Claudia Ghigna
Istituto di Genetica Molecolare “Luigi Luca Cavalli-Sforza”
Via Abbiategrasso, 207 – 27100 PAVIA
tel: +39 0382 546324
fax: +39 0382 546370
E-mail: claudia.ghigna@igm.cnr.it
Curriculum – download
List of publications – download
Employment/Education
- 2004-2005 Visiting Scientist, Howard Hughes Medical Institute, University of Massachusetts, Worcester, MA, USA
- 2001-present Researcher, Institute of Molecular Genetic – Italian National Research Council (IGM-CNR), Pavia
- 2000 Advanced School of Integrated Studies (SAFI), Institute of Superior Studies, University of Pavia
- 2000 PhD Genetics and Molecular Biology, University of Pavia
- 1997 Qualified Professional Biologist, University of Pavia
- 1995 Degree in Biological Sciences cum laude, University of Pavia
Research activity
Alternative splicing (AS) is the process producing different mature transcripts (mRNAs) from a single primary RNA (pre-mRNA). AS decisions are modulated by a number of cis-acting sequence motifs bound by trans-acting splicing regulatory factors (SRFs) that function in a coordinate manner to promote or inhibit the inclusion of specific exons. Approximately 95% of human protein-coding genes undergoes AS giving rise to different protein isoforms with distinct structural and functional properties. Interestingly, the majority of human AS events displays tissue-dependent expression with significant cell, tissue or condition-specific regulation. Hence, AS represents one of the major mechanism to expand the coding potential of our genome in order to establish and maintain fundamental properties in development and tissue identity.
In the past decade, several findings highlighted a direct role of AS in promoting cancer progression. In particular, altered expression of specific SRFs allow neoplastic cells to generate cancer-specific AS isoforms involved in tumor establishment, progression and resistance to therapeutic treatments. For this reason, SRFs and cancer-specific AS events are a promising source of new diagnostic and prognostic tools for human cancer. In addition, targeting these “oncogenic AS switches” represents a particularly intriguing approach to improve the efficacy of anti-cancer treatments.
Research Project
Regolazione post-trascrizionale dell’angiogenesi
Recent Publications
2023 |
Di Matteo A; Belloni E; Pradella D; Chiaravalli AM; Pini GM; Bugatti M; Alfieri R; Barzan C; Franganillo Tena E; Bione S; Terenzani E; Sessa F; Wyatt CDR; Vermi W; Ghigna C Alternative Splicing Changes Promoted by NOVA2 Upregulation in Endothelial Cells and Relevance for Gastric Cancer Journal Article In: International journal of molecular sciences, vol. 24, iss. 9, pp. 8102, 2023. @article{%a1.%Yb_89,Angiogenesis is crucial for cancer progression. While several anti-angiogenic drugs are in use for cancer treatment, their clinical benefits are unsatisfactory. Thus, a deeper understanding of the mechanisms sustaining cancer vessel growth is fundamental to identify novel biomarkers and therapeutic targets. Alternative splicing (AS) is an essential modifier of human proteome diversity. Nevertheless, AS contribution to tumor vasculature development is poorly known. The Neuro-Oncological Ventral Antigen 2 (NOVA2) is a critical AS regulator of angiogenesis and vascular development. NOVA2 is upregulated in tumor endothelial cells (ECs) of different cancers, thus representing a potential driver of tumor blood vessel aberrancies. Here, we identified novel AS transcripts generated upon NOVA2 upregulation in ECs, suggesting a pervasive role of NOVA2 in vascular biology. In addition, we report that NOVA2 is also upregulated in ECs of gastric cancer (GC), and its expression correlates with poor overall survival of GC patients. Finally, we found that the AS of the Rap Guanine Nucleotide Exchange Factor 6 (RapGEF6), a newly identified NOVA2 target, is altered in GC patients and associated with NOVA2 expression, tumor angiogenesis, and poor patient outcome. Our findings provide a better understanding of GC biology and suggest that AS might be exploited to identify novel biomarkers and therapeutics for anti-angiogenic GC treatments. |
Lecca M; Bedeschi MF; Izzi C; Dordoni C; Rinaldi B; Peluso F; Caraffi SG; Prefumo F; Signorelli M; Zanzucchi M; Bione S; Ghigna C; Sassi S; Novelli A; Valente EM; Superti-Furga A; Garavelli L; Errichiello E Identification of bi-allelic LFNG variants in three patients and further clinical and molecular refinement of spondylocostal dysostosis 3 Journal Article In: Clinical genetics, vol. 104, iss. 2, pp. 230, 2023. @article{%a1.%Yb_99,Spondylocostal dysostosis (SCD), a condition characterized by multiple segmentation defects of the vertebrae and rib malformations, is caused by bi-allelic variants in one of the genes involved in the Notch signaling pathway that tunes the ""segmentation clock"" of somitogenesis: DLL3, HES7, LFNG, MESP2, RIPPLY2, and TBX6. To date, seven individuals with LFNG variants have been reported in the literature. In this study we describe two newborns and one fetus with SCD, who were found by trio-based exome sequencing (trio-ES) to carry homozygous (c.822-5C>T) or compound heterozygous (c.[863dup];[1063G>A]) and (c.[521G>T];[890T>G]) variants in LFNG. Notably, the c.822-5C>T change, affecting the polypyrimidine tract of intron 5, is the first non-coding variant reported in LFNG. This study further refines the clinical and molecular features of spondylocostal dysostosis 3 and adds to the numerous investigations supporting the usefulness of trio-ES approach in prenatal and neonatal settings. |
2022 |
Monti M; Celli J; Missale F; Cersosimo F; Russo M; Belloni E; Di Matteo A; Lonardi S; Vermi W; Ghigna C; Giurisato E Clinical Significance and Regulation of ERK5 Expression and Function in Cancer Journal Article In: Cancers (Basel), vol. 14, iss. 2, pp. 348, 2022. @article{%a1.%Yb_58,Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of normal cells, ERK5 has recently attracted the attention of several research groups given its relevance in inflammatory disorders and cancer. Accumulating evidence reported its role in tumor initiation and progression. In this review, we explore the gene expression profile of ERK5 among cancers correlated with its clinical impact, as well as the prognostic value of ERK5 and pERK5 expression levels in tumors. We also summarize the importance of ERK5 in the maintenance of a cancer stem-like phenotype and explore the major known contributions of ERK5 in the tumor-associated microenvironment. Moreover, although several questions are still open concerning ERK5 molecular regulation, different ERK5 isoforms derived from the alternative splicing process are also described, highlighting the potential clinical relevance of targeting ERK5 pathways. |
2021 |
Pradella D; Deflorian G; Pezzotta A; Di Matteo A; Belloni E; Campolungo D; Paradisi A; Bugatti M; Vermi W; Campioni M; Chiapparino A; Scietti L; Forneris F; Giampietro C; Volf N; Rehman M; Zacchigna S; Paronetto MP; Pistocchi A; Eichmann A; Mehlen P; Ghigna C A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis Journal Article In: Nature communications, vol. 12, no. 1, pp. 4872, 2021. @article{%a1:%Ybv,The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B's necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis. |
Biamonti G; Amato A; Belloni E; Di Matteo A; Infantino L; Pradella D; Ghigna C Alternative splicing in Alzheimer's disease. Journal Article In: Aging clinical and experimental research, vol. 33, no. 4, pp. 747-758, 2021. @article{%a1:%Y_91,Alzheimer's disease (AD) is the most frequent neurodegenerative disorder in the elderly, occurring in approximately 20% of people older than 80. The molecular causes of AD are still poorly understood. However, recent studies have shown that Alternative Splicing (AS) is involved in the gene expression reprogramming associated with the functional changes observed in AD patients. In particular, mutations in cis-acting regulatory sequences as well as alterations in the activity and sub-cellular localization of trans-acting splicing factors and components of the spliceosome machinery are associated with splicing abnormalities in AD tissues, which may influence the onset and progression of the disease. In this review, we discuss the current molecular understanding of how alterations in the AS process contribute to AD pathogenesis. Finally, recent therapeutic approaches targeting aberrant AS regulation in AD are also reviewed. |
Oh J; Pradella D; Kim Y; Shao C; Li H; Choi N; Ha J; Di Matteo A; Fu XD; Zheng X; Ghigna C; Shen H Global Alternative Splicing Defects in Human Breast Cancer Cells Journal Article In: Cancers, vol. 13, no. 12, pp. 3071, 2021. @article{%a1:%Ybv,Breast cancer is the most frequently occurred cancer type and the second cause of death in women worldwide. Alternative splicing (AS) is the process that generates more than one mRNA isoform from a single gene, and it plays a major role in expanding the human protein diversity. Aberrant AS contributes to breast cancer metastasis and resistance to chemotherapeutic interventions. Therefore, identifying cancer-specific isoforms is the prerequisite for therapeutic interventions intended to correct aberrantly expressed AS events. Here, we performed RNA-mediated oligonucleotide annealing, selection, and ligation coupled with next-generation sequencing (RASL-seq) in breast cancer cells, to identify global breast cancer-specific AS defects. By RT-PCR validation, we demonstrate the high accuracy of RASL-seq results. In addition, we analyzed identified AS events using the Cancer Genome Atlas (TCGA) database in a large number of non-pathological and breast tumor specimens and validated them in normal and breast cancer samples. Interestingly, aberrantly regulated AS cassette exons in cancer tissues do not encode for known functional domains but instead encode for amino acids constituting regions of intrinsically disordered protein portions characterized by high flexibility and prone to be subjected to post-translational modifications. Collectively, our results reveal novel AS errors occurring in human breast cancer, potentially affecting breast cancer-related biological processes. |
Choi N; Liu Y; Oh J; Ha J; Ghigna C; Zheng X; Shen H Relative strength of 5' splice-site strength defines functions of SRSF2 and SRSF6 in alternative splicing of Bcl-x pre-mRNA Journal Article In: BMC Reports, vol. 54, no. 3, pp. 176-181, 2021. @article{%a1:%Ybvy,Bcl-x, a member of the Bcl-2 family, plays a key role in apoptosis. Alternative splicing of Bcl-x pre-mRNA through alternative 5' splice-site selection produces an anti-apoptotic mRNA isoform that includes exon 2b and a pro-apoptotic Bcl-x mRNA isoform that excludes exon 2b. Here we used Bcl-x minigene and identified SRSF2 and SRSF6 as two regulatory factors of 5' splice-site selection of Bcl-x pre-mRNA. We selected binding clusters closer to 5' splice-sites from multiple potential binding sites of SRSF2 and SRSF6 to perform loss of functions analysis through site-directed mutagenesis. Our results demonstrated that these mutations did not abolish regulatory functions of SRSF2 or SRSF6, indicating that a single binding motif or a cluster was not a functional target of these proteins in Bcl-x pre-mRNA splicing. Random deletion mutagenesis did not disrupt the role of SRSF2 and SRSF6. Importantly, mutagenesis of 5' splice-site to a conserved or a weaker score demonstrated that the weaker strength of the target 5' splice-site or higher strength of the other 5' splice-site strength limited the role of SRSF2 and SRSF6 in 5' splice-site activation. [BMB Reports 2021; 54(3): 176-181]. |
Ha J; Jang H; Choi N; Oh J; Min C; Pradella D; Jung DW; Williams DR; Park D; Ghigna C; Zheng X; Shen H SRSF9 Regulates Cassette Exon Splicing of Caspase-2 by Interacting with Its Downstream Exon. Journal Article In: Cells, vol. 1o, no. 3, pp. 679, 2021. @article{%a1:%Y__513,Alternative splicing (AS) is an important posttranscriptional regulatory process. Damaged or unnecessary cells need to be removed though apoptosis to maintain physiological processes. Caspase-2 pre-mRNA produces pro-apoptotic long mRNA and anti-apoptotic short mRNA isoforms through AS. How AS of Caspase-2 is regulated remains unclear. In the present study, we identified a novel regulatory protein SRSF9 for AS of Caspase-2 cassette exon 9. Knock-down (KD) of SRSF9 increased inclusion of cassette exon and on the other hand, overexpression of SRSF9 decreased inclusion of this exon. Deletion mutagenesis demonstrated that exon 9, parts of intron 9, exon 8 and exon 10 were not required for the role of SRSF9 in Caspase-2 AS. However, deletion and substitution mutation analysis revealed that AGGAG sequence located at exon 10 provided functional target for SRSF9. In addition, RNA-pulldown mediated immunoblotting analysis showed that SRSF9 interacted with this sequence. Gene ontology analysis of RNA-seq from SRSF9 KD cells demonstrates that SRSF9 could regulate AS of a subset of apoptosis related genes. Collectively, our results reveal a basis for regulation of Caspase-2 AS. |
Oh J; Pradella D; Shao C; Li H; Choi N; Ha J; Ruggiero S; Fu XD; Zheng X; Ghigna C; Shen H Widespread Alternative Splicing Changes in Metastatic Breast Cancer Cells Journal Article In: Cells, vol. 10, no. 4, pp. 858, 2021. @article{%a1:%Yb,Aberrant alternative splicing (AS) is a hallmark of cancer and a potential target for novel anti-cancer therapeutics. Breast cancer-associated AS events are known to be linked to disease progression, metastasis, and survival of breast cancer patients. To identify altered AS programs occurring in metastatic breast cancer, we perform a global analysis of AS events by using RNA-mediated oligonucleotide annealing, selection, and ligation coupled with next-generation sequencing (RASL-seq). We demonstrate that, relative to low-metastatic, high-metastatic breast cancer cells show different AS choices in genes related to cancer progression. Supporting a global reshape of cancer-related splicing profiles in metastatic breast cancer we found an enrichment of RNA-binding motifs recognized by several splicing regulators, which have aberrant expression levels or activity during breast cancer progression, including SRSF1. Among SRSF1-regulated targets we found DCUN1D5, a gene for which skipping of exon 4 in its pre-mRNA introduces a premature termination codon (PTC), thus generating an unstable transcript degraded by nonsense-mediated mRNA decay (NMD). Significantly, distinct breast cancer subtypes show different DCUN1D5 isoform ratios with metastatic breast cancer expressing the highest level of the NMD-insensitive DCUN1D5 mRNA, thus showing high DCUN1D5 expression levels, which are ultimately associated with poor overall and relapse-free survival in breast cancer patients. Collectively, our results reveal global AS features of metastatic breast tumors, which open new possibilities for the treatment of these aggressive tumor types. |
2020 |
Di Matteo A; Belloni E; Pradella D; Cappelletto A; Volf N; Zacchigna S; Ghigna C Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis. Journal Article In: Journal of experimental & clinical cancer research, vol. 39, no. 1, pp. 275, 2020. @article{%a1:%Y_446,Alternative splicing (AS) is a pervasive molecular process generating multiple protein isoforms, from a single gene. It plays fundamental roles during development, differentiation and maintenance of tissue homeostasis, while aberrant AS is considered a hallmark of multiple diseases, including cancer. Cancer-restricted AS isoforms represent either predictive biomarkers for diagnosis/prognosis or targets for anti-cancer therapies. Here, we discuss the contribution of AS regulation in cancer angiogenesis, a complex process supporting disease development and progression. We consider AS programs acting in a specific and non-redundant manner to influence morphological and functional changes involved in cancer angiogenesis. In particular, we describe relevant AS variants or splicing regulators controlling either secreted or membrane-bound angiogenic factors, which may represent attractive targets for therapeutic interventions in human cancer. |
Ghigna C; Paronetto MP Alternative Splicing: Recent Insights into Mechanisms and Functional Roles Journal Article In: Cells, vol. 9, no. 10, pp. 2327, 2020. @article{%a1:%Y_452,Alternative splicing generates multiple protein isoforms from one primary transcript and represents one of the major drivers of proteomic diversity in human cells [...]. |
Oh J; Liu Y; Choi N; Ha J; Pradella D; Ghigna C; Zheng X; Shen H Opposite Roles of Tra2beta and SRSF9 in the v10 Exon Splicing of CD44. Journal Article In: Cancers, vol. 12, no. 11, pp. 3195, 2020. @article{%a1:%Y_461,CD44 is a transmembrane glycoprotein involved in cell–cell and cell–matrix interactions. Several CD44 protein isoforms are generated in human through alternative splicing regulation of nine variable exons encoding for the extracellular juxta-membrane region. While the CD44 splicing variants have been described to be involved in cancer progression and development, the regulatory mechanism(s) underlying their production remain unclear. Here, we identify Tra2beta and SRSF9 as proteins with opposite roles in regulating CD44 exon v10 splicing. While Tra2beta promotes v10 inclusion, SRSF9 inhibits its inclusion. Mechanistically, we found that both proteins are able to target v10 exon, with GAAGAAG sequence being the binding site for Tra2beta and AAGAC that for SRSF9. Collectively, our data add a novel layer of complexity to the sequential series of events involved in the regulation of CD44 splicing. |
2019 |
Angiolini F; Belloni E; Giordano M; Campioni M; Forneris F; Paronetto MP; Lupia M; Brandas C; Pradella D; Di Matteo A; Giampietro C; Jodice G; Luise C; Bertalot G; Freddi S; Malinverno M; Irimia M; Moulton JD; Summerton J; Chiapparino A; Ghilardi C; Giavazzi R; Nyqvist D; Gabellini D; Dejana E; Cavallaro U; Ghigna C A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing. Journal Article In: ELIFE, vol. 8, pp. e44305, 2019. @article{%a1:%Y%e,The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-deltaTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-deltaTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-deltaTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-deltaTM are overexpressed in the vasculature of ovarian cancer, where L1-deltaTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-deltaTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-deltaTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies. 2019, Angiolini et al. |
Belloni E; Di Matteo A; Pradella D; Vacca M; Wyatt CDR; Alfieri R; Maffia A; Sabbioneda S; Ghigna C Gene Expression Profiles Controlled by the Alternative Splicing Factor Nova2 in Endothelial Cells. Journal Article In: Cells, vol. 8, no. 12, pp. pii: E1498, 2019. @article{%a1:%Y%j,Alternative splicing (AS) plays an important role in expanding the complexity of the human genome through the production of specialized proteins regulating organ development and physiological functions, as well as contributing to several pathological conditions. How AS programs impact on the signaling pathways controlling endothelial cell (EC) functions and vascular development is largely unknown. Here we identified, through RNA-seq, changes in mRNA steady-state levels in ECs caused by the neuro-oncological ventral antigen 2 (Nova2), a key AS regulator of the vascular morphogenesis. Bioinformatics analyses identified significant enrichment for genes regulated by peroxisome proliferator-activated receptor-gamma (Ppar-γ) and E2F1 transcription factors. We also showed that Nova2 in ECs controlled the AS profiles of Ppar-γ and E2F dimerization partner 2 (Tfdp2), thus generating different protein isoforms with distinct function (Ppar-γ) or subcellular localization (Tfdp2). Collectively, our results supported a mechanism whereby Nova2 integrated splicing decisions in order to regulate Ppar-γ and E2F1 activities. Our data added a layer to the sequential series of events controlled by Nova2 in ECs to orchestrate vascular biology. |
2018 |
Nakka K; Ghigna C; Gabellini D; Dilworth FJ Diversification of the muscle proteome through alternative splicing. Journal Article In: Skeletal Muscle, vol. 8, no. 1, pp. 8, 2018. @article{%a1:%Y_164,Skeletal Muscle |
2017 |
Pradella D; Naro C; Sette C; Ghigna C EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Journal Article In: Molecular cancer, vol. 16, no. 1, pp. 8, 2017. @article{%a1:%Y_195,Epithelial-to-mesenchymal transition (EMT) is associated with metastasis formation as well as with generation and maintenance of cancer stem cells. In this way, EMT contributes to tumor invasion, heterogeneity and chemoresistance. Morphological and functional changes involved in these processes require robust reprogramming of gene expression, which is only partially accomplished at the transcriptional level. Alternative splicing is another essential layer of gene expression regulation that expands the cell proteome. This step in post-transcriptional regulation of gene expression tightly controls cell identity between epithelial and mesenchymal states and during stem cell differentiation. Importantly, dysregulation of splicing factor function and cancer-specific splicing isoform expression frequently occurs in human tumors, suggesting the importance of alternative splicing regulation for cancer biology.In this review, we briefly discuss the role of EMT programs in development, stem cell differentiation and cancer progression. Next, we focus on selected examples of key factors involved in EMT and stem cell differentiation that are regulated post-transcriptionally through alternative splicing mechanisms. Lastly, we describe relevant oncogenic splice-variants that directly orchestrate cancer stem cell biology and tumor EMT, which may be envisioned as novel targets for therapeutic intervention. |
2015 |
Loh TJ; Cho S; Moon H; Jang HN; Williams DR; Jung DW; Kim IC; Ghigna C; Biamonti G; Zheng X; Shen H hnRNP L inhibits CD44 V10 exon splicing through interacting with its upstream intron Journal Article In: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, vol. 1849, no. 6, pp. 743-750, 2015. @article{%a1:%Y_369,CD44 is a complex cell adhesion molecule that mediates communication and adhesion between adjacent cells as well as between cells and the extracellular matrix. CD44 pre-mRNA produces various mRNA isoforms through alternative splicing of 20 exons, among which exons 1-5 (C1-C5) and 16-20 (C6-C10) are constant exons, whereas exons 6-15 (V1-V10) are variant exons. CD44 V10 exon has important roles in breast tumor progression and Hodgkin lymphoma. Here we show that increased expression of hnRNP L inhibits V10 exon splicing of CD44 pre-mRNA, whereas reduced expression of hnRNP L promotes V10 exon splicing. In addition, hnRNP L also promotes V10 splicing of endogenous CD44 pre-mRNA. Through mutation analysis, we demonstrate that the effects of hnRNP L on V10 splicing are abolished when the CA-rich sequence on the upstream intron of V10 exon is disrupted. However, hnRNP L effects are stronger if more CA-repeats are provided. Furthermore, we show that hnRNP L directly contacts the CA-rich sequence. Importantly, we provide evidences that hnRNP L inhibits U2AF65 binding on the upstream Py tract of V10 exon. Our results reveal that hnRNP L is a new regulator for CD44 V10 exon splicing. Copyright 2015 Elsevier B.V. All rights reserved. |
Ghigna C; Cartegni L; Jordan P; Paronetto MP Posttranscriptional Regulation and RNA Binding Proteins in Cancer Biology. Journal Article In: Biomed Research International, vol. 2015, pp. 897821, 2015. @article{%a1:%Y_396, |
Frisone P; Pradella D; Di Matteo A; Belloni E; Ghigna C; Paronetto MP SAM68: Signal Transduction and RNA Metabolism in Human Cancer. Journal Article In: Biomed Research International, vol. 2015, pp. 528954, 2015. @article{%a1:%Y_405,Alterations in expression and/or activity of splicing factors as well as mutations in cis-acting splicing regulatory sequences contribute to cancer phenotypes. Genome-wide studies have revealed more than 15,000 tumor-associated splice variants derived from genes involved in almost every aspect of cancer cell biology, including proliferation, differentiation, cell cycle control, metabolism, apoptosis, motility, invasion, and angiogenesis. In the past decades, several RNA binding proteins (RBPs) have been implicated in tumorigenesis. SAM68 (SRC associated in mitosis of 68 kDa) belongs to the STAR (signal transduction and activation of RNA metabolism) family of RBPs. SAM68 is involved in several steps of mRNA metabolism, from transcription to alternative splicing and then to nuclear export. Moreover, SAM68 participates in signaling pathways associated with cell response to stimuli, cell cycle transitions, and viral infections. Recent evidence has linked this RBP to the onset and progression of different tumors, highlighting misregulation of SAM68-regulated splicing events as a key step in neoplastic transformation and tumor progression. Here we review recent studies on the role of SAM68 in splicing regulation and we discuss its contribution to aberrant pre-mRNA processing in cancer. |
Giampietro C; Deflorian G; Gallo S; Di Matteo A; Pradella D; Bonomi S; Belloni E; Nyqvist D; Quaranta V; Confalonieri S; Bertalot G; Orsenigo F; Pisati F; Ferrero E; Biamonti G; Fredrickx E; Taveggia C; Wyatt CD; Irimia M; Di Fiore PP; Blencowe BJ; Dejana E; Ghigna C The alternative splicing factor Nova2 regulates vascular development and lumen formation. Journal Article In: Nature communications, vol. 6, pp. 8479, 2015. @article{%a1:%Y_411,Vascular lumen formation is a fundamental step during angiogenesis; yet, the molecular mechanisms underlying this process are poorly understood. Recent studies have shown that neural and vascular systems share common anatomical, functional and molecular similarities. Here we show that the organization of endothelial lumen is controlled at the post-transcriptional level by the alternative splicing (AS) regulator Nova2, which was previously considered to be neural cell-specific. Nova2 is expressed during angiogenesis and its depletion disrupts vascular lumen formation in vivo. Similarly, Nova2 depletion in cultured endothelial cells (ECs) impairs the apical distribution and the downstream signalling of the Par polarity complex, resulting in altered EC polarity, a process required for vascular lumen formation. These defects are linked to AS changes of Nova2 target exons affecting the Par complex and its regulators. Collectively, our results reveal that Nova2 functions as an AS regulator in angiogenesis and is a novel member of the 'angioneurins' family. |