scholarly journals The Role of RNA Splicing Factors in Cancer: Regulation of Viral and Human Gene Expression in Human Papillomavirus-Related Cervical Cancer

2020 ◽  
Vol 8 ◽  
Author(s):  
Andrea Cerasuolo ◽  
Luigi Buonaguro ◽  
Franco M. Buonaguro ◽  
Maria Lina Tornesello
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Rna Splicing ◽  
Human Gene ◽  
Splicing Factors ◽  
Human Gene Expression

scholarly journals The Spliceosome As a New Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3334-3334
Author(s):  
María Luz Morales ◽  
Roberto Garcia-Vicente ◽  
Alba Rodríguez García ◽  
Noemí Álvarez Sánchez-Redondo ◽  
Alejandra Ortiz-Ruiz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Board Of Directors ◽  
Rna Splicing ◽  
Ex Vivo ◽  
Sr Proteins ◽  
Splicing Factors ◽  
Advisory Committees ◽  
Paired Samples

Abstract Introduction. Despite the recent approval of several drugs for the treatment of AML, the 3 + 7 regimens remain as the standard of care for many patients. Its lack of efficacy represents the main cause of death, since only 10% of patients who show refractoriness/relapse overcome the disease. Therefore, there is still an urgent need for seeking more effective treatments. Aberrant RNA splicing has been described in AML, but its relevance as mechanism of resistance is unclear. In this study, we deepen the mechanism of resistance to cytarabine and the role of splicing factors SR proteins, involved in the spliceosome functionality, to seek more effective therapies for AML. Methods. First, the expression levels of genes encoding SR proteins were analyzed with the GEPIA2 platform, comparing the data from the TCGA-LAML (AML patients) and GTEx (healthy) projects. Then, the gene expression of one of the most overexpressed genes, SRRM2, was validated by qPCR in samples of AML patients compared to controls and other myeloid disorders, as MDS and MPN (n=54). The resistance-associated phospho-proteomic profile was analyzed by LC-MS / MS after IMAC enrichment in paired samples from 3 AML patients. The expression of SR proteins and their phosphorylated forms was studied by immunohistochemistry (IHC) before and after resistance in paired bone marrow samples from 3 AML patients. We also analyzed by IHC the prognostic value of phospho-SR proteins at the moment of diagnosis in 64 patients with different responses to cytarabine (non-responders and responders). In order to validate an altered function of SR proteins, the analysis of the differential use of exons of paired samples from 25 AML patients was performed using RNAseq. Then, we evaluated in vitro the efficacy of some splicing modulators, and its combination with other approved drugs, in cytarabine-sensitive and resistant cells. The combination of H3B-8800, a spliceosome inhibitor, with venetoclax was tested in ex vivo samples from AML patients and healthy donors. Results. We found that the gene expression levels of SRSF9, SRSF12 and SRRM2 were altered in AML (Fig 1A-B). Immunohistochemical studies revealed that, although at the protein level no differences were found in SR proteins expression between the diagnosis and relapse moment, an increase in the levels of phosphorylated SR proteins was associated at the time of relapse (Fig 1C). Indeed, the phosphorylation levels of SRRM2, among other SR proteins, were found to be increased during cytarabine resistance by phospho-proteomics (Fig 1D). Moreover, the phosphorylation levels of SR proteins predicted the response to cytarabine treatment, as AML patients that were non-responders presented significantly higher levels compared to responders ones (Fig 1E). The observed alterations in the phosphorylation of these proteins were correlated with a differential use of exons in some of their known targets, when comparing the diagnostic condition and drug resistance moment. Based on this evidence, the efficacy of combining different therapeutic options was evaluated in vitro using sensitive or cytarabine-resistant cell models (Fig 1F). The combination of H3B-8800 together with venetoclax was the most effective in vitro and also presented synergic effects ex vivo in AML patients samples (Fig 1G). Furthermore, this combination did not show toxicity over healthy hematopoietic progenitors, since the same doses that were effective in AML did not show toxicity in a healthy context (Fig 1H). Conclusions. The results of this work shed light on the role of the RNA splicing process in cytarabine resistance in AML. Interestingly, the high levels of phosphorylated splicing factors SR proteins at diagnosis in refractory patients, would allow us to use them as a predictive biomarker of response to cytarabine treatment. Otherwise, due to the need to search effective and safe treatments in this disease, we have found that the combination of splicing inhibitors with venetoclax should be a good strategy for the treatment of AML. Acknowledgment. This work has been possible thanks to the granting of the project PI19/01518 from the Carlos III Health Institute and the CRIS Against Cancer Foundation. ML.M. enjoys a research grant from the Spanish Society of Hematology and Hemotherapy and R.GV. a FPU grant from the Ministry of Science, Innovation and Universities. Figure 1 Figure 1. Disclosures Sanchez: Altum sequencing: Current Employment. Ayala: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Celgene: Honoraria.

Further evidence for a role of S100B in mood disorders: A human gene expression mega-analysis

2014 ◽  
Vol 53 ◽  
pp. 84-86 ◽  
Author(s):  
Matthias L. Schroeter ◽  
Johann Steiner ◽  
Peter Schönknecht ◽  
Karsten Mueller
Keyword(s):  
Gene Expression ◽  
Mood Disorders ◽  
Human Gene ◽  
Human Gene Expression

scholarly journals RNA sequencing reveals the role of splicing polymorphisms in regulating human gene expression

2010 ◽  
Vol 21 (4) ◽  
pp. 545-554 ◽  
Author(s):  
E. Lalonde ◽  
K. C. H. Ha ◽  
Z. Wang ◽  
A. Bemmo ◽  
C. L. Kleinman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Sequencing ◽  
Human Gene ◽  
Human Gene Expression

scholarly journals Characterization of the mouse thrombospondin gene and evaluation of the role of the first intron in human gene expression.

1990 ◽  
Vol 265 (27) ◽  
pp. 16691-16698 ◽  
Author(s):  
P Bornstein ◽  
D Alfi ◽  
S Devarayalu ◽  
P Framson ◽  
P Li
Keyword(s):  
Gene Expression ◽  
Human Gene ◽  
Human Gene Expression ◽  
First Intron

scholarly journals Role of Epstein-Barr Virus and Human Papillomavirus Coinfection in Cervical Intraepithelial Neoplasia in Chinese Women Living With HIV

2021 ◽  
Vol 11 ◽  
Author(s):  
Min Feng ◽  
Rufei Duan ◽  
Yang Gao ◽  
Han Zhang ◽  
Youlin Qiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cervical Intraepithelial Neoplasia ◽  
Epstein Barr Virus ◽  
Intraepithelial Neoplasia ◽  
Hpv Infection ◽  
Barr Virus ◽  
Epstein Barr

Given that only a small percentage of human papillomavirus (HPV)-positive women develop cancer, HPV is necessary but insufficient for carcinogenesis. Mucosally transmitted viral cofactors appear to contribute to HPV-related cervical cancer, such as Epstein-Barr virus (EBV), but previous studies have shown inconsistent outcomes. The exact role of EBV in cervical cancer remains unclear, and more studies are needed to determine its involvement. In this study, we describe the prevalence of EBV and HPV coinfection in HIV-positive women and explore how abnormal host immune status induced by viral coinfections modulates epithelial gene expression. We found a significant correlation between EBV-HPV coinfection and the incidence of high-grade cervical intraepithelial neoplasia (CIN2+). RNA sequencing indicated that CIN tissues coinfected with EBV and HPV led to significant changes in the gene expression of epithelial differentiation and development compared to normal tissues with HPV infection alone. In particular, several differentially expressed genes (DEGs) are closely associated with cancer, such as CACNG4, which was confirmed to be upregulated at both the mRNA and protein levels. Therefore, these findings provide some evidence that EBV may act as a cofactor or mediator in HPV-related cervical cancer. Specific genes or proteins, such as CACNG4, may serve as biomarkers that can risk stratify patients based on pathological changes in the cervix.

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