Matilde Lleonart - Academia.edu (original) (raw)

Papers by Matilde Lleonart

Research paper thumbnail of Expression patterns and bioinformatic analysis of miR-1260a and miR-1274a in Prostate Cancer Tunisian patients

Molecular Biology Reports, 2018

Currently, microRNAs (miRs) represent great biomarkers in cancer due to their stability and their... more Currently, microRNAs (miRs) represent great biomarkers in cancer due to their stability and their potential role in diagnosis, prognosis and therapy. This study aims to evaluate the expression levels of miRs-1260 and-1274a in prostate cancer (PC) samples and to identify their eventual targets by using bioinformatic analysis. In this project, we evaluated the expression status of miRs-1260 and-1274a in 86 PC patients and 19 controls by using real-time quantitative PCR and 2 −ΔΔCt method. Moreover, we retrieved validated and predicted targets of miRs from several datasets by using the "multiMir" R/Bioconductor package. We have found that miRs-1260 and-1274a were over-expressed in PC patients compared to controls (p < 1 × 10 −5). Moreover ROC curve for miRs-1260 and 1274a showed a good performance to distinguish between controls group and PC samples with an area under the ROC curve of 0.897 and 0.784 respectively. However, no significant association could be shown between these two miRs and clinical parameters such as PSA levels, Gleason score, tumor stage, D'Amico classification, lymph node metastasis statues, tumor recurrence, metastasis status and progression after a minimum of 5 years follow-up. Finally, a bioinformatic analysis revealed the association between these two miRs and several targets implicated in prostate cancer initiation pathways.

Research paper thumbnail of Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma

Cancers

To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma ... more To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma (HNSCC), we explored the expression profiles of the following cisplatin (CDDP) resistant (R) versus parental (sensitive) cell lines by RNA-sequencing (RNA-seq): JHU029, HTB-43 and CCL-138. Using the parental condition as a control, 30 upregulated and 85 downregulated genes were identified for JHU029-R cells; 263 upregulated and 392 downregulated genes for HTB-43-R cells, and 154 upregulated and 68 downregulated genes for CCL-138-R cells. Moreover, we crossed-checked the RNA-seq results with the proteomic profiles of HTB-43-R (versus HTB-43) and CCL-138-R (versus CCL-138) cell lines. For the HTB-43-R cells, 21 upregulated and 72 downregulated targets overlapped between the proteomic and transcriptomic data; whereas in CCL-138-R cells, four upregulated and three downregulated targets matched. Following an extensive literature search, six genes from the RNA-seq (CLDN1, MAGEB2, CD24, CEACAM6...

Research paper thumbnail of Editorial: Sphingolipid metabolism and cancer

Frontiers in Oncology

Editorial on the Research Topic Sphingolipid metabolism and cancer We are pleased to present this... more Editorial on the Research Topic Sphingolipid metabolism and cancer We are pleased to present this Research Topic entitled "Sphingolipid Metabolism and Cancer", which features review articles focusing on sphingolipid metabolism in the regulation of cancer pathogenesis and therapy. Bioactive sphingolipids and ceramides modulate the composition of plasma membranes and play a critical role in cell signal transduction (1, 2). Metabolism of sphingolipid is essential for cellular processes, cell growth and proliferation, mitochondrial-autophagy-lysosomal pathways, apoptosis, invasion and metastasis, and immune function (3-5). Moreover, trapping of sphingolipids and their metabolites in lysosomes due to altered sphingolipid metabolism directly affects the lipid compositions of membranes. Accumulating undigested substrates in lysosomes due to deficiencies of various enzymes related to sphingolipid metabolism is linked to more than 50 types of lysosomal storage diseases (6). Recent studies have shown that some sphingolipids and ceramides are involved in cancer progression, malignancy, and drug resistance (7). The knowledge of molecular details of the roles of sphingolipids and their downstream targets in cancer progression opens a new window to develop new therapies to target sphingolipids. The Research Topic focuses on the functional disruption of sphingolipid metabolism in cancer pathology and a review of novel therapeutic agents targeting sphingolipid metabolism. This Topic gathered a pool of 4 papers, including one research article and three systematic reviews. They all provide essential data on targeting sphingolipids for cancer therapy and cancer drug resistance. Ceramide synthesis is a central hub of sphingolipid metabolism (8). In addition, ceramide isoforms play a distinct role in the autophagy-lysosomal signaling pathway, ER stress, and apoptosis. C16 ceramide is part of the mitochondrial outer membrane and forms channels that increase permeability and apoptosis (9). Trapika et al. showed the role of C16 ceramide levels in the prostate cancer model. The authors demonstrated that erianin increased the level of C16 ceramide in androgen-dependent prostate cancer cells

Research paper thumbnail of The Role of Sphingolipids Metabolism in Cancer Drug Resistance

Frontiers in Oncology, 2021

Drug resistance continues to be one of the major challenges to cure cancer. As research in this f... more Drug resistance continues to be one of the major challenges to cure cancer. As research in this field evolves, it has been proposed that numerous bioactive molecules might be involved in the resistance of cancer cells to certain chemotherapeutics. One well-known group of lipids that play a major role in drug resistance are the sphingolipids. Sphingolipids are essential components of the lipid raft domains of the plasma membrane and this structural function is important for apoptosis and/or cell proliferation. Dysregulation of sphingolipids, including ceramide, sphingomyelin or sphingosine 1-phosphate, has been linked to drug resistance in different types of cancer, including breast, melanoma or colon cancer. Sphingolipid metabolism is complex, involving several lipid catabolism with the participation of key enzymes such as glucosylceramide synthase (GCS) and sphingosine kinase 1 (SPHK1). With an overview of the latest available data on this topic and its implications in cancer thera...

Research paper thumbnail of Targeting Sphingolipids for Cancer Therapy

Frontiers in Oncology, 2021

Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from... more Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from proliferation to cell death. Sphingolipids are modified in multiple cancers and are responsible for tumor proliferation, progression, and metastasis. Several inhibitors or activators of sphingolipid signaling, such as fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, α-galactosylceramide, fingolimod, and sonepcizumab, have been described. The objective of this review was to analyze the results from preclinical and clinical trials of these drugs for the treatment of cancer. Sphingolipid-targeting drugs have been tested alone or in combination with chemotherapy, exhibiting antitumor activity alone and in synergism with chemotherapy in vitro and in vivo. As a consequence of treatments, the most frequent mechanism of cell death is apoptosis, followed by autophagy. Aslthough all these drugs have produced good results in preclinical studies of multiple cancers, the outc...

Research paper thumbnail of Advance Access publication January 19, 2008

PPP1CA contributes to the senescence program induced by oncogenic Ras

Research paper thumbnail of Cold-inducible RNA binding protein promotes breast cancer cell malignancy by regulating Cystatin C levels

RNA, 2020

Cold-inducible RNA binding protein (CIRBP) is a stress-responsive protein that promotes cancer de... more Cold-inducible RNA binding protein (CIRBP) is a stress-responsive protein that promotes cancer development and inflammation. Critical to most CIRBP functions is its capacity to bind and posttranscriptionally modulate mRNA. However, a transcriptome-wide analysis of CIRBP mRNA targets in cancer has not yet been performed. Here, we use an ex vivo breast cancer model to identify CIRBP targets and mechanisms. We find that CIRBP transcript levels correlate with breast cancer subtype and are an indicator of luminal A/B prognosis. Accordingly, overexpression of CIRBP in nontumoral MCF-10A cells promotes cell growth and clonogenicity, while depletion of CIRBP from luminal A MCF-7 cells has opposite effects. We use RNA immunoprecipitation followed by high-throughput sequencing (RIP-seq) to identify a set of 204 high confident CIRBP targets in MCF-7 cells. About 10% of these showed complementary changes after CIRBP manipulation in MCF-10A and MCF-7 cells, and were highly interconnected with kn...

Research paper thumbnail of Editor's Note: Immortalization of Primary Human Prostate Epithelial Cells by c-Myc

Cancer Research

The editors are publishing this note to alert readers to concerns about this article (1). We were... more The editors are publishing this note to alert readers to concerns about this article (1). We were informed by the authors that in Fig. 1B, the panels showing E7-and mdm2-expressing cells originated from the same picture of mdm2-expressing cells. In addition, in Fig. 2C, the Western blots showing hTERT and c-Myc expression were spliced but this was not indicated in the figure legend.

Research paper thumbnail of Editorial: How Do Metabolism, Angiogenesis, and Hypoxia Modulate Resistance?

Frontiers in Oncology

Metabolic alterations were among the first discovered hallmarks of cancer. They were first descri... more Metabolic alterations were among the first discovered hallmarks of cancer. They were first described 90 years ago when Otto Warburg realized that cancer cells in culture had a relatively increased metabolic rate (the Warburg hypothesis). It has been proposed that the drastic changes seen in cancer metabolism are in part attributed to mutations in the mtDNA, metabolic reprogramming, or mitochondrial dysfunction. However, novel players in cancer metabolism are emerging. In this regard, the review of Fernández et al. describes how lipidic alterations impact cancer prognosis and response to treatment. For example, it has been described that obesity increases the risk of cancer death, possibly due to the consequences of lipid accumulation throughout a lifetime. Lipid accumulation changes the microenvironment and produces chronic inflammation by increasing several cytokines. While the levels of genetic or epigenetic modifications diverge in different cancer types, all cancer cells adapt to drastic microenvironmental conditions. This adaptation entails metabolic reprogramming to cope with scarce nutrients and oxygen. Lipid metabolism sustains cancer initiation and contributes to cancer progression and therapy resistance. The role of lipids has been underestimated, as they have largely been considered scaffolds of biological membranes. In recent decades, the role of lipids in cancer has emerged in parallel to the characterization of lipids as essential components of cell signaling, redox homeostasis control, and energy sources (i.e., ß-fatty acid oxidation). Moreover, while de novo synthesis of fatty acids and cholesterol is restricted to the liver and adipocytes in normal cells, cancer cells can synthesize such components. This altered lipid metabolism affects key steps involved in the metastatic process, like migration, invasion, and angiogenesis, and can also be associated with prognosis. Moreover, Fernández et al. provide a list of preclinical and clinical studies with bioactive compounds from natural sources to target lipid metabolism and associated risk factors in cancer. Tumor adaptation to hypoxia is another important aspect that modulates resistance in cancer. Hypoxia is a forced situation where oxygen levels are different from normal physiological conditions. Hypoxia occurs in higher or minor levels in most cancers, if not all. The detection of hypoxic areas by clinical imaging would improve cancer chemotherapeutic treatments and optimal radiotherapy planning. The technique of positron emission tomography (PET) measures cancer metabolism and cellular proliferation, but it can also measure blood flow and oxygen use. PET can

Research paper thumbnail of TSPAN1: A Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance

Cancers

Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in can... more Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial–mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 wit...

Research paper thumbnail of SDCBP Modulates Stemness and Chemoresistance in Head and Neck Squamous Cell Carcinoma through Src Activation

Cancers

To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic ... more To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeu...

Research paper thumbnail of Five microRNAs in Serum Are Able to Differentiate Breast Cancer Patients From Healthy Individuals

Research paper thumbnail of Autophagy Takes Center Stage as a Possible Cancer Hallmark

Research paper thumbnail of Common metabolic pathways implicated in resistance to chemotherapy point to a key mitochondrial role in breast cancer

Molecular & cellular proteomics : MCP, Jan 29, 2018

Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by t... more Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumour growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumour recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and down-regulated proteins from metabolic pathways that suggests their dependence on mitochondria for survival. Here, we selected antibiotics, in particular - linezolid, inhibiting translation of mitoribosomes and inducing mitochondrial dysfunction. We provided the first in vivo evidence demonstrating that linezolid suppressed tumour growth rate, accompanied by increased autophagy. In addition, our results revealed that bactericidal antibiotics used in combination with autophagy blocker decrease tumour growth. This study puts mitochondria in a spotlight for cancer therapy and...

Research paper thumbnail of Otologic, audiometric and speech findings in patients undergoing surgery for cleft palate

BMC Pediatrics

Background: Although considerable progress has been made in the last 30 years in the treatment of... more Background: Although considerable progress has been made in the last 30 years in the treatment of cleft palate (CP), a multidisciplinary approach combining examinations by a paediatrician, maxillofacial surgeon, otolaryngologist and speech and language pathologist followed by surgical operation is still required. In this work, we performed an observational cross-sectional study to determine whether the CP grade or number of ventilation tubes received was associated with tympanic membrane abnormalities, hearing loss or speech outcomes. Methods: Otologic, audiometric, tympanometric and speech evaluations were performed in a cohort of 121 patients (children > 6 years) who underwent an operation for CP at the Vall d'Hebron Hospital, Barcelona from 2000 to 2014. Results: The most and least frequent CP types evaluated according to the Veau grade were type III (55.37%) and I (8.26%), respectively. A normal appearance of the membrane was observed in 58% individuals, of whom 55% never underwent ventilation ear tube insertion. No statistically significant associations were identified between the CP type and number of surgeries for insertion of tubes (p = 0.820). The degree of hearing loss (p = 0.616), maximum impedance (p = 0.800) and tympanic membrane abnormalities indicative of chronic otitis media (COM) (p = 0.505) among examined patients revealed no statistically significant association with the grade of CP. However, an association was identified between hypernasality and the grade of CP (p = 0.053), COM (p = 0.000), hearing loss (p = 0.000) and number of inserted ventilation tubes. Conclusion: Although the placement of tympanic ventilation tubes has been accompanied by an increased rate of COM, it is still important to assess whether this is a result of the number of ventilation tubes inserted or it is intrinsic to the natural history of middle ear inflammatory disease of such patients. Our results do not support improvements in speech, hearing, or tympanic membrane abnormalities with more aggressive management of COM with tympanostomy tubes.

Research paper thumbnail of miR-99a reveals two novel oncogenic proteins E2F2 and EMR2 and represses stemness in lung cancer

Cell death & disease, Oct 26, 2017

Lung cancer is one of the most aggressive tumours with very low life expectancy. Altered microRNA... more Lung cancer is one of the most aggressive tumours with very low life expectancy. Altered microRNA expression is found in human tumours because it is involved in tumour growth, progression and metastasis. In this study, we analysed microRNA expression in 47 lung cancer biopsies. Among the most downregulated microRNAs we focussed on the miR-99a characterisation. In vitro experiments showed that miR-99a expression decreases the proliferation of H1650, H1975 and H1299 lung cancer cells causing cell cycle arrest and apoptosis. We identified two novel proteins, E2F2 (E2F transcription factor 2) and EMR2 (EGF-like module-containing, mucin-like, hormone receptor-like 2), downregulated by miR-99a by its direct binding to their 3'-UTR. Moreover, miR-99a expression prevented cancer cell epithelial-to-mesenchymal transition (EMT) and repressed the tumourigenic potential of the cancer stem cell (CSC) population in both these cell lines and mice tumours originated from H1975 cells. The expres...

Research paper thumbnail of Prostate Tumor Overexpressed-1 (PTOV1) promotes docetaxel-resistance and survival of castration resistant prostate cancer cells

Oncotarget

Metastatic prostate cancer is presently incurable. The oncogenic protein PTOV1, first described i... more Metastatic prostate cancer is presently incurable. The oncogenic protein PTOV1, first described in prostate cancer, was reported as overexpressed and significantly correlated with poor survival in numerous tumors. Here, we investigated the role of PTOV1 in prostate cancer survival to docetaxel and self-renewal ability. Transduction of PTOV1 in docetaxel-sensitive Du145 and PC3 cells significantly increased cell survival after docetaxel exposure and induced docetaxel-resistance genes expression (ABCB1, CCNG2 and TUBB2B). In addition, PTOV1 induced prostatospheres formation and self-renewal genes expression (ALDH1A1, LIN28A, MYC and NANOG). In contrast, Du145 and PC3 cells knockdown for PTOV1 significantly accumulated in the G2/M phase, presented a concomitant increased subG1 peak, and cell death by apoptosis. These effects were enhanced in docetaxel-resistant cells. Analyses of tumor datasets show that PTOV1 expression significantly correlated with prostate tumor grade, drug resistance (CCNG2) and self-renewal (ALDH1A1, MYC) markers. These genes are concurrently overexpressed in most metastatic lesions. Metastases also show PTOV1 genomic amplification in significant co-occurrence with docetaxel-resistance and selfrenewal genes. Our findings identify PTOV1 as a promoter of docetaxel-resistance and self-renewal characteristics for castration resistant prostate cancer. The concomitant increased expression of PTOV1, ALDH1A1 and CCNG2 in primary tumors, may predict metastasis and bad prognosis.

Research paper thumbnail of DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders

Scientific reports, Jan 18, 2017

This work provides a comprehensive CpG methylation landscape of the different layers of the human... more This work provides a comprehensive CpG methylation landscape of the different layers of the human eye that unveils the gene networks associated with their biological functions and how these are disrupted in common visual disorders. Herein, we firstly determined the role of CpG methylation in the regulation of ocular tissue-specification and described hypermethylation of retinal transcription factors (i.e., PAX6, RAX, SIX6) in a tissue-dependent manner. Second, we have characterized the DNA methylome of visual disorders linked to internal and external environmental factors. Main conclusions allow certifying that crucial pathways related to Wnt-MAPK signaling pathways or neuroinflammation are epigenetically controlled in the fibrotic disorders involved in retinal detachment, but results also reinforced the contribution of neurovascularization (ETS1, HES5, PRDM16) in diabetic retinopathy. Finally, we had studied the methylome in the most frequent intraocular tumors in adults and childr...

Research paper thumbnail of Mitochondrial dysfunction and potential anticancer therapy

Medicinal research reviews, Jan 6, 2017

Mitochondrial dysfunction (MDF) has been identified as an important factor in various diseases ra... more Mitochondrial dysfunction (MDF) has been identified as an important factor in various diseases ranging from neurological disorders, to diseases of the cardiovascular system and metabolic syndromes. MDF was also found in cancer as well as in cancer predisposition syndromes with defective DNA damage response (DDR) machinery. Moreover, a recent highlight arises from the detection of MDF in eukaryotic cells upon treatment with antibiotics. In this review, we focus on recent studies of MDF in pathological conditions with a particular emphasis on the effects of various classes of antibiotics on mitochondria. Special attention is given to the role of autophagy/mitophagy in MDF and repurposing antibiotics as anticancer drugs.

Research paper thumbnail of Reactive Oxygen Species-Mediated Autophagy Defines the Fate of Cancer Stem Cells

Antioxidants & redox signaling, Jan 4, 2017

A fraction of tumorigenic cells, also known as tumor initiating or cancer stem cells (CSCs), is t... more A fraction of tumorigenic cells, also known as tumor initiating or cancer stem cells (CSCs), is thought to drive tumor growth, metastasis, and chemoresistance. However, little is known regarding mechanisms that convey relevant pathways contributing to their self-renewal, proliferation, and differentiation abilities. Recent Advances: Recent works on CSCs provide evidence on the role of redox disruption and regulation of autophagic flux. This has been linked to increased DNA repair capacity and chemoresistance. The current review summarizes the most recent studies assessing the role of redox homeostasis, autophagy, and chemoresistance in CSCs, including some novel findings on microRNAs and their role in horizontal transfer within cancer cell populations. Rational anticancer therapy and prevention should rely on the fact that cancer is a redox disease with the CSCs being the apex modulated by redox-mediated autophagy. Antioxid. Redox Signal. 00, 000-000.

Research paper thumbnail of Expression patterns and bioinformatic analysis of miR-1260a and miR-1274a in Prostate Cancer Tunisian patients

Molecular Biology Reports, 2018

Currently, microRNAs (miRs) represent great biomarkers in cancer due to their stability and their... more Currently, microRNAs (miRs) represent great biomarkers in cancer due to their stability and their potential role in diagnosis, prognosis and therapy. This study aims to evaluate the expression levels of miRs-1260 and-1274a in prostate cancer (PC) samples and to identify their eventual targets by using bioinformatic analysis. In this project, we evaluated the expression status of miRs-1260 and-1274a in 86 PC patients and 19 controls by using real-time quantitative PCR and 2 −ΔΔCt method. Moreover, we retrieved validated and predicted targets of miRs from several datasets by using the "multiMir" R/Bioconductor package. We have found that miRs-1260 and-1274a were over-expressed in PC patients compared to controls (p < 1 × 10 −5). Moreover ROC curve for miRs-1260 and 1274a showed a good performance to distinguish between controls group and PC samples with an area under the ROC curve of 0.897 and 0.784 respectively. However, no significant association could be shown between these two miRs and clinical parameters such as PSA levels, Gleason score, tumor stage, D'Amico classification, lymph node metastasis statues, tumor recurrence, metastasis status and progression after a minimum of 5 years follow-up. Finally, a bioinformatic analysis revealed the association between these two miRs and several targets implicated in prostate cancer initiation pathways.

Research paper thumbnail of Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma

Cancers

To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma ... more To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma (HNSCC), we explored the expression profiles of the following cisplatin (CDDP) resistant (R) versus parental (sensitive) cell lines by RNA-sequencing (RNA-seq): JHU029, HTB-43 and CCL-138. Using the parental condition as a control, 30 upregulated and 85 downregulated genes were identified for JHU029-R cells; 263 upregulated and 392 downregulated genes for HTB-43-R cells, and 154 upregulated and 68 downregulated genes for CCL-138-R cells. Moreover, we crossed-checked the RNA-seq results with the proteomic profiles of HTB-43-R (versus HTB-43) and CCL-138-R (versus CCL-138) cell lines. For the HTB-43-R cells, 21 upregulated and 72 downregulated targets overlapped between the proteomic and transcriptomic data; whereas in CCL-138-R cells, four upregulated and three downregulated targets matched. Following an extensive literature search, six genes from the RNA-seq (CLDN1, MAGEB2, CD24, CEACAM6...

Research paper thumbnail of Editorial: Sphingolipid metabolism and cancer

Frontiers in Oncology

Editorial on the Research Topic Sphingolipid metabolism and cancer We are pleased to present this... more Editorial on the Research Topic Sphingolipid metabolism and cancer We are pleased to present this Research Topic entitled "Sphingolipid Metabolism and Cancer", which features review articles focusing on sphingolipid metabolism in the regulation of cancer pathogenesis and therapy. Bioactive sphingolipids and ceramides modulate the composition of plasma membranes and play a critical role in cell signal transduction (1, 2). Metabolism of sphingolipid is essential for cellular processes, cell growth and proliferation, mitochondrial-autophagy-lysosomal pathways, apoptosis, invasion and metastasis, and immune function (3-5). Moreover, trapping of sphingolipids and their metabolites in lysosomes due to altered sphingolipid metabolism directly affects the lipid compositions of membranes. Accumulating undigested substrates in lysosomes due to deficiencies of various enzymes related to sphingolipid metabolism is linked to more than 50 types of lysosomal storage diseases (6). Recent studies have shown that some sphingolipids and ceramides are involved in cancer progression, malignancy, and drug resistance (7). The knowledge of molecular details of the roles of sphingolipids and their downstream targets in cancer progression opens a new window to develop new therapies to target sphingolipids. The Research Topic focuses on the functional disruption of sphingolipid metabolism in cancer pathology and a review of novel therapeutic agents targeting sphingolipid metabolism. This Topic gathered a pool of 4 papers, including one research article and three systematic reviews. They all provide essential data on targeting sphingolipids for cancer therapy and cancer drug resistance. Ceramide synthesis is a central hub of sphingolipid metabolism (8). In addition, ceramide isoforms play a distinct role in the autophagy-lysosomal signaling pathway, ER stress, and apoptosis. C16 ceramide is part of the mitochondrial outer membrane and forms channels that increase permeability and apoptosis (9). Trapika et al. showed the role of C16 ceramide levels in the prostate cancer model. The authors demonstrated that erianin increased the level of C16 ceramide in androgen-dependent prostate cancer cells

Research paper thumbnail of The Role of Sphingolipids Metabolism in Cancer Drug Resistance

Frontiers in Oncology, 2021

Drug resistance continues to be one of the major challenges to cure cancer. As research in this f... more Drug resistance continues to be one of the major challenges to cure cancer. As research in this field evolves, it has been proposed that numerous bioactive molecules might be involved in the resistance of cancer cells to certain chemotherapeutics. One well-known group of lipids that play a major role in drug resistance are the sphingolipids. Sphingolipids are essential components of the lipid raft domains of the plasma membrane and this structural function is important for apoptosis and/or cell proliferation. Dysregulation of sphingolipids, including ceramide, sphingomyelin or sphingosine 1-phosphate, has been linked to drug resistance in different types of cancer, including breast, melanoma or colon cancer. Sphingolipid metabolism is complex, involving several lipid catabolism with the participation of key enzymes such as glucosylceramide synthase (GCS) and sphingosine kinase 1 (SPHK1). With an overview of the latest available data on this topic and its implications in cancer thera...

Research paper thumbnail of Targeting Sphingolipids for Cancer Therapy

Frontiers in Oncology, 2021

Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from... more Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from proliferation to cell death. Sphingolipids are modified in multiple cancers and are responsible for tumor proliferation, progression, and metastasis. Several inhibitors or activators of sphingolipid signaling, such as fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, α-galactosylceramide, fingolimod, and sonepcizumab, have been described. The objective of this review was to analyze the results from preclinical and clinical trials of these drugs for the treatment of cancer. Sphingolipid-targeting drugs have been tested alone or in combination with chemotherapy, exhibiting antitumor activity alone and in synergism with chemotherapy in vitro and in vivo. As a consequence of treatments, the most frequent mechanism of cell death is apoptosis, followed by autophagy. Aslthough all these drugs have produced good results in preclinical studies of multiple cancers, the outc...

Research paper thumbnail of Advance Access publication January 19, 2008

PPP1CA contributes to the senescence program induced by oncogenic Ras

Research paper thumbnail of Cold-inducible RNA binding protein promotes breast cancer cell malignancy by regulating Cystatin C levels

RNA, 2020

Cold-inducible RNA binding protein (CIRBP) is a stress-responsive protein that promotes cancer de... more Cold-inducible RNA binding protein (CIRBP) is a stress-responsive protein that promotes cancer development and inflammation. Critical to most CIRBP functions is its capacity to bind and posttranscriptionally modulate mRNA. However, a transcriptome-wide analysis of CIRBP mRNA targets in cancer has not yet been performed. Here, we use an ex vivo breast cancer model to identify CIRBP targets and mechanisms. We find that CIRBP transcript levels correlate with breast cancer subtype and are an indicator of luminal A/B prognosis. Accordingly, overexpression of CIRBP in nontumoral MCF-10A cells promotes cell growth and clonogenicity, while depletion of CIRBP from luminal A MCF-7 cells has opposite effects. We use RNA immunoprecipitation followed by high-throughput sequencing (RIP-seq) to identify a set of 204 high confident CIRBP targets in MCF-7 cells. About 10% of these showed complementary changes after CIRBP manipulation in MCF-10A and MCF-7 cells, and were highly interconnected with kn...

Research paper thumbnail of Editor's Note: Immortalization of Primary Human Prostate Epithelial Cells by c-Myc

Cancer Research

The editors are publishing this note to alert readers to concerns about this article (1). We were... more The editors are publishing this note to alert readers to concerns about this article (1). We were informed by the authors that in Fig. 1B, the panels showing E7-and mdm2-expressing cells originated from the same picture of mdm2-expressing cells. In addition, in Fig. 2C, the Western blots showing hTERT and c-Myc expression were spliced but this was not indicated in the figure legend.

Research paper thumbnail of Editorial: How Do Metabolism, Angiogenesis, and Hypoxia Modulate Resistance?

Frontiers in Oncology

Metabolic alterations were among the first discovered hallmarks of cancer. They were first descri... more Metabolic alterations were among the first discovered hallmarks of cancer. They were first described 90 years ago when Otto Warburg realized that cancer cells in culture had a relatively increased metabolic rate (the Warburg hypothesis). It has been proposed that the drastic changes seen in cancer metabolism are in part attributed to mutations in the mtDNA, metabolic reprogramming, or mitochondrial dysfunction. However, novel players in cancer metabolism are emerging. In this regard, the review of Fernández et al. describes how lipidic alterations impact cancer prognosis and response to treatment. For example, it has been described that obesity increases the risk of cancer death, possibly due to the consequences of lipid accumulation throughout a lifetime. Lipid accumulation changes the microenvironment and produces chronic inflammation by increasing several cytokines. While the levels of genetic or epigenetic modifications diverge in different cancer types, all cancer cells adapt to drastic microenvironmental conditions. This adaptation entails metabolic reprogramming to cope with scarce nutrients and oxygen. Lipid metabolism sustains cancer initiation and contributes to cancer progression and therapy resistance. The role of lipids has been underestimated, as they have largely been considered scaffolds of biological membranes. In recent decades, the role of lipids in cancer has emerged in parallel to the characterization of lipids as essential components of cell signaling, redox homeostasis control, and energy sources (i.e., ß-fatty acid oxidation). Moreover, while de novo synthesis of fatty acids and cholesterol is restricted to the liver and adipocytes in normal cells, cancer cells can synthesize such components. This altered lipid metabolism affects key steps involved in the metastatic process, like migration, invasion, and angiogenesis, and can also be associated with prognosis. Moreover, Fernández et al. provide a list of preclinical and clinical studies with bioactive compounds from natural sources to target lipid metabolism and associated risk factors in cancer. Tumor adaptation to hypoxia is another important aspect that modulates resistance in cancer. Hypoxia is a forced situation where oxygen levels are different from normal physiological conditions. Hypoxia occurs in higher or minor levels in most cancers, if not all. The detection of hypoxic areas by clinical imaging would improve cancer chemotherapeutic treatments and optimal radiotherapy planning. The technique of positron emission tomography (PET) measures cancer metabolism and cellular proliferation, but it can also measure blood flow and oxygen use. PET can

Research paper thumbnail of TSPAN1: A Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance

Cancers

Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in can... more Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial–mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 wit...

Research paper thumbnail of SDCBP Modulates Stemness and Chemoresistance in Head and Neck Squamous Cell Carcinoma through Src Activation

Cancers

To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic ... more To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeu...

Research paper thumbnail of Five microRNAs in Serum Are Able to Differentiate Breast Cancer Patients From Healthy Individuals

Research paper thumbnail of Autophagy Takes Center Stage as a Possible Cancer Hallmark

Research paper thumbnail of Common metabolic pathways implicated in resistance to chemotherapy point to a key mitochondrial role in breast cancer

Molecular & cellular proteomics : MCP, Jan 29, 2018

Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by t... more Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumour growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumour recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and down-regulated proteins from metabolic pathways that suggests their dependence on mitochondria for survival. Here, we selected antibiotics, in particular - linezolid, inhibiting translation of mitoribosomes and inducing mitochondrial dysfunction. We provided the first in vivo evidence demonstrating that linezolid suppressed tumour growth rate, accompanied by increased autophagy. In addition, our results revealed that bactericidal antibiotics used in combination with autophagy blocker decrease tumour growth. This study puts mitochondria in a spotlight for cancer therapy and...

Research paper thumbnail of Otologic, audiometric and speech findings in patients undergoing surgery for cleft palate

BMC Pediatrics

Background: Although considerable progress has been made in the last 30 years in the treatment of... more Background: Although considerable progress has been made in the last 30 years in the treatment of cleft palate (CP), a multidisciplinary approach combining examinations by a paediatrician, maxillofacial surgeon, otolaryngologist and speech and language pathologist followed by surgical operation is still required. In this work, we performed an observational cross-sectional study to determine whether the CP grade or number of ventilation tubes received was associated with tympanic membrane abnormalities, hearing loss or speech outcomes. Methods: Otologic, audiometric, tympanometric and speech evaluations were performed in a cohort of 121 patients (children > 6 years) who underwent an operation for CP at the Vall d'Hebron Hospital, Barcelona from 2000 to 2014. Results: The most and least frequent CP types evaluated according to the Veau grade were type III (55.37%) and I (8.26%), respectively. A normal appearance of the membrane was observed in 58% individuals, of whom 55% never underwent ventilation ear tube insertion. No statistically significant associations were identified between the CP type and number of surgeries for insertion of tubes (p = 0.820). The degree of hearing loss (p = 0.616), maximum impedance (p = 0.800) and tympanic membrane abnormalities indicative of chronic otitis media (COM) (p = 0.505) among examined patients revealed no statistically significant association with the grade of CP. However, an association was identified between hypernasality and the grade of CP (p = 0.053), COM (p = 0.000), hearing loss (p = 0.000) and number of inserted ventilation tubes. Conclusion: Although the placement of tympanic ventilation tubes has been accompanied by an increased rate of COM, it is still important to assess whether this is a result of the number of ventilation tubes inserted or it is intrinsic to the natural history of middle ear inflammatory disease of such patients. Our results do not support improvements in speech, hearing, or tympanic membrane abnormalities with more aggressive management of COM with tympanostomy tubes.

Research paper thumbnail of miR-99a reveals two novel oncogenic proteins E2F2 and EMR2 and represses stemness in lung cancer

Cell death & disease, Oct 26, 2017

Lung cancer is one of the most aggressive tumours with very low life expectancy. Altered microRNA... more Lung cancer is one of the most aggressive tumours with very low life expectancy. Altered microRNA expression is found in human tumours because it is involved in tumour growth, progression and metastasis. In this study, we analysed microRNA expression in 47 lung cancer biopsies. Among the most downregulated microRNAs we focussed on the miR-99a characterisation. In vitro experiments showed that miR-99a expression decreases the proliferation of H1650, H1975 and H1299 lung cancer cells causing cell cycle arrest and apoptosis. We identified two novel proteins, E2F2 (E2F transcription factor 2) and EMR2 (EGF-like module-containing, mucin-like, hormone receptor-like 2), downregulated by miR-99a by its direct binding to their 3'-UTR. Moreover, miR-99a expression prevented cancer cell epithelial-to-mesenchymal transition (EMT) and repressed the tumourigenic potential of the cancer stem cell (CSC) population in both these cell lines and mice tumours originated from H1975 cells. The expres...

Research paper thumbnail of Prostate Tumor Overexpressed-1 (PTOV1) promotes docetaxel-resistance and survival of castration resistant prostate cancer cells

Oncotarget

Metastatic prostate cancer is presently incurable. The oncogenic protein PTOV1, first described i... more Metastatic prostate cancer is presently incurable. The oncogenic protein PTOV1, first described in prostate cancer, was reported as overexpressed and significantly correlated with poor survival in numerous tumors. Here, we investigated the role of PTOV1 in prostate cancer survival to docetaxel and self-renewal ability. Transduction of PTOV1 in docetaxel-sensitive Du145 and PC3 cells significantly increased cell survival after docetaxel exposure and induced docetaxel-resistance genes expression (ABCB1, CCNG2 and TUBB2B). In addition, PTOV1 induced prostatospheres formation and self-renewal genes expression (ALDH1A1, LIN28A, MYC and NANOG). In contrast, Du145 and PC3 cells knockdown for PTOV1 significantly accumulated in the G2/M phase, presented a concomitant increased subG1 peak, and cell death by apoptosis. These effects were enhanced in docetaxel-resistant cells. Analyses of tumor datasets show that PTOV1 expression significantly correlated with prostate tumor grade, drug resistance (CCNG2) and self-renewal (ALDH1A1, MYC) markers. These genes are concurrently overexpressed in most metastatic lesions. Metastases also show PTOV1 genomic amplification in significant co-occurrence with docetaxel-resistance and selfrenewal genes. Our findings identify PTOV1 as a promoter of docetaxel-resistance and self-renewal characteristics for castration resistant prostate cancer. The concomitant increased expression of PTOV1, ALDH1A1 and CCNG2 in primary tumors, may predict metastasis and bad prognosis.

Research paper thumbnail of DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders

Scientific reports, Jan 18, 2017

This work provides a comprehensive CpG methylation landscape of the different layers of the human... more This work provides a comprehensive CpG methylation landscape of the different layers of the human eye that unveils the gene networks associated with their biological functions and how these are disrupted in common visual disorders. Herein, we firstly determined the role of CpG methylation in the regulation of ocular tissue-specification and described hypermethylation of retinal transcription factors (i.e., PAX6, RAX, SIX6) in a tissue-dependent manner. Second, we have characterized the DNA methylome of visual disorders linked to internal and external environmental factors. Main conclusions allow certifying that crucial pathways related to Wnt-MAPK signaling pathways or neuroinflammation are epigenetically controlled in the fibrotic disorders involved in retinal detachment, but results also reinforced the contribution of neurovascularization (ETS1, HES5, PRDM16) in diabetic retinopathy. Finally, we had studied the methylome in the most frequent intraocular tumors in adults and childr...

Research paper thumbnail of Mitochondrial dysfunction and potential anticancer therapy

Medicinal research reviews, Jan 6, 2017

Mitochondrial dysfunction (MDF) has been identified as an important factor in various diseases ra... more Mitochondrial dysfunction (MDF) has been identified as an important factor in various diseases ranging from neurological disorders, to diseases of the cardiovascular system and metabolic syndromes. MDF was also found in cancer as well as in cancer predisposition syndromes with defective DNA damage response (DDR) machinery. Moreover, a recent highlight arises from the detection of MDF in eukaryotic cells upon treatment with antibiotics. In this review, we focus on recent studies of MDF in pathological conditions with a particular emphasis on the effects of various classes of antibiotics on mitochondria. Special attention is given to the role of autophagy/mitophagy in MDF and repurposing antibiotics as anticancer drugs.

Research paper thumbnail of Reactive Oxygen Species-Mediated Autophagy Defines the Fate of Cancer Stem Cells

Antioxidants & redox signaling, Jan 4, 2017

A fraction of tumorigenic cells, also known as tumor initiating or cancer stem cells (CSCs), is t... more A fraction of tumorigenic cells, also known as tumor initiating or cancer stem cells (CSCs), is thought to drive tumor growth, metastasis, and chemoresistance. However, little is known regarding mechanisms that convey relevant pathways contributing to their self-renewal, proliferation, and differentiation abilities. Recent Advances: Recent works on CSCs provide evidence on the role of redox disruption and regulation of autophagic flux. This has been linked to increased DNA repair capacity and chemoresistance. The current review summarizes the most recent studies assessing the role of redox homeostasis, autophagy, and chemoresistance in CSCs, including some novel findings on microRNAs and their role in horizontal transfer within cancer cell populations. Rational anticancer therapy and prevention should rely on the fact that cancer is a redox disease with the CSCs being the apex modulated by redox-mediated autophagy. Antioxid. Redox Signal. 00, 000-000.