Chiara Brignola, Annalisa Pecoraro, Camilla Danisi, Nunzia Iaccarino, Anna Di Porzio, Francesca Romano, Pietro Carotenuto, Giulia Russo, and Annapina Russo
Subjects
drug resistance, cancer redox metabolic reprogramming, SLC7A11/xCT, ferroptosis, ribosomal protein uL3, CAM assay, Therapeutics. Pharmacology, RM1-950
Abstract
Despite advancements in therapeutic strategies, the development of drug resistance and metastasis remains a serious concern for the efficacy of chemotherapy against colorectal cancer (CRC). We have previously demonstrated that low expression of ribosomal protein uL3 positively correlates with chemoresistance in CRC patients. Here, we demonstrated that the loss of uL3 increased the metastatic capacity of CRC cells in chick embryos. Metabolomic analysis revealed large perturbations in amino acid and glutathione metabolism in resistant uL3-silenced CRC cells, indicating that uL3 silencing dramatically triggered redox metabolic reprogramming. RNA-Seq data revealed a notable dysregulation of 108 genes related to ferroptosis in CRC patients. Solute Carrier Family 7 Member 11 (SLC7A11) is one of the most dysregulated genes; its mRNA stability is negatively regulated by uL3, and its expression is inversely correlated with uL3 levels. Inhibition of SLC7A11 with erastin impaired resistant uL3-silenced CRC cell survival by inducing ferroptosis. Of interest, the combined treatment erastin plus uL3 enhanced the chemotherapeutic sensitivity of uL3-silenced CRC cells to erastin. The antimetastatic potential of the combined strategy was evaluated in chick embryos. Overall, our study sheds light on uL3-mediated chemoresistance and provides evidence of a novel therapeutic approach, erastin plus uL3, to induce ferroptosis, establishing individualized therapy by examining p53, uL3 and SLC7A11 profiles in tumors.
Anna Barbato, Fabiola Piscopo, Massimiliano Salati, Luca Reggiani-Bonetti, Brunella Franco, and Pietro Carotenuto
Subjects
non-coding RNA, microRNA, bile duct cancer, precision medicine, Pathology, RB1-214
Abstract
Bile-duct cancers (BDC) are a group of solid tumors arising from the biliary tree. Despite their classification as rare cancers, the incidence of BDC is increasing worldwide. Poor prognosis is a common feature of this type of cancer and is mainly determined by the following factors: late diagnosis, lack of effective therapeutic approaches, and resistance to conventional treatments. In the past few years, next-generation sequencing technologies has allowed us to study the genome, exome, and transcriptome of BDC deeper, revealing a previously underestimated class of RNA: the noncoding RNA (ncRNA). MicroRNAs (miRNAs) are small ncRNAs that play an important regulatory role in gene expression. The aberrant expression of miRNAs and their pivotal role as oncogenes or tumor suppressors in biliary carcinogenesis has been widely described in BDC. Due to their ability to regulate multiple gene networks, miRNAs are involved in all cancer hallmarks, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, activating invasion and metastasis, reprogramming cellular metabolism, and avoiding immune destruction. Their use as diagnostic, prognostic, and predictive biomarkers has been widely explored in several human cancers, including BDC. Furthermore, miRNA-based therapeutic strategies are currently the subject of numerous clinical trials that are providing evidence of their efficacy as potent anticancer agents. In this review, we will provide a detailed update of miRNAs affecting BDC, discussing their regulatory function in processes underlying the molecular pathology of BDC. Finally, an overview of their potential use as biomarkers or therapeutic tools in BDC will be further addressed.
Pietro Carotenuto, Francesco Amato, Andrea Lampis, Colin Rae, Somaieh Hedayat, Maria C. Previdi, Domenico Zito, Maya Raj, Vincenza Guzzardo, Francesco Sclafani, Andrea Lanese, Claudia Parisi, Caterina Vicentini, Ian Said-Huntingford, Jens C. Hahne, Albert Hallsworth, Vladimir Kirkin, Kate Young, Ruwaida Begum, Andrew Wotherspoon, Kyriakos Kouvelakis, Sergio Xavier Azevedo, Vasiliki Michalarea, Rosie Upstill-Goddard, Sheela Rao, David Watkins, Naureen Starling, Anguraj Sadanandam, David K. Chang, Andrew V. Biankin, Nigel B. Jamieson, Aldo Scarpa, David Cunningham, Ian Chau, Paul Workman, Matteo Fassan, Nicola Valeri, and Chiara Braconi
Subjects
Science
Abstract
Understanding which patients will respond to FOLFIRINOX therapy is important for clinical outcome. Here, the authors show that the MIR1307 is increased pancreatic cancer cell lines and inhibition of the microRNA sensitises cells to treatment.’ stratifying patients to achieve the best clinical outcome. Here, the authors show that the MIR1307 is increased in a subgroup of human pancreatic cancers and inhibition of the microRNA in in vitro and in vivo models of pancreatic cancer sensitises cells to treatment.
Kishor Pant, Seth Richard, Estanislao Peixoto, Jun Yin, Davis M. Seelig, Pietro Carotenuto, Massimiliano Salati, Brunella Franco, Lewis R. Roberts, and Sergio A. Gradilone
It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5′-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study’s findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin.
nanoparticle, β-carotene, Drug Discovery, Pharmaceutical Science, Molecular Medicine, chemoresistance, colorectal cancer, ribosomal protein uL3
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Despite recent therapeutic advancements, resistance to 5-fluorouracil (5-FU) remains a major obstacle to the successful treatment of this disease. We have previously identified the ribosomal protein uL3 as a key player in the cell response to 5-FU, and loss of uL3 is associated with 5-FU chemoresistance. Natural products, like carotenoids, have shown the ability to enhance cancer cell response to drugs and may provide a safer choice to defeat chemoresistance in cancer. Transcriptome analysis of a cohort of 594 colorectal patients revealed a correlation between uL3 expression and both progression-free survival and response to treatment. RNA-Seq data from uL3-silenced CRC cells demonstrated that a low uL3 transcriptional state was associated with an increased expression of specific ATP-binding cassette (ABC) genes. Using two-dimensional (2D) and three-dimensional (3D) models of 5-FU-resistant CRC cells stably silenced for uL3, we investigated the effect of a novel therapeutic strategy by combining β-carotene and 5-FU using nanoparticles (NPs) as a drug delivery system. Our results indicated that the combined treatment might overcome 5-FU chemoresistance, inducing cell cycle arrest in the G2/M phase and apoptosis. Furthermore, the combined treatment significantly reduced the expression levels of analyzed ABC genes. In conclusion, our findings suggest that β-carotene combined with 5-FU may be a more effective therapeutic approach for treating CRC cells with low levels of uL3.
The nucleolus is a distinct sub-cellular compartment structure in the nucleus. First observed more than 200 years ago, the nucleolus is detectable by microscopy in eukaryotic cells and visible during the interphase as a sub-nuclear structure immersed in the nucleoplasm, from which it is not separated from any membrane. A huge number of studies, spanning over a century, have identified ribosome biogenesis as the main function of the nucleolus. Recently, novel functions, independent from ribosome biogenesis, have been proposed by several proteomic, genomic, and functional studies. Several works have confirmed the non-canonical role for nucleoli in regulating important cellular processes including genome stability, cell-cycle control, the cellular senescence, stress responses, and biogenesis of ribonucleoprotein particles (RNPs). Many authors have shown that both canonical and non-canonical functions of the nucleolus are associated with several cancer-related processes. The association between the nucleolus and cancer, first proposed by cytological and histopathological studies showing that the number and shape of nucleoli are commonly altered in almost any type of cancer, has been confirmed at the molecular level by several authors who demonstrated that numerous mechanisms occurring in the nucleolus are altered in tumors. Recently, therapeutic approaches targeting the nucleolus in cancer have started to be considered as an emerging “hallmark” of cancer and several therapeutic interventions have been developed. This review proposes an up-to-date overview of available strategies targeting the nucleolus, focusing on novel targeted therapeutic approaches. Finally, a target-based classification of currently available treatment will be proposed.
Pietro Carotenuto, Cristin Roma, Anna Maria Rachiglio, and et al
Subjects
Therapeutics. Pharmacology, RM1-950
Abstract
Pietro Carotenuto1, Cristin Roma1, Anna Maria Rachiglio1, Raffaella Pasquale1, Renato Franco2, Giuseppe Antinolfi3, Francovito Piantedosi4, Alfonso Illiano5, Gerardo Botti2, Alessandro Morabito6, Nicola Normanno7, Antonella De Luca71Pharmacogenomic Laboratory, CROM – Centro Ricerche Oncologiche di Mercogliano, Avellino, Italy; 2Surgical Pathology Unit, INT Fondazione "G. Pascale", Naples, Italy; 3Surgical Pathology Unit, Monaldi Hospital, Naples, Italy; 4Pneumoncology DH Unit, Monaldi Hospital, Naples, Italy; 5Pneumoncology Unit, Monaldi Hospital, Naples, Italy; 6Medical Oncology, Thoracic Department, INT Fondazione "G. Pascale", Naples, Italy; 7Cell Biology and Biotherapy Unit, INT Fondazione "G. Pascale", Naples, ItalyAbstract: The epidermal growth factor receptor (EGFR) is expressed in the majority of non-small-cell lung cancer (NSCLC). However, only a restricted subgroup of NSCLC patients respond to treatment with the EGFR tyrosine kinase inhibitor (EGFR TKI) gefitinib. Clinical trials have demonstrated that patients carrying activating mutations of the EGFR significantly benefit from treatment with gefitinib. In particular, mutations of the EGFR TK domain have been shown to increase the sensitivity of the EGFR to exogenous growth factors and, at the same time, to EGFR TKIs such as gefitinib. EGFR mutations are more frequent in patients with particular clinical and pathological features such as female sex, nonsmoker status, adenocarcinoma histology, and East Asian ethnicity. A close correlation was found between EGFR mutations and response to gefitinib in NSCLC patients. More importantly, randomized Phase III studies have shown the superiority of gefitinib compared with chemotherapy in EGFR mutant patients in the first-line setting. In addition, gefitinib showed a good toxicity profile with an incidence of adverse events that was significantly lower compared with chemotherapy. Therefore, gefitinib is a major breakthrough for the management of EGFR mutant NSCLC patients and represents the first step toward personalized treatment of NSCLC.Keywords: gefitinib, EGFR, NSCLC, EGFR mutations
Pietro Carotenuto, Alessia Romano, Anna Barbato, Paola Quadrano, Simona Brillante, Mariagrazia Volpe, Luigi Ferrante, Roberta Tammaro, Manuela Morleo, Rossella De Cegli, Antonella Iuliano, Marialuisa Testa, Fabrizio Andreone, Gennaro Ciliberto, Eduardo Clery, Giancarlo Troncone, Giuseppe Palma, Claudio Arra, Antonio Barbieri, Mariaelena Capone, Gabriele Madonna, Paolo A. Ascierto, Luisa Lanfrancone, Alessia Indrieri, Brunella Franco, Carotenuto, Pietro, Romano, Alessia, Barbato, Anna, Quadrano, Paola, Brillante, Simona, Volpe, Mariagrazia, Ferrante, Luigi, Tammaro, Roberta, Morleo, Manuela, De Cegli, Rossella, Iuliano, Antonella, Testa, Marialuisa, Andreone, Fabrizio, Ciliberto, Gennaro, Clery, Eduardo, Troncone, Giancarlo, Palma, Giuseppe, Arra, Claudio, Barbieri, Antonio, Capone, Mariaelena, Madonna, Gabriele, Ascierto, Paolo A, Lanfrancone, Luisa, Indrieri, Alessia, and Franco, Brunella
Subjects
Salvage Therapy, Microphthalmia-Associated Transcription Factor, Apoptosi, Protein Kinase Inhibitor, Apoptosis, melanoma drug resistance, MAPK inhibitors, drug repositioning, MITF, APAF-1, epigenetic drugs, apoptosome, drug repositioning, apoptosome-independent cell death, General Biochemistry, Genetics and Molecular Biology, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Humans, Protein Kinase Inhibitors, CP: Cancer, Melanoma, Human
Abstract
Melanoma is a deadly form of cancer characterized by remarkable therapy resistance. Analyzing the transcriptome of MAPK inhibitor sensitive- and resistant-melanoma, we discovered that APAF-1 is negatively regulated by MITF in resistant tumors. This study identifies the MITF/APAF-1 axis as a molecular driver of MAPK inhibitor resistance. A drug-repositioning screen identified quinacrine and methylbenzethonium as potent activators of apoptosis in a context that mimics drug resistance mediated by APAF-1 inactivation. The compounds showed anti-tumor activity in invitro and invivo models, linked to suppression of MITF function. Both drugs profoundly sensitize melanoma cells to MAPK inhibitors, regulating key signaling networks in melanoma, including the MITF/APAF-1 axis. Significant activity of the two compounds in inhibiting specific epigenetic modulators of MITF/APAF-1 expression, such as histone deacetylases, was observed. In summary, we demonstrate that targeting the MITF/APAF-1 axis may overcome resistance and could be exploited as a potential therapeutic approach to treat resistant melanoma.
Massimiliano Salati, Luigi Marcheselli, Carlo Messina, Valeria Merz, Marco Messina, Pietro Carotenuto, Francesco Caputo, Fabio Gelsomino, Andrea Spallanzani, Luca Reggiani Bonetti, Stefania Caramaschi, Gabriele Luppi, Massimo Dominici, and Michele Ghidini
Subjects
Biliary tract cancer, Chemotherapy, Prognostic score, Second-line, Survival, Oncology, Cancer Management and Research
Abstract
Massimiliano Salati,1,2 Luigi Marcheselli,1 Carlo Messina,3 Valeria Merz,3,4 Marco Messina,5 Pietro Carotenuto,6 Francesco Caputo,1 Fabio Gelsomino,1 Andrea Spallanzani,1 Luca Reggiani Bonetti,7 Stefania Caramaschi,7 Gabriele Luppi,1 Massimo Dominici,1 Michele Ghidini8 1Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; 2PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy; 4Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy; 5Oncology Unit, Fondazione San Raffaele-Giglio, Cefaluâ, Palermo, Italy; 6Telethon Institute of Genetics and Medicine, Pozzuoli, 80078, Napoli, Italy; 7Pathology Section, University Hospital of Modena, Modena, Italy; 8Medical Oncology Unit, Fondazione IRCCS Caâ Granda Ospedale Maggiore Policlinico, Milan, ItalyCorrespondence: Massimiliano Salati, PhD Program Clinical and Experimental Medicine, University Hospital of Modena, Modena Cancer Centre, via del Pozzo 71, Modena, 41125, Italy, Tel +39/0594223808, Fax +39/0594222647, Email massimiliano.salati@unimore.itBackground: The role of second-line chemotherapy in advanced biliary cancers (ABCs) has only recently been established in phase III randomized trial and the optimal selection of patients most likely to benefit from it remains challenging.Methods: A cohort of 98 ABC treated second-line chemotherapy was used as a developmental dataset to identify covariates independently associated with overall survival (OS). KaplanâMeier analysis was used to investigate the association between variables and OS and those retaining statistically significance were combined in a multiplexed score.Results: The following pretreatment variables were independently associated with OS: ECOG PS > 0, peritoneal disease, LDH > 430 UI/L, albumin < 3.5 gr/dL, gamma-GT > 100 UI/L, sodium < 140 mEq/L, absolute lymphocyte count < 1000/mmc, and PFS to first-line < 6 months. Based on these results, a scoring system was developed that identified three subgroups with statistically different OS: low-risk (mOS 18 months), intermediate-risk (mOS 9.4 months) and high-risk (mOS 2.9 months) (p < 0.001). The prognostic model was both internally and externally validated in a multicentre cohort of 120 ABCs.Conclusion: The Modena score is a multiplexed scoring system capable of accurately risk-stratified ABCs treated with second-line chemotherapy. Based on its reproducibility, usability and generalizability, it has the potential for assisting therapeutic decision-making in the clinic and risk-stratification in future trials.Graphical Abstract: Keywords: biliary tract cancer, chemotherapy, second-line, prognostic score, survival
Francesco Caputo, Massimo Dominici, Cinzia Baldessari, Luca Reggiani Bonetti, Massimiliano Salati, Stefania Caramaschi, Marco Messina, Pietro Carotenuto, Salati, M., Caputo, F., Baldessari, C., Carotenuto, P., Messina, M., Caramaschi, S., Dominici, M., and Bonetti, L. R.
Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Druggability, Phases of clinical research, Disease, Review, Targeted therapy, Cholangiocarcinoma, Internal medicine, medicine, Biliary cancer, RC254-282, Intrahepatic Cholangiocarcinoma, Intrahepatic, Chemotherapy, Massive parallel sequencing, business.industry, Precision medicine, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, FGFR2, business
Abstract
Massimiliano Salati,1,2 Francesco Caputo,1 Cinzia Baldessari,1 Pietro Carotenuto,3 Marco Messina,4 Stefania Caramaschi,5 Massimo Dominici,1 Luca Reggiani Bonetti5 1Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; 2PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Department of Genomics, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; 4Department of Oncology, Fondazione Istituto G. Giglio, Cefalu, Italy; 5Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia – AOU Policlinico of Modena, Modena, ItalyCorrespondence: Massimiliano SalatiDepartment of Oncology and Hematology, University Hospital of Modena, Via del Pozzo 71, Modena, 41125, ItalyTel +390594223808Fax +390594222647Email massimiliano.salati@unimore.itAbstract: Intrahepatic cholangiocarcinoma (iCCA) is an anatomically and biologically distinct entity with a rising incidence and a poor prognosis on conventional treatments. Surgery followed by adjuvant chemotherapy is a potentially curative option in resectable cases, while palliative-intent chemotherapy is the standard-of-care in the advanced setting. Technological advances through massive parallel sequencing have enabled a deeper understanding of disease biology with the identification of several druggable molecular vulnerabilities in nearly 50% of cases. Among them, gene fusions involving the fibroblast growth factor receptor 2 (FGFR2) are the most therapeutically exploited so far with a number of Phase II clinical trials investigating FGFR2 inhibitors showing unprecedented efficacy results in this molecular subgroup. Over the last year, these efforts have culminated in the US FDA-approval of pemigatinib and infigratinib, the first two oral selective FGFR2 targeted agents for previously treated, locally advanced or metastatic iCCA driven by FGFR2 fusion or rearrangements. While first-line Phase III trials are currently underway to test these targeted approach against standard-of-care chemotherapy, translational studies are trying to better understand primary and secondary resistance mechanisms in order to optimize FGFR2 blockade in iCCA. In this article, we extensively reviewed the current evidence on the biological rationale, as well as preclinical and clinical development of FGFR inhibitors in iCCA.Keywords: biliary cancer, cholangiocarcinoma, intrahepatic, FGFR2, targeted therapy, precision medicine
Sabrina Carrella, Brunella Franco, Alessia Indrieri, Pietro Carotenuto, Sandro Banfi, Indrieri, A., Carrella, S., Carotenuto, P., Banfi, S., and Franco, B.
Subjects
microrna, parkinson’s disease, Review, Biology, Catalysis, Inorganic Chemistry, Pathogenesis, lcsh:Chemistry, Neoplasms, microRNA, medicine, Humans, cancer, RNA, Neoplasm, Physical and Theoretical Chemistry, Molecular Biology, lcsh:QH301-705.5, Spectroscopy, Cell Proliferation, Regulation of gene expression, Organic Chemistry, Autophagy, Neurodegeneration, central nervous system development, neurodegeneration, Cancer, Neurodegenerative Diseases, embryo development, alzheimer’s disease, General Medicine, mir-181, medicine.disease, Computer Science Applications, mitochondria, MicroRNAs, lcsh:Biology (General), lcsh:QD1-999, Signal transduction, Neuroscience, Function (biology)
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs playing a fundamental role in the regulation of gene expression. Evidence accumulating in the past decades indicate that they are capable of simultaneously modulating diverse signaling pathways involved in a variety of pathophysiological processes. In the present review, we provide a comprehensive overview of the function of a highly conserved group of miRNAs, the miR-181 family, both in physiological as well as in pathological conditions. We summarize a large body of studies highlighting a role for this miRNA family in the regulation of key biological processes such as embryonic development, cell proliferation, apoptosis, autophagy, mitochondrial function, and immune response. Importantly, members of this family have been involved in many pathological processes underlying the most common neurodegenerative disorders as well as different solid tumors and hematological malignancies. The relevance of this miRNA family in the pathogenesis of these disorders and their possible influence on the severity of their manifestations will be discussed. A better understanding of the miR-181 family in pathological conditions may open new therapeutic avenues for devasting disorders such as neurodegenerative diseases and cancer.
Giulia Russo, Annapina Russo, Pietro Carotenuto, Annalisa Pecoraro, Rossella De Cegli, Brunella Franco, Pecoraro, A., Carotenuto, P., Franco, B., De Cegli, R., Russo, G., and Russo, A.
The nucleolus is the site of ribosome biogenesis and has been recently described as important sensor for a variety of cellular stressors. In the last two decades, it has been largely demonstrated that many chemotherapeutics act by inhibiting early or late rRNA processing steps with consequent alteration of ribosome biogenesis and activation of nucleolar stress response. The overall result is cell cycle arrest and/or apoptotic cell death of cancer cells. Our previously data demonstrated that ribosomal protein uL3 is a key sensor of nucleolar stress activated by common chemotherapeutic agents in cancer cells lacking p53. We have also demonstrated that uL3 status is associated to chemoresistance, down-regulation of uL3 makes some chemotherapeutic drugs ineffective. Here, we demonstrate that in colon cancer cells, the uL3 status affects rRNA synthesis and processing with consequent activation of uL3-mediated nucleolar stress pathway. Transcriptome analysis of HCT 116p53&minus, /&minus, cells expressing uL3 and of a cell sub line stably depleted of uL3 treated with Actinomycin D suggests a new extra-ribosomal role of uL3 in the regulation of autophagic process. By using confocal microscopy and Western blotting experiments, we demonstrated that uL3 acts as inhibitory factor of autophagic process, the absence of uL3 is associated to increase of autophagic flux and to chemoresistance. Furthermore, experiments conducted in presence of chloroquine, a known inhibitor of autophagy, indicate a role of uL3 in chloroquine-mediated inhibition of autophagy. On the basis of these results and our previous findings, we hypothesize that the absence of uL3 in cancer cells might inhibit cancer cell response to drug treatment through the activation of cytoprotective autophagy. The restoration of uL3 could enhance the activity of many drugs thanks to its pro-apoptotic and anti-autophagic activity.
Andrea Lampis, Nicola Valeri, Stuart J. Forbes, Vladimir Kirkin, Vincenzo Cardinale, Pietro Carotenuto, Lorenza Rimassa, Armando Santoro, Vincenza Guzzardo, Sofia Ventura, Umberto Cillo, Ian Said-Huntingford, Massimo Roncalli, Domenico Alvaro, Vasiliki Michalarea, Luciano Cascione, Massimiliano Salati, Luke Boulter, Paul Workman, Chiara Braconi, Daniele Costantini, Michele Ghidini, Paul A. Clarke, Rachel V. Guest, David Cunningham, Georgios Vlachogiannis, Somaieh Hedayat, Guido Carpino, Elizabeth C Smyth, Matteo Fassan, Aldo Scarpa, Robert te Poele, Ruwaida Begum, Caterina Vicentini, Francesco Trevisani, Jens C. Hahne, Carotenuto, P., Hedayat, S., Fassan, M., Cardinale, V., Lampis, A., Guzzardo, V., Vicentini, C., Scarpa, A., Cascione, L., Costantini, D., Carpino, G., Alvaro, D., Ghidini, M., Trevisani, F., Te Poele, R., Salati, M., Ventura, S., Vlachogiannis, G., Hahne, J. C., Boulter, L., Forbes, S. J., Guest, R. V., Cillo, U., Said-Huntingford, I., Begum, R., Smyth, E., Michalarea, V., Cunningham, D., Rimassa, L., Santoro, A., Roncalli, M., Kirkin, V., Clarke, P., Workman, P., Valeri, N., and Braconi, C.
Subjects
High-Throughput Screening Assay, 0301 basic medicine, Xenograft Model Antitumor Assay, Cell Survival, Antineoplastic Agents, Cancer Stem Cell, chemotherapy, Deoxycytidine, Cholangiocarcinoma, FZD8, MIR1249, Antineoplastic Agent, 03 medical and health sciences, 0302 clinical medicine, In vivo, Cancer stem cell, Cell Line, Tumor, Gene expression, microRNA, Drug Discovery, medicine, Humans, Hepatobiliary Malignancies, CRISPR-Cas System, Viability assay, Cell Proliferation, Cisplatin, Hepatology, Chemistry, Original Articles, Xenograft Model Antitumor Assays, Gemcitabine, High-Throughput Screening Assays, Gene Expression Regulation, Neoplastic, MicroRNAs, 030104 developmental biology, Biliary Tract Neoplasms, Biliary Tract Neoplasm, Cell culture, Drug Resistance, Neoplasm, Cancer research, 030211 gastroenterology & hepatology, Original Article, CRISPR-Cas Systems, Human, medicine.drug
Abstract
Background and Aims: Changes in single microRNA (miRNA) expression have been associated with chemo-resistance in biliary tract cancers (BTCs). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy. Approach and Results: High-throughput screening (HTS) of 997 locked nucleic acid miRNA inhibitors was performed in six cholangiocarcinoma cell lines treated with cisplatin and gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with mirVana probes. MicroRNA and gene expression was assessed by TaqMan assay, RNA-sequencing, and in situ hybridization in four independent cohorts of human BTCs. Knockout of microRNA was achieved by CRISPR-CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in vitro and in vivo. HTS revealed that MIR1249 inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTCs. In validation experiments, MIR1249 inhibition did not alter cell viability in untreated or dimethyl sulfoxide–treated cells; however, it did increase the CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem cell niche of human BTCs as well as in CD133+ chemo-resistant CCLP cells. MIR1249 modulated the chemotherapy-induced enrichment of CD133+ cells by controlling their clonal expansion through the Wnt-regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of cancer stem cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumor shrinkage after exposure to weekly CG, whereas wild-type models showed only stable disease over treatment. Conclusions: MIR1249 mediates resistance to CG in BTCs and may be tested as a target for therapeutics.
Pietro Carotenuto, Umberto Cillo, Ian Said-Huntingford, Lorenza Rimassa, Claudia Mescoli, Andrea Lampis, Armando Santoro, Alessandro Zerbi, Matteo Fassan, Chiara Braconi, Massimo Rugge, Michele Ghidini, Maria C. Previdi, Nicola Valeri, Massimo Roncalli, Maya Raj, Francesco Trevisani, Jens C. Hahne, Guido Torzilli, Luciano Cascione, Ghidini, M., Cascione, L., Carotenuto, P., Lampis, A., Trevisani, F., Previdi, M. C., Hahne, J. C., Said-Huntingford, I., Raj, M., Zerbi, A., Mescoli, C., Cillo, U., Rugge, M., Roncalli, M., Torzilli, G., Rimassa, L., Santoro, A., Valeri, N., Fassan, M., and Braconi, C.
Although biliary tract cancers (BTCs) are known to have an inflammatory component, a detailed characterisation of immune-related transcripts has never been performed. In these studies, nCounter PanCancer Immune Profiling Panel was used to assess the expression of 770 immune-related transcripts in the tumour tissues (TTs) and matched adjacent tissues (ATs) of resected BTCs. Cox regression analysis and Kaplan–Meier methods were used to correlate findings with relapse-free survival (RFS). The first analysis in the TT and AT of an exploratory set (n = 22) showed deregulation of 39 transcripts associated with T-cell activation. Risk of recurrence was associated with a greater number of genes deregulated in AT in comparison to TT. Analysis in the whole set (n = 53) showed a correlation between AT cytotoxic T-lymphocyte antigen-4 (CTLA4) expression and RFS, which maintained statistical significance at multivariate analysis. CTLA4 expression correlated with forkhead box P3 (FOXP3) expression, suggesting enrichment in T regulatory cells. CTLA4 is known to act by binding to the cluster of differentiation 80 (CD80). No association was seen between AT CD80 expression and RFS. However, CD80 expression differentiated prognosis in patients who received adjuvant chemotherapy. We showed that the immunomodulatory transcriptome is deregulated in resected BTCs. Our study includes a small number of patients and does not enable to draw definitive conclusions; however, it provides useful insights into potential transcripts that may deserve further investigation in larger cohorts of patients. Transcript Profiling Nanostring data have been submitted to GEO repository: GSE90698 and GSE90699., Highlights • BTCs harbour a derangement of immune-related transcripts with an important role for the cytotoxic T-lymphocyte antigen-4 (CTLA4) axis. • CTLA4 expression in the peritumoural areas correlates with outcome and represents a potential promising prognostic factor. • Our data suggest that immunotherapy may have an impact in BTCs as a mean to re-address the host immune response to the tumour.
Nadia De Marco, Pietro Carotenuto, Livia Garzia, Anna Maria Bello, Chiara Campanella, Michelle Kim, Shin Ichi Ohnuma, Massimo Zollo, Aikaterini Bilitou, Bilitou, A, De Marco, N, Bello, Am, Garzia, L, Carotenuto, P, Kim, M, Campanella, C, Ohnuma, S, and Zollo, Massimo
The development of stratified retinal cell architecture is highly conserved in all vertebrates, implying that a common fundamental molecular mechanism is involved in the generation of the organized retina. However, the detailed molecular mechanisms of retinal development are not fully understood. Here we have identified the Xenopus ortholog of prune and show that it is expressed in both differentiating and differentiated retinal domains during development. Interestingly, these spatial and temporal expression patterns coincide with the expression of prune binding partners, the NM23 family members. Overexpression of prune in retinal precur- sor cells significantly increases the ratio of Müller glial cells as observed by modulation of NM23 activity (Mochizuki et al., 2009). However, a mutated form of prune that has replacement of four aspartate (D) res- idues (D'Angelo et al., 2004), essential for phosphodiesterase activity, does not exhibit gliogenic activity. Our observations suggest that Xenopus prune may regulate Müller gliogenesis through phosphodiesterase- mediated regulation of NM23 family members.
Natalia Palombi, Pietro Carotenuto, Vittorio Colantuoni, Lina Sabatino, Alessandra Fucci, Arturo Di Blasi, Gabriella Aquino, Anna Maria Dalena, Bruno Daniele, Massimo Pancione, Nicola Normanno, Pancione, M., Di Blasi, A., Sabatino, L., Fucci, A., Dalena, A. M., Palombi, N., Carotenuto, P., Aquino, G., Daniele, B., Normanno, N., and Colantuoni, V.
Subjects
Proto-Oncogene Proteins B-raf, Pathology, medicine.medical_specialty, Colorectal cancer, Biology, CpG island methylator phenotype, medicine.disease_cause, MLH1, Pathology and Forensic Medicine, Metastasis, Cytokeratin, medicine, Humans, Rhabdoid Tumor, Aged, Colonic Neoplasm, CpG Island Methylator Phenotype, Rhabdoid colorectal cancer, Microsatellite instability, DNA Methylation, medicine.disease, digestive system diseases, Phenotype, CpG site, Colonic Neoplasms, CpG Islands, Female, KRAS, CpG Island, Human
Amelia D'Alessio, Anna Maria Rachiglio, Cristin Roma, Gerardo Botti, Pietro Carotenuto, Nicola Normanno, Carotenuto, P., Roma, C., Rachiglio, A. M., Botti, G., D'Alessio, A., and Normanno, N.
M. Di Maio, F. Perrone, Pasqualina Giordano, Pietro Carotenuto, A. La Rocca, Raffaele Costanzo, Alessandro Morabito, Claudia Sandomenico, Maria Carmela Piccirillo, Gaetano Rocco, Jane Bryce, Gennaro Daniele, Nicola Normanno, Guido Carillio, Morabito, A., Piccirillo, M. C., Costanzo, R., Sandomenico, C., Carillio, G., Daniele, G., Giordano, P., Bryce, J., Carotenuto, P., La Rocca, A., Di Maio, M., Normanno, N., Rocco, G., and Perrone, F.
Veruska Aglio, Alessandra Andrè, Pietro Carotenuto, Livia Garzia, John L.R. Rubenstein, Ombretta Guardiola, Massimo Cocchia, Andrea Basile, Anna Maria Bello, Alessandro Bulfone, Massimo Zollo, Andrea Ballabio, Andrea Faedo, Bulfone, A., Carotenuto, P., Faedo, A., Aglio, V., Garzia, L., Bello, A. M., Basile, A., Andre, A., Cocchia, M., Guardiola, O., Ballabio, Andrea, Rubenstein, J. L., and Zollo, Massimo
The vertebrate telencephalon is composed of many architectonically and functionally distinct areas and structures, with billions of neurons that are precisely connected. This complexity is fine-tuned during development by numerous genes. To identify genes involved in the regulation of telencephalic development, a specific subset of differentially expressed genes was characterized. Here, we describe a set of cDNAs encoded by genes preferentially expressed during development of the mouse telencephalon that was identified through a functional genomics approach. Of 832 distinct transcripts found, 223 (27%) are known genes. Of the remaining, 228 (27%) correspond to expressed sequence tags of unknown function, 58 (7%) are homologs or orthologs of known genes, and 323 (39%) correspond to novel rare transcripts, including 48 (14%) new putative noncoding RNAs. As an example of this latter group of novel precursor transcripts of micro-RNAs, telencephalic embryonic subtractive sequence (TESS) 24.E3 was functionally characterized, and one of its targets was identified: the zinc finger transcription factorZFP9. The TESS transcriptome has been annotated, mapped for chromosome loci, and arrayed for its gene expression profiles during neural development and differentiation (in Neuro2a and neural stem cells). Within this collection, 188 genes were also characterized on embryonic and postnatal tissue byin situhybridization, demonstrating that most are specifically expressed in the embryonic CNS. The full information has been organized into a searchable database linked to other genomic resources, allowing easy access to those who are interested in the dissection of the molecular basis of telencephalic development.
Ralph Laufer, Michelle D'Antoni, Pietro Carotenuto, Silvia Attaccalite, Annalise Di Marco, Di Marco, A., D'Antoni, M., Attaccalite, S., Carotenuto, P., and Laufer, R.
Veruska Aglio, Gianluigi Arrigoni, Giuseppe Palmieri, Alessandra Andrè, Ombretta Guardiola, Pietro Carotenuto, Anna D’Angelo, Massimo Zollo, Livia Garzia, L Aravind, Antonio Cossu, D'Angelo, A, Garzia, L, André, A, Carotenuto, P, Aglio, V, Guardiola, O, Arrigoni, G, Cossu, A, Palmieri, G, Aravind, L, and Zollo, Massimo
We identify a new enzymatic activity underlying metastasis in breast cancer and describe its susceptibility to therapeutic inhibition. We show that human prune (h-prune), a phosphoesterase DHH family appertaining protein, has a hitherto unrecognized cyclic nucleotide phosphodiesterase activity effectively suppressed by dipyridamole, a phosphodiesterase inhibitor. H-prune physically interacts with nm23-H1, a metastasis suppressor gene. The h-prune PDE activity, suppressed by dipyridamole and enhanced by the interaction with nm23-H1, stimulates cellular motility and metastasis processes. Out of 59 metastatic breast cancer cases analyzed, 22 (37%) were found to overexpress h-prune, evidence that this novel enzymatic activity is involved in promoting cancer metastasis.
Despite advancements in therapeutic strategies, the development of drug resistance and metastasis remains a serious concern for the efficacy of chemotherapy against colorectal cancer (CRC). We have previously demonstrated that low expression of ribosomal protein uL3 positively correlates with chemoresistance in CRC patients. Here, we demonstrated that the loss of uL3 increased the metastatic capacity of CRC cells in chick embryos. Metabolomic analysis revealed large perturbations in amino acid and glutathione metabolism in resistant uL3-silenced CRC cells, indicating that uL3 silencing dramatically triggered redox metabolic reprogramming. RNA-Seq data revealed a notable dysregulation of 108 genes related to ferroptosis in CRC patients. Solute Carrier Family 7 Member 11 (SLC7A11) is one of the most dysregulated genes; its mRNA stability is negatively regulated by uL3, and its expression is inversely correlated with uL3 levels. Inhibition of SLC7A11 with erastin impaired resistant uL3-silenced CRC cell survival by inducing ferroptosis. Of interest, the combined treatment erastin plus uL3 enhanced the chemotherapeutic sensitivity of uL3-silenced CRC cells to erastin. The antimetastatic potential of the combined strategy was evaluated in chick embryos. Overall, our study sheds light on uL3-mediated chemoresistance and provides evidence of a novel therapeutic approach, erastin plus uL3, to induce ferroptosis, establishing individualized therapy by examining p53, uL3 and SLC7A11 profiles in tumors. [ABSTRACT FROM AUTHOR]
Background: The TLC Domain Containing 1 (TLCD1) protein, a key regulator of phosphatidylethanolamine (PE) composition, is distributed across several cellular membranes, including mitochondrial plasma membranes. Existing research has revealed the impact of TLCD1 on the development of non-alcoholic fatty liver disease. However, there remains a gap in comprehensive pan-cancer analyses of TLCD1, and the precise role of TLCD1 in cancer patient prognosis and immunological responses remains elusive. This study aims to provide a comprehensive visualization of the prognostic landscape associated with TLCD1 across a spectrum of cancers, while shedding light on the potential links between TLCD1 expression within the tumor microenvironment and immune infiltration characteristics. Methods: TLCD1 expression data were obtained from GTEx, TCGA, and HPA data repositories. Multiple databases including TIMER, HPA, TISIDB, cBioPortal, GEPIA2, STRING, KEGG, GO, and CancerSEA were used to investigate the expression pattern, diagnostic and prognostic significance, mutation status, functional analysis, and functional status of TLCD1. In addition, we evaluated the relationship between TLCD1 expression and immune infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), and immune-related genes in pan-cancer. Furthermore, the association of TLCD1 with drug sensitivity was analyzed using the CellMiner database. Results: We found that TLCD1 is generally highly expressed in pan-cancers and is significantly associated with the staging and prognosis of various cancers. Furthermore, our results also showed that TLCD1 was significantly associated with immune cell infiltration and immune regulatory factor expression. Using CellMiner database analysis, we then found a strong correlation between TLCD1 expression and sensitivity to anticancer drugs, indicating its potential as a therapeutic target. The most exciting finding is that high TLCD1 expression is associated with worse survival and prognosis in GBM and SKCM patients receiving anti-PD1 therapy. These findings highlight the potential of TLCD1 as a predictive biomarker for response to immunotherapy. Conclusion: TLCD1 plays a role in the regulation of immune infiltration and affects the prognosis of patients with various cancers. It serves as both a prognostic and immunologic biomarker in human cancer. [ABSTRACT FROM AUTHOR]
AIR pollutants, WNT genes, LINCRNA, PULMONARY alveoli, PARTICULATE matter, MICRORNA
Abstract
Air pollution, especially fine particulate matter (PM2.5, with an aerodynamic diameter of less than 2.5 μm), represents a risk factor for human health. Many studies, regarding cancer onset and progression, correlated with the short and/or long exposition to PM2.5. This is mainly mediated by the ability of PM2.5 to reach the pulmonary alveoli by penetrating into the blood circulation. This review recapitulates the methodologies used to study PM2.5 in cellular models and the downstream effects on the main molecular pathways implicated in cancer. We report a set of data from the literature, that describe the involvement of miRNAs or long noncoding RNAs on the main biological processes involved in oxidative stress, inflammation, autophagy (PI3K), cell proliferation (NFkB, STAT3), and EMT (Notch, AKT, Wnt/β-catenin) pathways. microRNAs, as well as gene expression profile, responds to air pollution environment modulating some key genes involved in epigenetic modification or in key mediators of the biological processes described below. In this review, we provide some scientific evidences about the thigh correlation between miRNAs dysregulation, PM2.5 exposition, and gene pathways involved in cancer progression. [ABSTRACT FROM AUTHOR]
Cilia are microtubule-based organelles that project from the cell surface with motility or sensory functions. Primary cilia work as antennae to sense and transduce extracellular signals. Cilia critically control proliferation by mediating cell-extrinsic signals and by regulating cell cycle entry. Recent studies have shown that primary cilia and their associated proteins also function in autophagy and genome stability, which are important players in oncogenesis. Abnormal functions of primary cilia may contribute to oncogenesis. Indeed, defective cilia can either promote or suppress cancers, depending on the cancer-initiating mutation, and the presence or absence of primary cilia is associated with specific cancer types. Together, these findings suggest that primary cilia play important, but distinct roles in different cancer types, opening up a completely new avenue of research to understand the biology and treatment of cancers. In this review, we discuss the roles of primary cilia in promoting or inhibiting oncogenesis based on the known or predicted functions of cilia and cilia-associated proteins in several key processes and related clinical implications. [ABSTRACT FROM AUTHOR]
Pant, Kishor, Richard, Seth, Peixoto, Estanislao, Yin, Jun, Seelig, Davis M., Carotenuto, Pietro, Salati, Massimiliano, Franco, Brunella, Roberts, Lewis R., and Gradilone, Sergio A.
Subjects
NAD (Coenzyme), CELL growth, CISPLATIN, CHOLANGIOCARCINOMA, CELL survival
Abstract
It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5′-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study's findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin. [ABSTRACT FROM AUTHOR]
MOLECULAR genetics, CILIA & ciliary motion, MEDICAL genetics, CELL motility, MEDICAL sciences
Abstract
Cancer, Cell Surface Extensions, Cilia, Drugs and Therapies, Genetics, Health and Medicine, Oncology Keywords: Cancer; Cell Surface Extensions; Cilia; Drugs and Therapies; Genetics; Health and Medicine; Oncology EN Cancer Cell Surface Extensions Cilia Drugs and Therapies Genetics Health and Medicine Oncology 1107 1107 1 07/31/23 20230804 NES 230804 2023 AUG 1 (NewsRx) -- By a News Reporter-Staff News Editor at Drug Week -- Investigators publish new report on cancer. [Extracted from the article]
Although I FEBS Open Bio i does not seek to judge the importance of submissions, our reviewers carefully scrutinize the experimental design and results of all papers and challenge authors about their conclusions. The editors of I FEBS Open Bio i would like to thank all those who have given their time and expertise to review articles submitted for publication in Volume 12. [Extracted from the article]
FIBROBLASTS, THYROID gland tumors, ENDOCRINE gland tumors, METASTASIS, CELL physiology, CANCER, DISEASE prevalence, CELL lines, DRUG resistance in cancer cells
Abstract
Simple Summary: Thyroid cancer is the most common solid tumor of the endocrine glands. The cancer cell contribution to thyroid cancer development and progression has been studied extensively, whereas the involvement of the tumor microenvironment, particularly of cancer-associated fibroblasts (CAFs), in thyroid cancer growth still must be largely analyzed. The tumor microenvironment, comprising molecules, blood and lymphatic tumor vessels and several non cancer stromal cells, such as CAFs, dramatically influences solid tumor growth and therapy resistance. In particular, investigations on CAF contribution to solid tumor growth and therapeutic resistance represent an important area of oncological research. Moreover, studies focused on the role of CAFs in thyroid cancer could lead to a better comprehension of mechanisms regulating cancer growth and to the development of new therapeutic strategies. Therefore, in this paper, we review the hallmarks of CAFs and their role on thyroid cancer. Thyroid cancer is the most common type of endocrine cancer, and its prevalence continue to rise. Non-metastatic thyroid cancer patients are successfully treated. However, looking for new therapeutic strategies is of great importance for metastatic thyroid cancers that still lead to death. With respect to this, the tumor microenvironment (TME), which plays a key role in tumor progression, should be considered as a new promising therapeutic target to hamper thyroid cancer progression. Indeed, thyroid tumors consist of cancer cells and a heterogeneous and ever-changing niche, represented by the TME, which contributes to establishing most of the features of cancer cells. The TME consists of extracellular matrix (ECM) molecules, soluble factors, metabolites, blood and lymphatic tumor vessels and several stromal cell types that, by interacting with each other and with tumor cells, affect TME remodeling, cancer growth and progression. Among the thyroid TME components, cancer-associated fibroblasts (CAFs) have gained more attention in the last years. Indeed, recent important evidence showed that thyroid CAFs strongly sustain thyroid cancer growth and progression by producing soluble factors and ECM proteins, which, in turn, deeply affect thyroid cancer cell behavior and aggressiveness. Hence, in this article, we describe the thyroid TME, focusing on the desmoplastic stromal reaction, which is a powerful indicator of thyroid cancer progression and an invasive growth pattern. In addition, we discuss the origins and features of the thyroid CAFs, their influence on thyroid cancer growth and progression, their role in remodeling the ECM and their immune-modulating functions. We finally debate therapeutic perspectives targeting CAFs. [ABSTRACT FROM AUTHOR]
Objective: Cholangiocarcinoma (CHOL) is a deadly cancer worldwide with limited available therapies. The aim of this study was to investigate key exosomal miRNAs and their functions in CHOL development. Methods: Serum exosomes were isolated from patients with CHOL and healthy controls, followed by miRNA sequencing for identifying differentially expressed miRNAs (DEMs) and their functions. Then, the expression of key DEMs was experimentally validated in exosomes from clinical CHOL patients and CHOL cells. The effects of overexpression of key DEMs on CHOL cell migration and proliferation were investigated. A key exosomal DEM miR-3124-5p was identified. The effects of overexpression or knockdown of exosomal miR-3124-5p on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were investigated. Moreover, the function of exosomal miR-3124-5p on tumor growth in vivo was explored. Results: A total of 632 exosomal DEMs were identified between CHOL and control samples. Target genes of DEMs were significantly enriched in pathways, such as the p53 signaling pathway. miR-3124-5p was upregulated in serum exosomes from CHOL patients and exosomes from CHOL cells, and overexpression of miR-3124-5p promoted RBE cell migration and viability. Moreover, overexpression of exosomal miR-3124-5p promoted the proliferation, migration, and angiogenesis of HUVECs, while knockdown of miR-3124-5p had the opposite effect. miR-3124-5p could target growth differentiation factor 11 (GDF11) and downregulate GDF11 expression. Furthermore, exosomal miR-3124-5p promoted tumor growth in vivo. Conclusions: Our findings revealed that exosome-encapsulated miR-3124-5p promoted the malignant progression of CHOL by targeting GDF11. Exosomal miR-3124-5p and GDF11 could be promising biomarkers or therapeutic targets for CHOL. [ABSTRACT FROM AUTHOR]
CANCER cells, MYOFIBROBLASTS, TUMOR microenvironment, CELL aggregation, BREAST cancer, FIBROBLASTS, CELL migration
Abstract
Breast cancer-associated fibroblasts (BCAFs), the most abundant non-cancer stromal cells of the breast tumor microenvironment (TME), dramatically sustain breast cancer (BC) progression by interacting with BC cells. BCAFs, as well as myofibroblasts, display an up regulation of activation and inflammation markers represented by α-smooth muscle actin (α-SMA) and cyclooxygenase 2 (COX-2). BCAF aggregates have been identified in the peripheral blood of metastatic BC patients. We generated an in vitro stromal model consisting of human primary BCAFs grown as monolayers or 3D cell aggregates, namely spheroids and reverted BCAFs, obtained from BCAF spheroids reverted to 2D cell adhesion growth after 216 h of 3D culture. We firstly evaluated the state of activation and inflammation and the mesenchymal status of the BCAF monolayers, BCAF spheroids and reverted BCAFs. Then, we analyzed the MCF-7 cell viability and migration following treatment with conditioned media from the different BCAF cultures. After 216 h of 3D culture, the BCAFs acquired an inactivated phenotype, associated with a significant reduction in α-SMA and COX-2 protein expression. The deactivation of the BCAF spheroids at 216 h was further confirmed by the cytostatic effect exerted by their conditioned medium on MCF-7 cells. Interestingly, the reverted BCAFs also retained a less activated phenotype as indicated by α-SMA protein expression reduction. Furthermore, the reverted BCAFs exhibited a reduced pro-tumor phenotype as indicated by the anti-migratory effect exerted by their conditioned medium on MCF-7 cells. The deactivation of BCAFs without drug treatment is possible and leads to a reduced capability of BCAFs to sustain BC progression in vitro. Consequently, this study could be a starting point to develop new therapeutic strategies targeting BCAFs and their interactions with cancer cells. [ABSTRACT FROM AUTHOR]
Barbato, Anna, Piscopo, Fabiola, Salati, Massimiliano, Reggiani-Bonetti, Luca, Franco, Brunella, and Carotenuto, Pietro
Subjects
MICRORNA, CHOLANGIOCARCINOMA, DNA sequencing, TRANSCRIPTOMES, GENE expression
Abstract
Bile-duct cancers (BDC) are a group of solid tumors arising from the biliary tree. Despite their classification as rare cancers, the incidence of BDC is increasing worldwide. Poor prognosis is a common feature of this type of cancer and is mainly determined by the following factors: late diagnosis, lack of effective therapeutic approaches, and resistance to conventional treatments. In the past few years, next-generation sequencing technologies has allowed us to study the genome, exome, and transcriptome of BDC deeper, revealing a previously underestimated class of RNA: the noncoding RNA (ncRNA). MicroRNAs (miRNAs) are small ncRNAs that play an important regulatory role in gene expression. The aberrant expression of miRNAs and their pivotal role as oncogenes or tumor suppressors in biliary carcinogenesis has been widely described in BDC. Due to their ability to regulate multiple gene networks, miRNAs are involved in all cancer hallmarks, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, activating invasion and metastasis, reprogramming cellular metabolism, and avoiding immune destruction. Their use as diagnostic, prognostic, and predictive biomarkers has been widely explored in several human cancers, including BDC. Furthermore, miRNA-based therapeutic strategies are currently the subject of numerous clinical trials that are providing evidence of their efficacy as potent anticancer agents. In this review, we will provide a detailed update of miRNAs affecting BDC, discussing their regulatory function in processes underlying the molecular pathology of BDC. Finally, an overview of their potential use as biomarkers or therapeutic tools in BDC will be further addressed. [ABSTRACT FROM AUTHOR]
LYMPHOCYTE count, CLINICAL trials, PATIENT selection, CANCER chemotherapy, PERITONEUM diseases, BILIARY tract cancer
Abstract
Background: The role of second-line chemotherapy in advanced biliary cancers (ABCs) has only recently been established in phase III randomized trial and the optimal selection of patients most likely to benefit from it remains challenging. Methods: A cohort of 98 ABC treated second-line chemotherapy was used as a developmental dataset to identify covariates independently associated with overall survival (OS). Kaplan–Meier analysis was used to investigate the association between variables and OS and those retaining statistically significance were combined in a multiplexed score. Results: The following pretreatment variables were independently associated with OS: ECOG PS > 0, peritoneal disease, LDH > 430 UI/L, albumin < 3.5 gr/dL, gamma-GT > 100 UI/L, sodium < 140 mEq/L, absolute lymphocyte count < 1000/mmc, and PFS to first-line < 6 months. Based on these results, a scoring system was developed that identified three subgroups with statistically different OS: low-risk (mOS 18 months), intermediate-risk (mOS 9.4 months) and high-risk (mOS 2.9 months) (p < 0.001). The prognostic model was both internally and externally validated in a multicentre cohort of 120 ABCs. Conclusion: The Modena score is a multiplexed scoring system capable of accurately risk-stratified ABCs treated with second-line chemotherapy. Based on its reproducibility, usability and generalizability, it has the potential for assisting therapeutic decision-making in the clinic and risk-stratification in future trials. Graphical [ABSTRACT FROM AUTHOR]
Here, we aim at describing the pattern of care, survival outcome and prognostic factors of ABC patients (pts) receiving third-line chemotherapy. Institutional registries across three academic medical centers were retrospectively reviewed. Kaplan–Meier estimators were used to calculate survival, the log-rank test to make comparisons, and the Cox proportional hazard models to assess the progostic impact of variables. Among 101 pts included in the analysis. 68 (67.3%), 19 (18.8%) and 14 (13.8%) had intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, respectively. Atotal of 63 (62.3%) pts received monochemotherapy, while 38 (37.6%) were treated with adoublet. The median OS and PFS were 5 and 3 months, respectively. Disease control rate was achieved in 23 (22.7%) pts, with 2 (2%) partial responses. Grade 3–4 treatment-related adverse events were reported in 22 (21.7%) pts. At multivariate analysis, ECOG PS (p < 0.001), tumor burden (p = 0.01) and lymphocyte-to-monocyte ratio (p =0.02) were independent predictors of survival. Third-line chemotherapy displayed limited activity in this real-world cohort, although prognostic factors have been identified that may assist in treatment decision. The results of this multicenter experience, highlight the need for more effective therapies and provide a benchmark for future trials in this setting. [ABSTRACT FROM AUTHOR]
PANCREATIC cancer, CANCER chemotherapy, DNA damage, IRINOTECAN, CANCER cells, TREATMENT effectiveness
Abstract
FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome. Understanding which patients will respond to FOLFIRINOX therapy is important for clinical outcome. Here, the authors show that the MIR1307 is increased pancreatic cancer cell lines and inhibition of the microRNA sensitises cells to treatment.' stratifying patients to achieve the best clinical outcome. Here, the authors show that the MIR1307 is increased in a subgroup of human pancreatic cancers and inhibition of the microRNA in in vitro and in vivo models of pancreatic cancer sensitises cells to treatment. [ABSTRACT FROM AUTHOR]
Intrahepatic cholangiocarcinoma (iCCA) is an anatomically and biologically distinct entity with a rising incidence and a poor prognosis on conventional treatments. Surgery followed by adjuvant chemotherapy is a potentially curative option in resectable cases, while palliative-intent chemotherapy is the standard-of-care in the advanced setting. Technological advances through massive parallel sequencing have enabled a deeper understanding of disease biology with the identification of several druggable molecular vulnerabilities in nearly 50% of cases. Among them, gene fusions involving the fibroblast growth factor receptor 2 (FGFR2) are the most therapeutically exploited so far with a number of Phase II clinical trials investigating FGFR2 inhibitors showing unprecedented efficacy results in this molecular subgroup. Over the last year, these efforts have culminated in the US FDA-approval of pemigatinib and infigratinib, the first two oral selective FGFR2 targeted agents for previously treated, locally advanced or metastatic iCCA driven by FGFR2 fusion or rearrangements. While first-line Phase III trials are currently underway to test these targeted approach against standard-of-care chemotherapy, translational studies are trying to better understand primary and secondary resistance mechanisms in order to optimize FGFR2 blockade in iCCA. In this article, we extensively reviewed the current evidence on the biological rationale, as well as preclinical and clinical development of FGFR inhibitors in iCCA. [ABSTRACT FROM AUTHOR]
A research study conducted at the University of Naples "Federico II" in Italy has found that low expression of ribosomal protein uL3 is associated with chemoresistance in colorectal cancer (CRC) patients. The study also revealed that the loss of uL3 increased the metastatic capacity of CRC cells. Metabolomic analysis showed significant changes in amino acid and glutathione metabolism in uL3-silenced CRC cells, indicating a reprogramming of redox metabolism. The researchers identified Solute Carrier Family 7 Member 11 (SLC7A11) as one of the most dysregulated genes related to ferroptosis in CRC patients, and inhibiting SLC7A11 with erastin induced ferroptosis and impaired the survival of uL3-silenced CRC cells. The combined treatment of erastin and uL3 enhanced the chemotherapeutic sensitivity of uL3-silenced CRC cells. The study suggests that targeting uL3 and SLC7A11 could be a potential therapeutic approach for CRC patients. [Extracted from the article]
Salpietro, Vincenzo, Zollo, Massimo, Vandrovcova, Jana, Ryten, Mina, Botia, Juan A., Ferrucci, Veronica, Manole, Andreea, Efthymiou, Stephanie, Al Mutairi, Fuad, Bertini, Enrico, Tartaglia, Marco, Houlden, Henry, and SYNAPS Study Group
COLON cancer, COLORECTAL cancer, BETA carotene, CANCER cells, DRUG resistance in cancer cells
Abstract
Natural products, like carotenoids, have shown the ability to enhance cancer cell response to drugs and may provide a safer choice to defeat chemoresistance in cancer. Keywords: Naples; Italy; Europe; Alkenes; Biological Factors; Cancer; Carotenoids; Colon Cancer; Colorectal Research; Cyclohexanes; Cycloparaffins; Drugs and Therapies; Emerging Technologies; Gastroenterology; Health and Medicine; Hydrocarbons; Nanoparticles; Nanotechnology; Oncology; Pharmaceuticals; beta Carotene EN Naples Italy Europe Alkenes Biological Factors Cancer Carotenoids Colon Cancer Colorectal Research Cyclohexanes Cycloparaffins Drugs and Therapies Emerging Technologies Gastroenterology Health and Medicine Hydrocarbons Nanoparticles Nanotechnology Oncology Pharmaceuticals beta Carotene 1143 1143 1 05/22/23 20230526 NES 230526 2023 MAY 23 (NewsRx) -- By a News Reporter-Staff News Editor at Drug Week -- A new study on Oncology - Colon Cancer is now available. [Extracted from the article]
Keywords: Alkylating Agents; Antineoplastics; Cancer; Chlorine Compounds; Cisplatin Therapy; Drugs and Therapies; Health and Medicine; Nitrogen Compounds; Oncology; Pharmaceuticals; Platinum Compounds EN Alkylating Agents Antineoplastics Cancer Chlorine Compounds Cisplatin Therapy Drugs and Therapies Health and Medicine Nitrogen Compounds Oncology Pharmaceuticals Platinum Compounds 290 290 1 03/27/23 20230331 NES 230331 2023 MAR 28 (NewsRx) -- By a News Reporter-Staff News Editor at Drug Week -- Researchers detail new data in cancer. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. [Extracted from the article]
Frezzetti, D, Menna, M De, Zoppoli, P, Guerra, C, Ferraro, A, Bello, A M, Luca, P De, Calabrese, C, Fusco, A, Ceccarelli, M, Zollo, M, Barbacid, M, Lauro, R Di, and Vita, G De
miR-21 is a microRNA (miRNA) frequently overexpressed in human cancers. Here we show that miR-21 is upregulated both in vitro and in vivo by oncogenic Ras, thus linking this miRNA to one of the most frequently activated oncogenes in human cancers. Ras regulation of miR-21 occurs with a delayed kinetic and requires at least two Ras downstream pathways. A screen of human thyroid cancers and non-small-cell lung cancers for the expression of miR-21 reveals that it is overexpressed mainly in anaplastic thyroid carcinomas, the most aggressive form of thyroid cancer, whereas in lung its overexpression appears to be inversely correlated with tumor progression. We also show that a LNA directed against miR-21 slows down tumor growth in mice. Consistently, a search for mRNAs downregulated by miR-21 shows an enrichment for mRNAs encoding cell cycle checkpoints regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation. [ABSTRACT FROM AUTHOR]
A genetic interaction between PRUNE and NM23/NDPK has been postulated in Drosophila melanogaster. Many have focused on Drosophila for the genetic combination between PRUNE “knock down”and AWD/NM23 fly mutants bearing the P97S mutation (K-pn, Killer of PRUNE mutation). We postulated a role for PRUNE-NM23 interactions in vertebrate development, demonstrating a physical interaction between the human PRUNE and NM23-H1 proteins, and partially characterizing their functional significance in cancer progression. Here, we present an initial analysis towards the functional characterization of the PRUNE-NM23 interaction during mammalian embryogenesis. Our working hypothesis is that PRUNE, NM23-H1 and their protein-protein interaction partners have important roles in mammalian brain development and adult brain function. Detailed expression analyses from early mouse brain development to adulthood show significant co-expression of these two genes during embryonic stages of brain development, especially focusing on the cortex, hippocampus, midbrain and cerebellum. We hypothesize that their abnormal expression results in an altered pathway of activation, influencing protein complex formation and its protein partner interactions in early embryogenesis. In the adult brain, their function appears concentrated towards their enzyme activities, wherein biochemical variations can result in brain dysfunction. [ABSTRACT FROM AUTHOR]