progression and immune regulation. Improved immunotherapy implementation might benefit from a better knowledge of HPV E6 splicing-related immune gene expressions and immunocyte infiltration in cervical cancer. This study aimed to identify the potential therapeutic and prognostic roles of unspliced/spliced E6 ratio (E6 ratio) in cervical cancer.MethodsData from the TCGA were used to analyze the E6 condition and clinical information. Nomogram and K-M analysis were used to analyze assess the prognostic significance, IOBR was used to investigate immunological infiltrates. Functions and pathway enrichment analysis of DEGs were investigated through GO analysis and KEGG pathway analysis, respectively. A core module was taken from the competitive endogenous RNA (ceRNA) network and used to build a lncRNA-miRNA-mRNA network. QT-qPCR was used to detect the expression of genes. CCK-8, colony formation, wound healing and migration assays were used to detect cell functions.ResultsOur study found that HPV E6 ratio had significantly correlation with overall survival. In cervical cancer, a high E6 ratio was adversely linked with infiltrating levels of aDC, M1 macrophages, monocytes, NKT, and Tgd. High E6 ratio phenotypes were shown to be implicated in immune response regulation, cell adhesion, and Wnt signaling pathways, according to functional enrichment analysis. Subsequently, we constructed an immune-related ceRNA network based on E6 splicing in cervical cancer, including three lncRNA (LINC00943, LIFR-AS1, DANT2, and RASSF8-AS1), four miRNA (miR-205-5p, miR-181d-5p, miR-222-3p, and miR-221-3p), and seven mRNA (FGFR1, PRLR, CXCL2, ISG20, ISG15, SDC1, and NR2F2). Among them, CXCL2, SDC1, and miR-221-3p were associated with survival and immune cell infiltration.ConclusionsThese data imply that a high E6 ratio in cervical cancer contributes to the immune-related ceRNA network, resulting in a low amount of infiltrating effector immune cells and tumor growth. As a result, the E6 ratio might be employed as a biomarker in cervical cancer to determine prognosis and treatment success.

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Section: Discussionmentioning

confidence: 99%

“…Mirza S et al. reported that knockdown ECD lead to aberrations in E6/E7 RNA splicing, as well as RNA splicing of several HPV oncogenesis-linked cellular genes ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Construction of an immune-related ceRNA network in cervical cancer based on HPV E6 splicing

Jiang

Zhou

et al. 2022

Front. Oncol.

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“…2), and loss of Prp8 or Ecd led to defective splicing (3). ECD associates with several RNA biogenesis components such as DDX39A and regulates nuclear mRNA export (4), as well as mRNA splicing machinery to regulate mRNA splicing (5).…”

Section: Introductionmentioning

confidence: 99%

“…ECD overexpression is frequent in several cancers, such as breast (4,14), pancreas (15), cervical, head and neck (5), and gastric (16). ECD mRNA and protein overexpression in patients with breast cancer correlate with shorter survival (4,14).…”

Section: Introductionmentioning

confidence: 99%

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Ecdysoneless Overexpression Drives Mammary Tumorigenesis through Upregulation of C-MYC and Glucose Metabolism

Mohapatra

Mirza

Bele

et al. 2022

Molecular Cancer Research

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Ecdysoneless (ECD) protein is essential for embryogenesis, cell-cycle progression, and cellular stress mitigation with an emerging role in mRNA biogenesis. We have previously shown that ECD protein as well as its mRNA are overexpressed in breast cancer and ECD overexpression predicts shorter survival in patients with breast cancer. However, the genetic evidence for an oncogenic role of ECD has not been established. Here, we generated transgenic mice with mammary epithelium-targeted overexpression of an inducible human ECD transgene (ECDTg). Significantly, ECDTg mice develop mammary hyperplasia, preneoplastic lesions, and heterogeneous tumors with occasional lung metastasis. ECDTg tumors exhibit epithelial to mesenchymal transition and cancer stem cell characteristics. Organoid cultures of ECDTg tumors showed ECD dependency for in vitro oncogenic phenotype and in vivo growth when implanted in mice. RNA sequencing (RNA-seq) analysis of ECDTg tumors showed a c-MYC signature, and alterations in ECD levels regulated c-MYC mRNA and protein levels as well as glucose metabolism. ECD knockdown-induced decrease in glucose uptake was rescued by overexpression of mouse ECD as well as c-MYC. Publicly available expression data analyses showed a significant correlation of ECD and c-MYC overexpression in breast cancer, and ECD and c-MYC coexpression exhibits worse survival in patients with breast cancer. Taken together, we establish a novel role of overexpressed ECD as an oncogenesis driver in the mouse mammary gland through upregulation of c-MYC–mediated glucose metabolism. Implications: We demonstrate ECD overexpression in the mammary gland of mice led to the development of a tumor progression model through upregulation of c-MYC signaling and glucose metabolism.

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Xrp1 governs the stress response program to spliceosome dysfunction

Stanković,

Tain,

Uhlirova

2024

Nucleic Acids Research

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Co-transcriptional processing of nascent pre-mRNAs by the spliceosome is vital to regulating gene expression and maintaining genome integrity. Here, we show that the deficiency of functional U5 small nuclear ribonucleoprotein particles (snRNPs) in Drosophila imaginal cells causes extensive transcriptome remodeling and accumulation of highly mutagenic R-loops, triggering a robust stress response and cell cycle arrest. Despite compromised proliferative capacity, the U5 snRNP-deficient cells increased protein translation and cell size, causing intra-organ growth disbalance before being gradually eliminated via apoptosis. We identify the Xrp1-Irbp18 heterodimer as the primary driver of transcriptional and cellular stress program downstream of U5 snRNP malfunction. Knockdown of Xrp1 or Irbp18 in U5 snRNP-deficient cells attenuated JNK and p53 activity, restored normal cell cycle progression and growth, and inhibited cell death. Reducing Xrp1-Irbp18, however, did not rescue the splicing defects, highlighting the requirement of accurate splicing for cellular and tissue homeostasis. Our work provides novel insights into the crosstalk between splicing and the DNA damage response and defines the Xrp1-Irbp18 heterodimer as a critical sensor of spliceosome malfunction and mediator of the stress-induced cellular senescence program.

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Ecdysoneless Protein Regulates Viral and Cellular mRNA Splicing to Promote Cervical Oncogenesis

Cited by 6 publications

References 58 publications

Construction of an immune-related ceRNA network in cervical cancer based on HPV E6 splicing

Construction of an immune-related ceRNA network in cervical cancer based on HPV E6 splicing

Ecdysoneless Overexpression Drives Mammary Tumorigenesis through Upregulation of C-MYC and Glucose Metabolism

Xrp1 governs the stress response program to spliceosome dysfunction

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