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1.
Int J Mol Sci ; 23(23)2022 Nov 29.
Article in English | MEDLINE | ID: mdl-36499267

ABSTRACT

Osteosarcoma represents a rare cause of cancer in the general population, accounting for <1% of malignant neoplasms globally. Nonetheless, it represents the main cause of malignant bone neoplasm in children, adolescents and young adults under 20 years of age. It also presents another peak of incidence in people over 50 years of age and is associated with rheumatic diseases. Numerous environmental risk factors, such as bone diseases, genetics and a history of previous neoplasms, have been widely described in the literature, which allows monitoring a certain group of patients. Diagnosis requires numerous imaging tests that make it possible to stratify both the local involvement of the disease and its distant spread, which ominously determines the prognosis. Thanks to various clinical trials, the usefulness of different chemotherapy regimens, radiotherapy and surgical techniques with radical intent has now been demonstrated; these represent improvements in both prognosis and therapeutic approaches. Osteosarcoma patients should be evaluated in reference centres by multidisciplinary committees with extensive experience in proper management. Although numerous genetic and rheumatological diseases and risk factors have been described, the use of serological, genetic or other biomarkers has been limited in clinical practice compared to other neoplasms. This limits both the initial follow-up of these patients and screening in populations at risk. In addition, we cannot forget that the diagnosis is mainly based on the direct biopsy of the lesion and imaging tests, which illustrates the need to study new diagnostic alternatives. Therefore, the purpose of this study is to review the natural history of the disease and describe the main biomarkers, explaining their clinical uses, prognosis and limitations.


Subject(s)
Bone Neoplasms , Osteosarcoma , Child , Adolescent , Young Adult , Humans , Middle Aged , Osteosarcoma/diagnosis , Osteosarcoma/genetics , Osteosarcoma/therapy , Bone Neoplasms/diagnosis , Bone Neoplasms/genetics , Bone Neoplasms/therapy , Incidence
2.
Cells ; 10(8)2021 07 24.
Article in English | MEDLINE | ID: mdl-34440648

ABSTRACT

The gene expression program induced by NRF2 transcription factor plays a critical role in cell defense responses against a broad variety of cellular stresses, most importantly oxidative stress. NRF2 stability is fine-tuned regulated by KEAP1, which drives its degradation in the absence of oxidative stress. In the context of cancer, NRF2 cytoprotective functions were initially linked to anti-oncogenic properties. However, in the last few decades, growing evidence indicates that NRF2 acts as a tumor driver, inducing metastasis and resistance to chemotherapy. Constitutive activation of NRF2 has been found to be frequent in several tumors, including some lung cancer sub-types and it has been associated to the maintenance of a malignant cell phenotype. This apparently contradictory effect of the NRF2/KEAP1 signaling pathway in cancer (cell protection against cancer versus pro-tumoral properties) has generated a great controversy about its functions in this disease. In this review, we will describe the molecular mechanism regulating this signaling pathway in physiological conditions and summarize the most important findings related to the role of NRF2/KEAP1 in lung cancer. The focus will be placed on NRF2 activation mechanisms, the implication of those in lung cancer progression and current therapeutic strategies directed at blocking NRF2 action.


Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , NF-E2-Related Factor 2/metabolism , Small Cell Lung Carcinoma/metabolism , Animals , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Gene Expression Regulation, Neoplastic , Humans , Kelch-Like ECH-Associated Protein 1/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Molecular Targeted Therapy , NF-E2-Related Factor 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , Signal Transduction , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/pathology
3.
Trends Cancer ; 5(4): 233-244, 2019 04.
Article in English | MEDLINE | ID: mdl-30961830

ABSTRACT

Dysregulation of the PI3K/PTEN pathway is a frequent event in cancer, and PIK3CA and PTEN are the most commonly mutated genes after TP53. PIK3R1 is the predominant regulatory isoform of PI3K. PIK3R2 is an ubiquitous isoform that has been so far overlooked, but data from The Cancer Genome Atlas shows that increased expression of PIK3R2 is also frequent in cancer. In contrast to PIK3R1, which is a tumor-suppressor gene, PIK3R2 is an oncogene. We review here the opposing roles of PIK3R1 and PIK3R2 in cancer, the regulatory mechanisms that control PIK3R2 expression, and emerging therapeutic approaches targeting PIK3R2.


Subject(s)
Biomarkers, Tumor , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Disease Susceptibility , Neoplasms/etiology , Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Animals , Cell Adhesion , Class Ia Phosphatidylinositol 3-Kinase/chemistry , Class Ia Phosphatidylinositol 3-Kinase/genetics , Humans , Neoplasms/pathology , Oncogene Proteins/genetics , Oncogene Proteins/metabolism , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/genetics , Protein Binding , Protein Interaction Domains and Motifs , Protein Transport , Signal Transduction , Structure-Activity Relationship , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
4.
Oncotarget ; 7(51): 85063-85078, 2016 Dec 20.
Article in English | MEDLINE | ID: mdl-27835880

ABSTRACT

Oncogenic mutations in the PI3K/AKT pathway are present in nearly half of human tumors. Nonetheless, inhibitory compounds of the pathway often induce pathway rebound and tumor resistance. We find that lung squamous cell carcinoma (SQCC), which accounts for ~20% of lung cancer, exhibits increased expression of the PI3K subunit PIK3R2, which is at low expression levels in normal tissues. We tested a new approach to interfere with PI3K/AKT pathway activation in lung SQCC. We generated tumor xenografts of SQCC cell lines and examined the consequences of targeting PIK3R2 expression. In tumors with high PIK3R2 expression, and independently of PIK3CA, KRAS, or PTEN mutations, PIK3R2 depletion induced lung SQCC xenograft regression without triggering PI3K/AKT pathway rebound. These results validate the use PIK3R2 interfering tools for the treatment of lung squamous cell carcinoma.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Lung Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Animals , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Mice , Mice, Inbred BALB C , Molecular Targeted Therapy , Phosphatidylinositol 3-Kinases/genetics , RNA, Small Interfering/genetics , Tumor Burden , Up-Regulation , Xenograft Model Antitumor Assays
5.
Nucleic Acids Res ; 40(1): 116-31, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21911366

ABSTRACT

Global mechanisms defining the gene expression programs specific for hematopoiesis are still not fully understood. Here, we show that promoter DNA demethylation is associated with the activation of hematopoietic-specific genes. Using genome-wide promoter methylation arrays, we identified 694 hematopoietic-specific genes repressed by promoter DNA methylation in human embryonic stem cells and whose loss of methylation in hematopoietic can be associated with gene expression. The association between promoter methylation and gene expression was studied for many hematopoietic-specific genes including CD45, CD34, CD28, CD19, the T cell receptor (TCR), the MHC class II gene HLA-DR, perforin 1 and the phosphoinositide 3-kinase (PI3K) and results indicated that DNA demethylation was not always sufficient for gene activation. Promoter demethylation occurred either early during embryonic development or later on during hematopoietic differentiation. Analysis of the genome-wide promoter methylation status of induced pluripotent stem cells (iPSCs) generated from somatic CD34(+) HSPCs and differentiated derivatives from CD34(+) HSPCs confirmed the role of DNA methylation in regulating the expression of genes of the hemato-immune system, and indicated that promoter methylation of these genes may be associated to stemness. Together, these data suggest that promoter DNA demethylation might play a role in the tissue/cell-specific genome-wide gene regulation within the hematopoietic compartment.


Subject(s)
DNA Methylation , Gene Expression Regulation , Hematopoiesis/genetics , Hematopoietic Stem Cells/metabolism , Promoter Regions, Genetic , Animals , Cell Dedifferentiation , Cell Line , Embryonic Stem Cells/metabolism , Hematopoietic Stem Cells/cytology , Humans , Infant, Newborn , Mice , Oligonucleotide Array Sequence Analysis
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