100 results on '"Michela Garofalo"'
Search Results
2. Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells
- Author
-
Marta Buzzetti, Sonia Morlando, Dimitrios Solomos, Ammara Mehmood, Alexander W. I. Cox, Mattia Chiesa, Yuri D’Alessandra, Michela Garofalo, Caroline H. Topham, and Gianpiero Di Leva
- Subjects
Medicine ,Science - Abstract
Abstract Medulloblastoma (MB) is the most common aggressive paediatric brain tumour and, despite the recent progress in the treatments of MB patients, there is still an urgent need of complementary or alternative therapeutic options for MB infants. Cyclin Dependent Kinase inhibitors (CDKi) are at the front-line of novel targeted treatments for multiple cancers and the CDK4/6 specific inhibitor palbociclib has been pre-clinically identified as an effective option for MB cells. Herein, we identified the pan-CDKi dinaciclib as a promising alternative to palbociclib for the suppression of MB cells proliferation. We present evidence supporting dinaciclib’s ability to inhibit MB cells in vitro proliferation at considerably lower doses than palbociclib. Sequencing data and pathway analysis suggested that dinaciclib is a potent cell death inducer in MB cells. We found that dinaciclib-triggered apoptosis is triggered by CDK9 inhibition and the resultant reduction in RNA pol II phosphorylation, which leads to the downregulation of the oncogenic marker MYC, and the anti-apoptotic protein MCL-1. Specifically, we demonstrated that MCL-1 is a key apoptotic mediator for MB cells and co-treatment of dinaciclib with BH3 mimetics boosts the therapeutic efficacy of dinaciclib. Together, these findings highlight the potential of multi-CDK inhibition by dinaciclib as an alternative option to CDK4/6 specific inhibition, frequently associated with drug resistance in patients.
- Published
- 2021
- Full Text
- View/download PDF
3. Correction: MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer
- Author
-
Michela Garofalo, Young-Jun Jeon, Gerard J. Nuovo, Justin Middleton, Paola Secchiero, Pooja Joshi, Hansjuerg Alder, Natalya Nazaryan, Gianpiero Di Leva, Giulia Romano, Melissa Crawford, Patrick Nana-Sinkam, and Carlo M. Croce
- Subjects
Medicine ,Science - Published
- 2022
4. miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC
- Author
-
Young-Jun Jeon, Taewan Kim, Dongju Park, Gerard J. Nuovo, Siyeon Rhee, Pooja Joshi, Bum-Kyu Lee, Johan Jeong, Sung-suk Suh, Jeff E. Grotzke, Sung-Hak Kim, Jieun Song, Hosung Sim, Yonghwan Kim, Yong Peng, Youngtae Jeong, Michela Garofalo, Nicola Zanesi, Jonghwan Kim, Guang Liang, Ichiro Nakano, Peter Cresswell, Patrick Nana-Sinkam, Ri Cui, and Carlo M. Croce
- Subjects
Science - Abstract
TUSC3 resides on chromosome 8p which is frequently deleted in advanced stage tumors. Here, the authors show that TUSC3 loss mediated by miR-224/-520c promotes NSCLC metastasis where it enhances ATF-6α-dependent UPR and HRD-1 dependent ERAD, which in turn suppress p53-NM23H1/2 tumor suppressor pathway.
- Published
- 2018
- Full Text
- View/download PDF
5. Vulnerability of drug‐resistant EML4‐ALK rearranged lung cancer to transcriptional inhibition
- Author
-
Athanasios R Paliouras, Marta Buzzetti, Lei Shi, Ian J Donaldson, Peter Magee, Sudhakar Sahoo, Hui‐Sun Leong, Matteo Fassan, Matthew Carter, Gianpiero Di Leva, Matthew G Krebs, Fiona Blackhall, Christine M Lovly, and Michela Garofalo
- Subjects
ALK/EML4 translocation ,ALKi ,CDKi ,drug resistance ,NSCLC ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract A subset of lung adenocarcinomas is driven by the EML4‐ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on‐target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4‐ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti‐apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first‐, second‐ and third‐generation ALK inhibitors.
- Published
- 2020
- Full Text
- View/download PDF
6. LncRNAs in Non-Small-Cell Lung Cancer
- Author
-
Lucy Ginn, Lei Shi, Manuela La Montagna, and Michela Garofalo
- Subjects
non-small-cell lung cancer ,long non-coding RNAs ,Genetics ,QH426-470 - Abstract
Lung cancer is associated with a high mortality, with around 1.8 million deaths worldwide in 2018. Non-small-cell lung cancer (NSCLC) accounts for around 85% of cases and, despite improvement in the management of NSCLC, most patients are diagnosed at advanced stage and the five-year survival remains around 15%. This highlights a need to identify novel ways to treat the disease to reduce the burden of NSCLC. Long non-coding RNAs (lncRNAs) are non-coding RNA molecules longer than 200 nucleotides in length which play important roles in gene expression and signaling pathways. Recently, lncRNAs were implicated in cancer, where their expression is dysregulated resulting in aberrant functions. LncRNAs were shown to function as both tumor suppressors and oncogenes in a variety of cancer types. Although there are a few well characterized lncRNAs in NSCLC, many lncRNAs remain un-characterized and their mechanisms of action largely unknown. LncRNAs have success as therapies in neurodegenerative diseases, and having a detailed understanding of their function in NSCLC may guide novel therapeutic approaches and strategies. This review discusses the role of lncRNAs in NSCLC tumorigenesis, highlighting their mechanisms of action and their clinical potential.
- Published
- 2020
- Full Text
- View/download PDF
7. Non-Coding RNAs and Cancer
- Author
-
Michela Garofalo, Federica Calore, and Francesca Lovat
- Subjects
small non-coding RNAs ,long non-coding RNAs ,cancer ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The discovery of the biological relevance of non-coding RNA (ncRNAs) molecules represents one of the most significant advances in contemporary molecular biology. Expression profiling of human tumors, based on the expression of miRNAs and other short or long ncRNAs, has identified signatures associated with diagnosis, staging, progression, prognosis, and response to treatment. In this review we will discuss the recent remarkable advancement in the understanding the biological functions of human ncRNAs in cancer, the mechanisms of expression and the therapeutic potential.
- Published
- 2013
- Full Text
- View/download PDF
8. Correction: MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer.
- Author
-
Michela Garofalo, Young-Jun Jeon, Gerard J Nuovo, Justin Middleton, Paola Secchiero, Pooja Joshi, Hansjuerg Alder, Natalya Nazaryan, Gianpiero Di Leva, Giulia Romano, Melissa Crawford, Patrick Nana-Sinkam, and Carlo M Croce
- Subjects
Medicine ,Science - Published
- 2015
- Full Text
- View/download PDF
9. Correction: Estrogen Mediated-Activation of miR-191/425 Cluster Modulates Tumorigenicity of Breast Cancer Cells Depending on Estrogen Receptor Status.
- Author
-
Gianpiero Di Leva, Claudia Piovan, Pierluigi Gasparini, Apollinaire Ngankeu, Cristian Taccioli, Daniel Briskin, Douglas G. Cheung, Brad Bolon, Laura Anderlucci, Hansjuerg Alder, Gerard Nuovo, Meng Li, Marilena V. Iorio, Marco Galasso, Santhanam Ramasamy, Guido Marcucci, Danilo Perrotti, Kimerly A. Powell, Anna Bratasz, Michela Garofalo, Kenneth P. Nephew, and Carlo M. Croce
- Subjects
Genetics ,QH426-470 - Published
- 2013
- Full Text
- View/download PDF
10. A mathematical model for microRNA in lung cancer.
- Author
-
Hye-Won Kang, Melissa Crawford, Muller Fabbri, Gerard Nuovo, Michela Garofalo, S Patrick Nana-Sinkam, and Avner Friedman
- Subjects
Medicine ,Science - Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Lack of early detection and limited options for targeted therapies are both contributing factors to the dismal statistics observed in lung cancer. Thus, advances in both of these areas are likely to lead to improved outcomes. MicroRNAs (miRs or miRNAs) represent a class of non-coding RNAs that have the capacity for gene regulation and may serve as both diagnostic and prognostic biomarkers in lung cancer. Abnormal expression patterns for several miRNAs have been identified in lung cancers. Specifically, let-7 and miR-9 are deregulated in both lung cancers and other solid malignancies. In this paper, we construct a mathematical model that integrates let-7 and miR-9 expression into a signaling pathway to generate an in silico model for the process of epithelial mesenchymal transition (EMT). Simulations of the model demonstrate that EGFR and Ras mutations in non-small cell lung cancers (NSCLC), which lead to the process of EMT, result in miR-9 upregulation and let-7 suppression, and this process is somewhat robust against random input into miR-9 and more strongly robust against random input into let-7. We elected to validate our model in vitro by testing the effects of EGFR inhibition on downstream MYC, miR-9 and let-7a expression. Interestingly, in an EGFR mutated lung cancer cell line, treatment with an EGFR inhibitor (Gefitinib) resulted in a concentration specific reduction in c-MYC and miR-9 expression while not changing let-7a expression. Our mathematical model explains the signaling link among EGFR, MYC, and miR-9, but not let-7. However, very little is presently known about factors that regulate let-7. It is quite possible that when such regulating factors become known and integrated into our model, they will further support our mathematical model.
- Published
- 2013
- Full Text
- View/download PDF
11. MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer.
- Author
-
Michela Garofalo, Young-Jun Jeon, Gerard J Nuovo, Justin Middleton, Paola Secchiero, Pooja Joshi, Hansjuerg Alder, Natalya Nazaryan, Gianpiero Di Leva, Giulia Romano, Melissa Crawford, Patrick Nana-Sinkam, and Carlo M Croce
- Subjects
Medicine ,Science - Abstract
Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-α/β and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-α/β by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells.
- Published
- 2013
- Full Text
- View/download PDF
12. Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status.
- Author
-
Gianpiero Di Leva, Claudia Piovan, Pierluigi Gasparini, Apollinaire Ngankeu, Cristian Taccioli, Daniel Briskin, Douglas G Cheung, Brad Bolon, Laura Anderlucci, Hansjuerg Alder, Gerard Nuovo, Meng Li, Marilena V Iorio, Marco Galasso, Ramasamy Santhanam, Guido Marcucci, Danilo Perrotti, Kimerly A Powell, Anna Bratasz, Michela Garofalo, Kenneth P Nephew, and Carlo M Croce
- Subjects
Genetics ,QH426-470 - Abstract
MicroRNAs (miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to cancer. Although tumor-suppressive and oncogenic functions have been characterized for some miRNAs, the majority of microRNAs have not been investigated for their ability to promote and modulate tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the hormone 17β-estradiol (estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive breast cancer cells from hormone starvation-induced apoptosis through the suppression of tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive breast cancer cells altered global gene expression profiles and enabled us to identify important tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired tumorigenesis and metastasis, and increased expression of epithelial markers in aggressive breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on cancer initiation and progression of breast cancer cells.
- Published
- 2013
- Full Text
- View/download PDF
13. Akt regulates drug-induced cell death through Bcl-w downregulation.
- Author
-
Michela Garofalo, Cristina Quintavalle, Ciro Zanca, Assunta De Rienzo, Giulia Romano, Mario Acunzo, Loredana Puca, Mariarosaria Incoronato, Carlo M Croce, and Gerolama Condorelli
- Subjects
Medicine ,Science - Abstract
Akt is a serine threonine kinase with a major role in transducing survival signals and regulating proteins involved in apoptosis. To find new interactors of Akt involved in cell survival, we performed a two-hybrid screening in yeast using human full-length Akt c-DNA as bait and a murine c-DNA library as prey. Among the 80 clones obtained, two were identified as Bcl-w. Bcl-w is a member of the Bcl-2 family that is essential for the regulation of cellular survival, and that is up-regulated in different human tumors, such as gastric and colorectal carcinomas. Direct interaction of Bcl-w with Akt was confirmed by immunoprecipitation assays. Subsequently, we addressed the function of this interaction: by interfering with the activity or amount of Akt, we have demonstrated that Akt modulates the amount of Bcl-w protein. We have found that inhibition of Akt activity may promote apoptosis through the downregulation of Bcl-w protein and the consequential reduction in interaction of Bcl-w with pro-apoptotic members of the Bcl-2 family. Our data provide evidence that Bcl-w is a new member of the Akt pathway and that Akt may induce anti-apoptotic signals at least in part through the regulation of the amount and activity of Bcl-w.
- Published
- 2008
- Full Text
- View/download PDF
14. Supplementary Figure 6 from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
Differentially expressed genes in CKAP2L-depleted cells
- Published
- 2023
15. Supplementary Figure 1 from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
Correlation analysis between LuAd gene expression and CIN
- Published
- 2023
16. Supplementary Data from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
Supplementary methods
- Published
- 2023
17. Supplementary Table 1 from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
List of all primers used in the study
- Published
- 2023
18. Supplementary Table 2 from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
CKAP2L binding partners were identified by LC-MS
- Published
- 2023
19. fullscanofwesternblots.pptx from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
unprocessed original images of western blots
- Published
- 2023
20. Supplementary Table 3 from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
Functional annotation analysis of genes showing RPB1 reduced binding upon CKAP2L downregulation
- Published
- 2023
21. Supplementary Figure 5 from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
Effect of CKAP2L depletion on RNA Pol II distribution
- Published
- 2023
22. Supplementary Figure 4 from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
Characterization of CKAP2L role in cell proliferation
- Published
- 2023
23. Data from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
Chromosomal instability (CIN) is a driver of clonal diversification and intratumor heterogeneity, providing genetic diversity that contributes to tumor progression. It is estimated that approximately 80% of solid cancers, including non–small cell lung cancer (NSCLC), exhibit features of CIN, which affects tumor growth and response to therapy. However, the molecular mechanisms connecting CIN to tumor progression are still poorly understood. Through an RNAi screen performed on genes involved in CIN and overexpressed in human lung adenocarcinoma samples, we identified the cytoskeleton-associated protein 2-like (CKAP2L) as a potential oncogene that promotes lung cancer proliferation and growth in vitro and in vivo. Mechanistically, CKAP2L directly interacted with RNA Pol II and regulated transcription elongation of key genes involved in spindle assembly checkpoint, chromosome segregation, cell cycle, and E2F signaling. Furthermore, depletion of CKAP2L increased the sensitivity of NSCLC cells to alvocidib, a pan-CDK inhibitor, leading to a significant reduction of cell proliferation and an increase in cell death. Altogether, these findings shed light on the molecular mechanisms through which CKAP2L, a protein involved in CIN, promotes cancer progression and suggest that its inhibition represents a novel therapeutic strategy in NSCLC.Significance:These findings demonstrate the oncogenic function of CKAP2L through regulation of transcription elongation and suggest that targeting CKAP2L could enhance therapeutic response in patients with NSCLC.
- Published
- 2023
24. Supplementary Figure 2 from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
CKAP2L regulates cell migration and its expression correlates with tumour progression of human LuAd
- Published
- 2023
25. Supplementary Figure 3 from CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Michela Garofalo, Matteo Fassan, Hui Sun Leong, Alexander R. Baker, Robert Sellers, Dave Lee, Lei Shi, Peter Magee, Manuela La Montagna, Sudhakar Sahoo, and Tiziana Monteverde
- Abstract
Downregulation of MYC and KRAS signalling
- Published
- 2023
26. Supplementary Figure Legend from miR-212 Increases Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Sensitivity in Non–Small Cell Lung Cancer by Targeting the Antiapoptotic Protein PED
- Author
-
Gerolama Condorelli, Carlo Maria Croce, Gerald Nuovo, Margherita Iaboni, Ciro Zanca, Cristina Quintavalle, Giulia Romano, Loredana Urso, Michela Garofalo, and Mariarosaria Incoronato
- Abstract
Supplementary Figure Legend from miR-212 Increases Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Sensitivity in Non–Small Cell Lung Cancer by Targeting the Antiapoptotic Protein PED
- Published
- 2023
27. Supplementary Figure 1 from miR-212 Increases Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Sensitivity in Non–Small Cell Lung Cancer by Targeting the Antiapoptotic Protein PED
- Author
-
Gerolama Condorelli, Carlo Maria Croce, Gerald Nuovo, Margherita Iaboni, Ciro Zanca, Cristina Quintavalle, Giulia Romano, Loredana Urso, Michela Garofalo, and Mariarosaria Incoronato
- Abstract
Supplementary Figure 1 from miR-212 Increases Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Sensitivity in Non–Small Cell Lung Cancer by Targeting the Antiapoptotic Protein PED
- Published
- 2023
28. Long non-coding RNA HIF1A-As2 and MYC form a double-positive feedback loop to promote cell proliferation and metastasis in KRAS-driven non-small cell lung cancer
- Author
-
Kaixin Yang, Wenyang Zhang, Linghui Zhong, Yinan Xiao, Sudhakar Sahoo, Matteo Fassan, Kang Zeng, Peter Magee, Michela Garofalo, and Lei Shi
- Subjects
Cell Biology ,Molecular Biology - Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the main oncogenic driver in lung cancer that can be activated by gene mutation or amplification, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Through gain and loss of function approaches, we identified that lncRNA HIF1A-As2, a KRAS-induced lncRNA, is required for cell proliferation, epithelial-mesenchymal transition (EMT) and tumor propagation in non-small cell lung cancer (NSCLC) in vitro and in vivo. Integrative analysis of HIF1A-As2 transcriptomic profiling reveals that HIF1A-As2 modulates gene expression in trans, particularly regulating transcriptional factor genes including MYC. Mechanistically, HIF1A-As2 epigenetically activates MYC by recruiting DHX9 on MYC promoter, consequently stimulating the transcription of MYC and its target genes. In addition, KRAS promotes HIF1A-As2 expression via the induction of MYC, suggesting HIF1A-As2 and MYC form a double-regulatory loop to strengthen cell proliferation and tumor metastasis in lung cancer. Inhibition of HIF1A-As2 by LNA GapmeR antisense oligonucleotides (ASO) significantly improves sensitization to 10058-F4 (a MYC-specific inhibitor) and cisplatin treatment in PDX and KRASLSLG12D-driven lung tumors, respectively.
- Published
- 2023
29. Retraction Note: EGFR and MET receptor tyrosine kinase–altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers
- Author
-
Michela Garofalo, Giulia Romano, Gianpiero Di Leva, Gerard Nuovo, Young-Jun Jeon, Apollinaire Ngankeu, Jin Sun, Francesca Lovat, Hansjuerg Alder, Gerolama Condorelli, Jeffrey A. Engelman, Mayumi Ono, Jin Kyung Rho, Luciano Cascione, Stefano Volinia, Kenneth P. Nephew, and Carlo M. Croce
- Subjects
Male ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Gefitinib ,General Medicine ,Proto-Oncogene Proteins c-met ,General Biochemistry, Genetics and Molecular Biology ,Article ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Mice ,MicroRNAs ,Cell Transformation, Neoplastic ,Drug Resistance, Neoplasm ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Quinazolines ,Animals ,Humans ,Cell Proliferation ,Signal Transduction - Abstract
The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ɛ (PKC-ɛ) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.
- Published
- 2022
30. Retraction Notice to: Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development
- Author
-
Flavia Pichiorri, Sung-Suk Suh, Alberto Rocci, Luciana De Luca, Cristian Taccioli, Ramasamy Santhanam, Wenchao Zhou, Don M. Benson, Craig Hofmainster, Hansjuerg Alder, Michela Garofalo, Gianpiero Di Leva, Stefano Volinia, Huey-Jen Lin, Danilo Perrotti, Michael Kuehl, Rami I. Aqeilan, Antonio Palumbo, and Carlo M. Croce
- Subjects
Cancer Research ,Down-Regulation ,Models, Biological ,Article ,Receptor, IGF Type 1 ,Mice ,Cell Movement ,Cell Line, Tumor ,Animals ,Homeostasis ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,Insulin-Like Growth Factor I ,Promoter Regions, Genetic ,Cell Proliferation ,Chromosomes, Human, Pair 11 ,Cell Cycle ,Proto-Oncogene Proteins c-mdm2 ,DNA Methylation ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Oncology ,Tumor Suppressor Protein p53 ,Multiple Myeloma ,Precancerous Conditions ,Mutagens - Abstract
In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development.
- Published
- 2022
31. CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
- Author
-
Manuela La Montagna, Lei Shi, Dave Lee, Alexander R Baker, Peter Magee, Sudhakar Sahoo, Matteo Fassan, Tiziana Monteverde, Robert Sellers, Michela Garofalo, and Hui Sun Leong
- Subjects
0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Transcription Elongation, Genetic ,Carcinogenesis ,Mice, SCID ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,RNA, Small Interfering ,Lung cancer ,E2F ,Oncogene ,Cell growth ,Cancer ,Cell cycle ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Cytoskeletal Proteins ,HEK293 Cells ,030104 developmental biology ,Oncology ,A549 Cells ,Tumor progression ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Adenocarcinoma ,Female - Abstract
Chromosomal instability (CIN) is a driver of clonal diversification and intratumor heterogeneity, providing genetic diversity that contributes to tumor progression. It is estimated that approximately 80% of solid cancers, including non–small cell lung cancer (NSCLC), exhibit features of CIN, which affects tumor growth and response to therapy. However, the molecular mechanisms connecting CIN to tumor progression are still poorly understood. Through an RNAi screen performed on genes involved in CIN and overexpressed in human lung adenocarcinoma samples, we identified the cytoskeleton-associated protein 2-like (CKAP2L) as a potential oncogene that promotes lung cancer proliferation and growth in vitro and in vivo. Mechanistically, CKAP2L directly interacted with RNA Pol II and regulated transcription elongation of key genes involved in spindle assembly checkpoint, chromosome segregation, cell cycle, and E2F signaling. Furthermore, depletion of CKAP2L increased the sensitivity of NSCLC cells to alvocidib, a pan-CDK inhibitor, leading to a significant reduction of cell proliferation and an increase in cell death. Altogether, these findings shed light on the molecular mechanisms through which CKAP2L, a protein involved in CIN, promotes cancer progression and suggest that its inhibition represents a novel therapeutic strategy in NSCLC. Significance: These findings demonstrate the oncogenic function of CKAP2L through regulation of transcription elongation and suggest that targeting CKAP2L could enhance therapeutic response in patients with NSCLC.
- Published
- 2021
32. Mechanisms of drug resistance mediated by long non-coding RNAs in non-small-cell lung cancer
- Author
-
Lucy Ginn, Michela Garofalo, and Manuela La Montagna
- Subjects
0301 basic medicine ,Drug ,Cancer Research ,Chemotherapy ,business.industry ,medicine.medical_treatment ,media_common.quotation_subject ,Drug resistance ,medicine.disease ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer cell ,medicine ,Cancer research ,Molecular Medicine ,Lung cancer ,Carcinogenesis ,business ,Molecular Biology ,Survival rate ,media_common - Abstract
Non-small-cell lung cancer (NSCLC) is the most prevalent form of lung cancer and has a poor five-year survival rate of 15%. Chemotherapy and targeted therapies have significantly improved patients' prognosis. Nevertheless, after a successful initial response, some patients relapse when cancer cells become resistant to drug treatments, representing an important clinical limitation. Therefore, investigating the mechanisms of drug resistance is of significant importance. Recently, considerable attention has been given to long non-coding RNAs (lncRNAs), a heterogeneous class of regulatory molecules that play essential roles in tumorigenesis by modulating genes and signalling pathways involved in cell growth, metastasis and drug response. In this article, we review recent research findings on the role of lncRNAs in drug resistance in NSCLC, highlighting their mechanisms of action.
- Published
- 2020
33. Retraction Notice to: miR-221&222 Regulate TRAIL Resistance and Enhance Tumorigenicity through PTEN and TIMP3 Downregulation
- Author
-
Michela, Garofalo, Gianpiero, Di Leva, Giulia, Romano, Gerard, Nuovo, Sung-Suk, Suh, Apollinaire, Ngankeu, Cristian, Taccioli, Flavia, Pichiorri, Hansjuerg, Alder, Paola, Secchiero, Pierluigi, Gasparini, Arianna, Gonelli, Stefan, Costinean, Mario, Acunzo, Gerolama, Condorelli, and Carlo Maria, Croce
- Subjects
Cancer Research ,Oncology ,Article - Abstract
Lung and liver cancers are among the most deadly types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor, underlining the need for development of targeted therapies. MicroRNAs represent a class of small RNAs, frequently deregulated in human malignancies. We now report that miR221&222 are over-expressed in aggressive non small cell lung cancer and hepatocarcinoma cells, as compared with less invasive and/or normal lung and liver cells. We show that miR-221&222, by targeting PTEN and TIMP3 tumor suppressors, induce TRAIL resistance and enhance cellular migration through the activation of the AKT pathway and metallopeptidases. Finally, we demonstrate that the MET oncogene is involved in miR-221&222 activation, through the c-Jun transcription factor.
- Published
- 2022
34. AMPKα loss promotes KRAS-mediated lung tumorigenesis
- Author
-
Lei Shi, Michela Garofalo, Sudhakar Sahoo, Manuela La Montagna, Matteo Fassan, and Peter Magee
- Subjects
0301 basic medicine ,Lung Neoplasms ,Carcinogenesis ,Mutant ,AMP-Activated Protein Kinases ,medicine.disease_cause ,Article ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Gene silencing ,Animals ,Humans ,Protein kinase A ,Molecular Biology ,Chemistry ,Cell growth ,AMPK ,Cell Biology ,In vitro ,respiratory tract diseases ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,KRAS - Abstract
AMP-activated protein kinase (AMPK) is a critical sensor of energy status that coordinates cell growth with energy balance. In non-small cell lung cancer (NSCLC) the role of AMPKα is controversial and its contribution to lung carcinogenesis is not well-defined. Furthermore, it remains largely unknown whether long non-coding RNAs (lncRNAs) are involved in the regulation of AMPK-mediated pathways. Here, we found that loss of AMPKα in combination with activation of mutant KRAS(G12D) increased lung tumour burden and reduced survival in Kras(LSLG12D/+)/AMPKα(fl/fl) mice. In agreement, functional in vitro studies revealed that AMPKα silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPKα-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPKα activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPKα loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPKα axis that could be exploited for therapeutic purposes.
- Published
- 2021
35. A KRAS-responsive long non-coding RNA controls microRNA processing
- Author
-
Hui Sun Leong, Lei Shi, Stefano Cairo, Francesca Galuppini, Sudhakar Sahoo, Gianpiero Di Leva, D. Smith, Raymond T. O'Keefe, Laura Brulle-Soumare, Matteo Fassan, Robert Sellers, Kang Zeng, Michela Garofalo, Stefano Volinia, Dave Lee, Athanasios R. Paliouras, Tiziana Monteverde, and Peter Magee
- Subjects
0301 basic medicine ,Lung Neoplasms ,endocrine system diseases ,General Physics and Astronomy ,Kaplan-Meier Estimate ,Mice, SCID ,medicine.disease_cause ,Microprocessor complex ,0302 clinical medicine ,Mice, Inbred NOD ,Carcinoma, Non-Small-Cell Lung ,Mice, Knockout ,Multidisciplinary ,Manchester Cancer Research Centre ,R735 ,Long non-coding RNA ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,RNA, Long Noncoding ,Female ,KRAS ,Nucleophosmin ,Lung Neoplasms/genetics ,Science ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Proto-Oncogene Proteins p21(ras) ,Proto-Oncogene Proteins p21(ras)/genetics ,03 medical and health sciences ,Carcinoma, Non-Small-Cell Lung/genetics ,Cell Line, Tumor ,microRNA ,medicine ,Gene silencing ,Animals ,Humans ,RNA, Long Noncoding/genetics ,Lung cancer ,neoplasms ,Gene Expression Profiling ,ResearchInstitutes_Networks_Beacons/mcrc ,Cancer ,General Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,respiratory tract diseases ,MicroRNAs ,MicroRNAs/genetics ,030104 developmental biology ,Gene Ontology ,Xenograft Model Antitumor Assays/methods ,A549 Cells ,Cancer research ,Long non-coding RNAs ,Gene Expression Profiling/methods ,Carcinogenesis ,Non-small-cell lung cancer - Abstract
Wild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRASWT overexpression in lung cancer progression is largely unexplored. Here, we identify and characterize a KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) and show that it correlates with KRAS levels both in cell lines and in lung cancer specimens. Mechanistically, KIMAT1 is a MYC target and drives lung tumorigenesis by promoting the processing of oncogenic microRNAs (miRNAs) through DHX9 and NPM1 stabilization while halting the biogenesis of miRNAs with tumor suppressor function via MYC-dependent silencing of p21, a component of the Microprocessor Complex. KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo. Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis., Wild-type KRAS amplification is known to induce KRAS activation in cancer leading to poor prognostic outcomes. Here the authors identify a KRAS-responsive lncRNA, KIMAT1 that maintains KRAS signalling in lung cancer, suggesting that its targeting may prevent KRAS-driven tumourigenesis.
- Published
- 2021
36. Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells
- Author
-
Dimitrios Solomos, Michela Garofalo, Alexander W I Cox, Ammara Mehmood, Caroline H Topham, Mattia Chiesa, Yuri D'Alessandra, Marta Buzzetti, Sonia Morlando, and Gianpiero Di Leva
- Subjects
Science ,Pyridinium Compounds ,Palbociclib ,Article ,Cyclic N-Oxides ,chemistry.chemical_compound ,Downregulation and upregulation ,RZ ,medicine ,Humans ,Dinaciclib ,Protein Kinase Inhibitors ,Cancer ,Cell Proliferation ,Medulloblastoma ,Multidisciplinary ,Molecular medicine ,business.industry ,Indolizines ,R735 ,medicine.disease ,Cyclin-Dependent Kinases ,Neoplasm Proteins ,chemistry ,Apoptosis ,Cancer research ,Medicine ,Phosphorylation ,Cyclin-dependent kinase 9 ,Drug Screening Assays, Antitumor ,business ,CDK inhibitor - Abstract
Medulloblastoma (MB) is the most common aggressive paediatric brain tumour and, despite the recent progress in the treatments of MB patients, there is still an urgent need of complementary or alternative therapeutic options for MB infants. Cyclin Dependent Kinase inhibitors (CDKi) are at the front-line of novel targeted treatments for multiple cancers and the CDK4/6 specific inhibitor palbociclib has been pre-clinically identified as an effective option for MB cells. Herein, we identified the pan-CDKi dinaciclib as a promising alternative to palbociclib for the suppression of MB cells proliferation. We present evidence supporting dinaciclib’s ability to inhibit MB cells in vitro proliferation at considerably lower doses than palbociclib. Sequencing data and pathway analysis suggested that dinaciclib is a potent cell death inducer in MB cells. We found that dinaciclib-triggered apoptosis is triggered by CDK9 inhibition and the resultant reduction in RNA pol II phosphorylation, which leads to the downregulation of the oncogenic marker MYC, and the anti-apoptotic protein MCL-1. Specifically, we demonstrated that MCL-1 is a key apoptotic mediator for MB cells and co-treatment of dinaciclib with BH3 mimetics boosts the therapeutic efficacy of dinaciclib. Together, these findings highlight the potential of multi-CDK inhibition by dinaciclib as an alternative option to CDK4/6 specific inhibition, frequently associated with drug resistance in patients.
- Published
- 2021
37. Mechanisms of drug resistance mediated by long non-coding RNAs in non-small-cell lung cancer
- Author
-
Manuela, La Montagna, Lucy, Ginn, and Michela, Garofalo
- Subjects
Lung Neoplasms ,Drug Resistance, Neoplasm ,Carcinoma, Non-Small-Cell Lung ,RNA, Long Noncoding - Abstract
Non-small-cell lung cancer (NSCLC) is the most prevalent form of lung cancer and has a poor five-year survival rate of 15%. Chemotherapy and targeted therapies have significantly improved patients' prognosis. Nevertheless, after a successful initial response, some patients relapse when cancer cells become resistant to drug treatments, representing an important clinical limitation. Therefore, investigating the mechanisms of drug resistance is of significant importance. Recently, considerable attention has been given to long non-coding RNAs (lncRNAs), a heterogeneous class of regulatory molecules that play essential roles in tumorigenesis by modulating genes and signalling pathways involved in cell growth, metastasis and drug response. In this article, we review recent research findings on the role of lncRNAs in drug resistance in NSCLC, highlighting their mechanisms of action.
- Published
- 2020
38. Vulnerability of drug‐resistant EML4‐ALK rearranged lung cancer to transcriptional inhibition
- Author
-
Matthew G Krebs, Marta Buzzetti, Michela Garofalo, Lei Shi, Athanasios R. Paliouras, Fiona H Blackhall, Ian J. Donaldson, Peter Magee, Christine M. Lovly, Matteo Fassan, Hui-Sun Leong, Sudhakar Sahoo, Matthew Carter, and Gianpiero Di Leva
- Subjects
0301 basic medicine ,Alectinib ,Medicine (General) ,Lung Neoplasms ,ALKi ,Oncogene Proteins, Fusion ,Transcription, Genetic ,Drug resistance ,QH426-470 ,Biology ,NSCLC ,Article ,RS ,RC0254 ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,R5-920 ,0302 clinical medicine ,Downregulation and upregulation ,Carcinoma, Non-Small-Cell Lung ,hemic and lymphatic diseases ,Genetics ,medicine ,Animals ,Humans ,ALK/EML4 translocation ,CDKi ,drug resistance ,Dinaciclib ,Lung cancer ,Protein Kinase Inhibitors ,Cancer ,Ceritinib ,Crizotinib ,Articles ,Alvocidib ,medicine.disease ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Cancer research ,Molecular Medicine ,Female ,030217 neurology & neurosurgery ,medicine.drug - Abstract
A subset of lung adenocarcinomas is driven by the EML4‐ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on‐target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4‐ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti‐apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first‐, second‐ and third‐generation ALK inhibitors., Acquired drug resistance to ALK inhibitors prevents the effective management of lung cancer. This study shows that treatment with CDK inhibitors may be tested as an alternative upon development of resistance.
- Published
- 2020
39. PDGFR-modulated miR-23b cluster and miR-125a-5p suppress lung tumorigenesis by targeting multiple components of KRAS and NF-kB pathways
- Author
-
Sudhakar Sahoo, Matteo Fassan, Peter Magee, Caroline Dive, Alessandro Laganà, Michela Garofalo, Hui Sun Leong, Justin Middleton, Lei Shi, Kristopher K. Frese, Melanie Galvin, Srivatsava Naidu, and Vincenza Guzzardo
- Subjects
0301 basic medicine ,Male ,Lung Neoplasms ,Carcinogenesis ,Down-Regulation ,lcsh:Medicine ,Antineoplastic Agents ,medicine.disease_cause ,Article ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,microRNA ,medicine ,Gene silencing ,Animals ,Humans ,Receptors, Platelet-Derived Growth Factor ,lcsh:Science ,Lung ,neoplasms ,Regulation of gene expression ,Multidisciplinary ,biology ,Manchester Cancer Research Centre ,ResearchInstitutes_Networks_Beacons/mcrc ,lcsh:R ,Transcription Factor RelA ,Genetic Therapy ,Middle Aged ,Xenograft Model Antitumor Assays ,RALA ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Multigene Family ,biology.protein ,Cancer research ,SOS1 ,lcsh:Q ,KRAS ,Tumor Suppressor Protein p53 ,Platelet-derived growth factor receptor ,Signal Transduction - Abstract
In NSCLC alterations in PDGF receptors are markers of worst prognosis and efficient targeting of these receptors is yet to be achieved. In this study, we explored PDGFR-regulated microRNAs demonstrating that miR-23b cluster and miR-125a-5p are downregulated by increased expression of PDGFR-α or PDGFR-β in NSCLC cells. Mechanistically, the expression of these microRNAs is positively regulated by p53 and negatively modulated by NF-kB p65. Forced expression of miR-23b cluster or miR-125a-5p enhanced drug sensitivity and suppressed invasiveness of NSCLC cells by silencing several genes involved in oncogenic KRAS and NF-kB pathways, including SOS1, GRB2, IQGAP1, RALA, RAF-1, IKKβ, AKT2, ERK2 and KRAS itself. Of note, an inverse correlation between miR-23b cluster, miR-125a-5p and respective target genes was also found in vivo in a large dataset of lung adenocarcinoma samples. Furthermore, in vivo delivery of miR-23b cluster or miR-125a-5p significantly repressed tumour growth in a highly aggressive NSCLC circulating tumour cell (CTC) patient derived explant (CDX) mouse model. In conclusion, our finding sheds light on the PDGFR signaling and endorses the possibility to employ miR-23b cluster and miR-125a-5p as therapeutic tools to silence simultaneously a range of redundant pathways and main effectors of tumorigenesis in NSCLC.
- Published
- 2017
40. Correction: MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer
- Author
-
Cristina Quintavalle, Ciro Zanca, Giulia Romano, Chang Gong Liu, Cristian Taccioli, G Di Leva, Michela Garofalo, Gianluigi Condorelli, and Carlo M. Croce
- Subjects
Cancer Research ,Apoptosis ,microRNA ,Genetics ,medicine ,Cancer research ,Trail resistance ,Non small cell ,Biology ,Lung cancer ,medicine.disease ,Molecular Biology ,Human genetics - Published
- 2021
41. miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC
- Author
-
Ri Cui, Jeff E. Grotzke, Pooja Joshi, Siyeon Rhee, Yonghwan Kim, Nicola Zanesi, Young-Jun Jeon, Youngtae Jeong, Yong Peng, Patrick Nana-Sinkam, Gerard J. Nuovo, Sung Hak Kim, Peter Cresswell, Dongju Park, Sung-Suk Suh, Bum Kyu Lee, Carlo M. Croce, Hosung Sim, Johan Jeong, Taewan Kim, Michela Garofalo, Ichiro Nakano, Jonghwan Kim, Jieun Song, and Guang Liang
- Subjects
0301 basic medicine ,Lung Neoplasms ,Cell ,General Physics and Astronomy ,law.invention ,Mice ,0302 clinical medicine ,law ,Carcinoma, Non-Small-Cell Lung ,Endoplasmic Reticulum-Associated Degradation/genetics ,lcsh:Science ,In Situ Hybridization ,Regulation of gene expression ,Multidisciplinary ,Manchester Cancer Research Centre ,Reverse Transcriptase Polymerase Chain Reaction ,Unfolded Protein Response/genetics ,Endoplasmic Reticulum-Associated Degradation ,3. Good health ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Tumor Suppressor Protein p53/genetics ,Signal Transduction ,Lung Neoplasms/genetics ,Science ,Ubiquitin-Protein Ligases ,Tumor Suppressor Proteins/genetics ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Cell Proliferation/genetics ,Carcinoma, Non-Small-Cell Lung/genetics ,Cell Line, Tumor ,microRNA ,Endoribonucleases/genetics ,Endoribonucleases ,medicine ,Carcinoma ,MicroRNAs/metabolism ,Animals ,Humans ,Ubiquitin-Protein Ligases/genetics ,Membrane Proteins/genetics ,Lung cancer ,Cell Proliferation ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Tumor Suppressor Proteins ,Cancer ,Membrane Proteins ,General Chemistry ,Activating Transcription Factor 6/genetics ,medicine.disease ,Xenograft Model Antitumor Assays ,Activating Transcription Factor 6 ,Gene Expression Regulation, Neoplastic/genetics ,MicroRNAs ,030104 developmental biology ,Unfolded protein response ,Cancer research ,Unfolded Protein Response ,Suppressor ,Signal Transduction/genetics ,lcsh:Q ,Tumor Suppressor Protein p53 ,business - Abstract
Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis., TUSC3 resides on chromosome 8p which is frequently deleted in advanced stage tumors. Here, the authors show that TUSC3 loss mediated by miR-224/-520c promotes NSCLC metastasis where it enhances ATF-6α-dependent UPR and HRD-1 dependent ERAD, which in turn suppress p53-NM23H1/2 tumor suppressor pathway.
- Published
- 2018
42. KRAS induces lung tumorigenesis through microRNAs modulation
- Author
-
Matteo Fassan, Alessandro Laganà, Dario Veneziano, Young-Jun Jeon, Lei Shi, Hui-Sun Leong, Philip A.J. Crosbie, Richard Booton, Michela Garofalo, Rajesh Shah, Justin Middleton, Peter Magee, and Sudhakar Sahoo
- Subjects
0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Carcinogenesis ,Immunology ,Biology ,medicine.disease_cause ,Article ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,ELK1 ,Gene expression ,microRNA ,medicine ,Gene silencing ,Animals ,Humans ,lcsh:QH573-671 ,Lung cancer ,Cisplatin ,Manchester Cancer Research Centre ,lcsh:Cytology ,ResearchInstitutes_Networks_Beacons/mcrc ,Cell Biology ,medicine.disease ,respiratory tract diseases ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,KRAS ,medicine.drug - Abstract
Oncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRASG12D) and using inducible human and mouse cell lines, we analyzed KRAS-regulated microRNAs in non-small-cell lung cancer (NSCLC). We show that miR-30c and miR-21 are significantly upregulated by both KRAS isoforms and induce drug resistance and enhance cell migration/invasion via inhibiting crucial tumor suppressor genes, such as NF1, RASA1, BID, and RASSF8. MiR-30c and miR-21 levels were significantly elevated in tumors from patients that underwent surgical resection of early stages NSCLC compared to normal lung and in plasma from the same patients. Systemic delivery of LNA-anti-miR-21 in combination with cisplatin in vivo completely suppressed the development of lung tumors in a mouse model of lung cancer. Mechanistically, we demonstrated that ELK1 is responsible for miR-30c and miR-21 transcriptional activation by direct binding to the miRNA proximal promoter regions. In summary, our study defines that miR-30c and miR-21 may be valid biomarkers for early NSCLC detection and their silencing could be beneficial for therapeutic applications.
- Published
- 2018
43. Oncogene-induced regulation of microRNA expression: Implications for cancer initiation, progression and therapy
- Author
-
Athanasios R. Paliouras, Tiziana Monteverde, and Michela Garofalo
- Subjects
0301 basic medicine ,Cancer Research ,Oncogene ,Cancer ,Oncogenes ,Biology ,medicine.disease ,Oncogene Addiction ,Metastasis ,Malignant transformation ,03 medical and health sciences ,MicroRNAs ,030104 developmental biology ,Signalling ,Oncology ,Neoplasms ,microRNA ,Gene expression ,Cancer research ,medicine ,Disease Progression ,Humans - Abstract
A plethora of tumours have characteristic oncogenic mutations which are the main causes of malignant transformation, exerting their effects through multiple signalling pathways. Downstream of such pathways, microRNAs are small non-coding RNAs that negatively regulate gene expression, assisting or antagonizing oncogenic signalling. The differential expression of microRNAs in cancer is well-documented and is considered a fundamental aspect of tumourigenesis. While data mapping the interaction between oncogenic lesions and microRNAs are accruing, we provide particular cases of such interaction. Except for notable, well-studied examples of microRNAs regulated by oncogenes, we examine the effect of this relationship in regard to tumour initiation, progression, metastasis and ultimately, its implications for the development of new therapeutics.
- Published
- 2017
44. MicroRNA-148a reduces tumorigenesis and increases TRAIL-induced apoptosis in NSCLC
- Author
-
Michela Garofalo, Alessandro Laganà, Justin Middleton, Carlo M. Croce, Young-Jun Jeon, Paola Secchiero, and Pooja Joshi
- Subjects
chemoresistance, lung cancer, microRNA ,Lung Neoplasms ,Carcinogenesis ,Apoptosis ,Biology ,medicine.disease_cause ,NO ,TNF-Related Apoptosis-Inducing Ligand ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,microRNA ,medicine ,Humans ,ROCK1 ,Lung cancer ,Multidisciplinary ,Kinase ,chemoresistance ,Cancer ,DNA Methylation ,Biological Sciences ,medicine.disease ,Molecular biology ,lung cancer ,MicroRNAs ,Cancer research ,MMP15 - Abstract
Nonsmall cell lung cancer (NSCLC) is one of the leading causes of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells without inducing significant toxicity in normal cells. However, several carcinomas, including lung cancer, remain resistant to TRAIL. MicroRNAs (miRNAs) are small noncoding RNAs of ∼ 24 nt that block mRNA translation and/or negatively regulate its stability. They are often aberrantly expressed in cancer and have been implicated in increasing susceptibility or resistance to TRAIL-induced apoptosis by inhibiting key functional proteins. Here we show that miR-148a is down-regulated in cells with acquired TRAIL-resistance compared with TRAIL-sensitive cells. Enforced expression of miR-148a sensitized cells to TRAIL and reduced lung tumorigenesis in vitro and in vivo through the down-modulation of matrix metalloproteinase 15 (MMP15) and Rho-associated kinase 1 (ROCK1). These findings suggest that miR-148a acts as a tumor suppressor and might have therapeutic application in the treatment of NSCLC.
- Published
- 2015
45. MicroRNAs in lung tumorigenesis and chemoresistance
- Author
-
L. Shi, Michela Garofalo, and Srivatsava Naidu
- Subjects
Lung ,medicine.anatomical_structure ,microRNA ,Cancer research ,medicine ,General Medicine ,Biology ,Carcinogenesis ,medicine.disease_cause - Published
- 2015
46. RETRACTED: Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development
- Author
-
Wenchao Zhou, Danilo Perrotti, Luciana De Luca, Flavia Pichiorri, Gianpiero Di Leva, Ramasamy Santhanam, Alberto Rocci, Rami I. Aqeilan, Cristian Taccioli, Hansjuerg Alder, Craig Hofmainster, Sung Suk Suh, Carlo M. Croce, Michael Kuehl, Huey Jen Lin, Don M. Benson, Antonio Palumbo, Michela Garofalo, and Stefano Volinia
- Subjects
0301 basic medicine ,Cancer Research ,Biology ,medicine.disease ,Molecular biology ,P53 mdm2 ,Loop (topology) ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,Cancer cell ,microRNA ,medicine ,Cancer research ,Multiple myeloma - Published
- 2016
47. MicroRNAs in Cancer
- Author
-
Carlo M. Croce, Gianpiero Di Leva, and Michela Garofalo
- Subjects
Transcription, Genetic ,Cell ,RNA ,Apoptosis ,Biology ,Bioinformatics ,Article ,Microvesicles ,Pathology and Forensic Medicine ,Cell biology ,MicroRNAs ,medicine.anatomical_structure ,Neoplasms ,Cancer cell ,microRNA ,medicine ,Animals ,Humans ,Gene silencing ,RNA, Messenger ,Signal transduction ,Biogenesis ,Signal Transduction - Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in cellular processes such as inflammation, cell-cycle regulation, stress response, differentiation, apoptosis, and migration. Thus, miRNAs have been implicated in the regulation of virtually all signaling circuits within a cell, and their dysregulation has been shown to play an essential role in the development and progression of cancer. Here, after a brief description of miRNA genomics, biogenesis, and function, we discuss the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies.
- Published
- 2014
48. Abstract 4761: Transcriptomic overview of EML4-ALK lung cancer cells resistant to ALK inhibitors highlights a vulnerability to CDK inhibitors
- Author
-
Fiona H Blackhall, Athanasios R. Paliouras, Sudhakar Sahoo, Matthew G Krebs, Peter Magee, Hui Sun Leong, Christine M. Lovly, and Michela Garofalo
- Subjects
Cancer Research ,biology ,Crizotinib ,Cell growth ,business.industry ,Kinase ,Cancer ,medicine.disease ,Transcriptome ,Oncology ,Cyclin-dependent kinase ,hemic and lymphatic diseases ,biology.protein ,Cancer research ,Medicine ,Cyclin-dependent kinase 6 ,business ,Lung cancer ,medicine.drug - Abstract
Introduction: EML4-ALK-driven lung cancer represents about 5% of lung adenocarcinomas. Despite the constant expansion of the armamentarium to inhibit ALK, patients typically develop acquired resistance to ALK inhibitors. In the case of resistance mediated by ALK mutations, sequencing of ALK inhibitors is recommended, but in ALK wild-type patients, a better understanding of acquired resistance, as well as new therapeutic strategies are needed. Here, we aimed to characterize the transcriptional network of EML4-ALK lung cancer and used these data to address acquired resistance to ALK inhibitors. Methods: We utilized EML4-ALK cell lines treated long-term with ALK inhibitors as a model of acquired resistance. Transcriptomic changes were quantified through means of RNA-seq or RT-qPCR. Results: We have found a dysregulation of several microRNAs in crizotinib-resistant cells. Specifically, the oncogenic miR-25 and miR-30c were upregulated and their inhibition resulted in cell cycle arrest. We analyzed plasma samples from patients with EML4-ALK lung cancer and found increased circulating levels of these miRNAs in 2 patients upon progression with crizotinib. In addition, the known tumour-suppressing miRNAs miR-103a and miR-149 were downregulated in crizotinib-resistant cells and restoration of miR-149 resulted in apoptotic induction. We show that CDK6 is a direct target of miR-103 and an indirect target of miR-149. Moreover, by comparing the transcriptome of parental and crizotinib-resistant cells we uncovered an upregulation of genes implicated in cell cycle. Treatment with Cyclin-Dependent Kinase (CDK) inhibitors led to suppression of cell proliferation and potent induction of apoptosis. Moreover, these inhibitors spared normal epithelial cells while they induced higher levels of apoptosis in EML4-ALK cells compared with other NSCLC cell lines, suggesting a preferential targeting of EML4-ALK cells .Lastly, a pilot xenograft experiment with a crizotinib-resistant cell line showed in vivo anti-tumor activity of CDK inhibition and we are currently expanding this in a larger mouse cohort. Conclusions: Crizotinib-resistant cells may exhibit several concurrent oncogenic alterations including miRNA- or coding gene-dysregulation, in the absence of ALK mutations. Moreover, the contribution of these alterations to acquired resistance cannot be easily and quickly assessed. A therapeutic intervention which does not rely on identifying the driver of resistance would be of high practical value. We suggest that CDK inhibition may be a new avenue to target relapsed EML4-ALK lung cancer refractory to ALK inhibitors. Citation Format: Athanasios R. Paliouras, Peter Magee, Sudhakar Sahoo, Hui Sun Leong, Matthew Krebs, Fiona Blackhall, Christine M. Lovly, Michela Garofalo. Transcriptomic overview of EML4-ALK lung cancer cells resistant to ALK inhibitors highlights a vulnerability to CDK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4761.
- Published
- 2019
49. Idiopathic pulmonary fibrosis is strongly associated with productive infection by herpesvirus saimiri
- Author
-
Gerard J. Nuovo, Virginia A Folcik, James J. Donegan, Elazar Rabbani, Gianpiero Di Leva, Jack Coleman, Allison Nuovo, Michela Garofalo, Saul Suster, and Cynthia M. Magro
- Subjects
Male ,Pathology ,medicine.medical_specialty ,DNA polymerase ,Cyclin D ,viruses ,In situ hybridization ,Q1 ,Pathology and Forensic Medicine ,Herpesvirus 2, Saimiriine ,herpesvirus saimiri ,Idiopathic pulmonary fibrosis ,Pulmonary fibrosis ,medicine ,Humans ,cyclin D ,Gene ,In Situ Hybridization ,Aged ,Lung ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,RNA ,Herpesviridae Infections ,Middle Aged ,medicine.disease ,idiopathic pulmonary fibrosis ,R1 ,IL-17 ,medicine.anatomical_structure ,Immunology ,DNA, Viral ,biology.protein ,Original Article ,Female - Abstract
Idiopathic pulmonary fibrosis is a fatal disease without effective therapy or diagnostic test. To investigate a\ud potential role for c�herpesviruses in this disease, 21 paraffin-embedded lung biopsies from patients diagnosed\ud with idiopathic pulmonary fibrosis and 21 lung biopsies from age-matched controls with pulmonary fibrosis of\ud known etiology were examined for a series of c�herpesviruses’ DNA/RNA and related proteins using in situ\ud hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR)-based methods. We detected four\ud proteins known to be in the genome of several c�herpesviruses (cyclin D, thymidylate synthase, dihydrofolate\ud reductase, and interleukin-17) that were strongly co-expressed in the regenerating epithelial cells of each of the\ud 21 idiopathic pulmonary fibrosis cases and not in the benign epithelia of the controls. Among the c�\ud herpesviruses, only herpesvirus saimiri expresses all four of these ‘pirated’ mammalian proteins. We found\ud herpesvirus saimiri DNA in the regenerating epithelial cells of 21/21 idiopathic pulmonary fibrosis cases using\ud four separate probe sets but not in the 21 controls. RT-PCR showed that the source of the cyclin D RNA in active\ud idiopathic pulmonary fibrosis was herpesvirus saimiri and not human. We cloned and sequenced part of\ud genome corresponding to the DNA polymerase herpesvirus saimiri gene from an idiopathic pulmonary fibrosis\ud sample and it matched 100% with the published viral sequence. These data are consistent with idiopathic\ud pulmonary fibrosis representing herpesvirus saimiri-induced pulmonary fibrosis. Thus, treatment directed\ud against viral proliferation and/or viral-associated proteins may halt disease progression. Further, demonstration\ud of the viral nucleic acids or proteins may help diagnose the disease.
- Published
- 2013
50. Non-Coding RNAs and Cancer
- Author
-
Federica Calore, Francesca Lovat, and Michela Garofalo
- Subjects
RNA, Untranslated ,Carcinogenesis ,Review ,Biology ,Bioinformatics ,medicine.disease_cause ,Catalysis ,lcsh:Chemistry ,Inorganic Chemistry ,long non-coding RNAs ,Neoplasms ,microRNA ,medicine ,Animals ,Humans ,cancer ,Genes, Tumor Suppressor ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Gene ,Spectroscopy ,Regulation of gene expression ,Organic Chemistry ,RNA ,Cancer ,General Medicine ,medicine.disease ,Long non-coding RNA ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,lcsh:Biology (General) ,lcsh:QD1-999 ,small non-coding RNAs - Abstract
The discovery of the biological relevance of non-coding RNA (ncRNAs) molecules represents one of the most significant advances in contemporary molecular biology. Expression profiling of human tumors, based on the expression of miRNAs and other short or long ncRNAs, has identified signatures associated with diagnosis, staging, progression, prognosis, and response to treatment. In this review we will discuss the recent remarkable advancement in the understanding the biological functions of human ncRNAs in cancer, the mechanisms of expression and the therapeutic potential.
- Published
- 2013
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.