Abstract The epidermal growth factor receptor (EGFR) is one of the main tumor drivers, and is an important therapeutic target for many cancers. Calcium is important in EGFR internalization and in EGFR signaling pathways. Sorcin is one of the most important calcium sensor proteins, overexpressed in many tumors, that promotes cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, malignant progression and resistance to chemotherapeutic drugs. The present work elucidates an important mechanism that links calcium homeostasis to EGFR signaling in cancer. Sorcin and EGFR overexpression are significantly correlated in cancer patients. Sorcin directly binds EGFR in a calcium-dependent fashion and regulates calcium (dys)homeostasis linked to EGF-dependent EGFR signaling. Sorcin controls EGFR signaling, increases its recycling, activates the PI3K/AKT signaling cascade, and controls the RAS/ERK cascade, participating in the regulation of cellular migration and invasion. Sorcin expression leads to increased cell migration, invasion and EMT, via PI3K/AKT signaling; Sorcin silencing reverses these cancer features, synergistically with EGFR inhibitors.
The occurrence of acute myeloid leukemia (AML) as a secondary tumor has been frequently reported in patients who received various chemotherapy regimens for hematologic malignancies wile the concomitant development of chronic lymphoproliferative diseases (CLD) and AML in previously untreated patients is extremely rare. We report a case with an apparently spontaneous occurrence of AML and non Hodgkin low-grade lymphoma diagnosed by immunological, cytogenetical and molecular analyses. In particular genetic studies allowed to identify the coexistence of a clonal lymphoid population and a myeloid blast component characterized by inv(16) marker and CBFbeta-MYH11 gene fusion. Complete remission of AML and the CLD was obtained following high doses of hydroxyurea and two consolidation cycles of fludarabine plus intermediate dose cytarabine.
Cancer Drug Resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal, molecular mechanisms of drug resistance and drug classes, etc. Both clinical and experimental aspects of drug resistance in cancer are included.
Remodeling of the chromatin template by inhibition of histone deacetylase (HDAC) activities represents a major goal for transcriptional therapy in neoplastic diseases. Recently, a number of specific and potent HDAC-inhibitors that modulate in vitro cell growth and differentiation have been developed. In this study we analyzed the effect of trichostatin A (TSA), a specific and potent HDAC-inhibitor, on mouse embryos developing in vivo. When administered i.p. to pregnant mice (at a concentration of 0.5-1 mg/kg) at postimplantation stages (embryonic day 8 to embryonic day 10), TSA was not toxic for the mother and did not cause any obvious malformation during somitogenesis or at later stages of development. Treated embryos were born at similar frequency and were indistinguishable from control animals, developed normally, and were fertile. Interestingly, embryos from TSA-treated mice killed during somitogenesis were modestly but consistently larger than control embryos and presented an increased (+2 to +6) number of somites. This correlated with an increased acetylation of histone H4, the number of somites expressing the myogenic factor Myf-5, and the expression of Notch, RARalpha2, and RARbeta2 mRNAs. These data indicate that the effects of TSA on transcription: (a) are not toxic for the mother; (b) transiently accelerated growth in mouse embryos without perturbing embryogenesis; and (c) do not result in teratogenesis, at least in rodents. Thus, TSA might represent a nontoxic and effective agent for the transcriptional therapy of neoplasia.
Abstract Understanding the mechanisms of breast cancer cell communication underlying cell spreading and metastasis formation is fundamental for developing new therapies. ID4 is a proto-oncogene overexpressed in the basal-like subtype of triple-negative breast cancer (TNBC), where it promotes angiogenesis, cancer stem cells, and BRACA1 misfunction. Here, we show that ID4 expression in BC cells correlates with the activation of motility pathways and promotes the production of VEGFA, which stimulates the interaction of VEGFR2 and integrin β3 in a paracrine fashion. This interaction induces the downstream focal adhesion pathway favoring migration, invasion, and stress fiber formation. Furthermore, ID4/ VEGFA/ VEGFR2/ integrin β3 signaling stimulates the nuclear translocation and activation of the Hippo pathway member’s YAP and TAZ, two critical executors for cancer initiation and progression. Our study provides new insights into the oncogenic roles of ID4 in tumor cell migration and YAP/TAZ pathway activation, suggesting VEGFA/ VEGFR2/ integrin β3 axis as a potential target for BC treatment.
Many epigenetic modifications occur in glioma, in particular the histone-deacetylase class proteins play a pivotal role in glioma development, driving the proliferation rate and the invasiveness of tumor cells, and modulating the tumor microenvironment. In this study, we evaluated the role of the histone deacetylase HDAC8 in the regulation of the immune response in glioma and tumor growth. We found that inhibition of HDAC8 by the specific inhibitor PCI-34051 reduces tumor volume in glioma mouse models. We reported that HDAC8 modulates the viability and the migration of human and murine glioma cells. Interestingly, HDAC8 inhibition increases the acetylation of alpha-tubulin, suggesting this epigenetic modification controls glioma migration. Furthermore, we identify HDAC8 as a key molecule that supports a poorly immunogenic tumor microenvironment, modulating microglial phenotype and regulating the gene transcription of NKG2D ligands that trigger the Natural Killer cell-mediated cytotoxicity of tumor cells. Altogether, these results identify HDAC8 as a key actor in glioma growth and tumor microenvironment, and pave the way to a better knowledge of the molecular mechanisms of immune escape in glioma.
Olympic trap clay target shooting (CTS) is currently performed by motor impaired individuals (MII), but not yet included in the International Paralympic Committee endorsement. This study aimed at supporting the development of a classification model that divides athletes competing in standing and sitting postures. Two groups of 5 standing and 5 sitting MII athletes were recruited for an instrumented CTS task execution. During competition, sitting athletes showed a lower rate of success with respect to the standing ones only for targets requiring wider ranges of motion, possibly due to fatigue. Their predominant use of upper body movements implies an adapted technique to reach a good performance, testified by a smoother movement, a lower peak accelerations at the gun tip, a smaller range for all absolute and relative rotations, and a different muscle activity.
The identification of a series of non-coding RNA (ncRNA) families, with regulatory roles in several biological processes, represents one of the most relevant advances derived from transcriptome analysis. These ncRNAs are actively transcribed from the genome of many organisms. Among them microRNAs (miRNAs) are small regulatory, single-stranded, RNA molecules (19–25 nucleotides in length) that are generated in the nucleus as hairpin primary transcripts. miRNAs processing is carried out initially in the nucleus and later on in the cytoplasm, where the mature miRNAs molecules, through a limited base-pairing complementarity, destabilize or block the translation of their phylogenetically conserved target transcripts [1]. miRNAs exert their function assembled in the RNA-induced silencing complexes (RISCs), where members of Argonaute (Ago) family of proteins provide a unique platform for target recognition and gene silencing. Interestingly, recent evidences also suggest that miRNAs and epigenetic pathways appear to form a complex regulatory circuit that modulates the expression of an increasing number of genes in the genome. miRNAs are not only modulated by epigenetic regulation but it is now emerging that miRNAs also have specific epigenetic functions for the regulation of the transcriptional landscape of the cell. Following the identification of a functional miRNAs pathway in C. elegans, their contribution to both embryonic development and maintenance of tissue homeostasis in adults has rapidly emerged also in mammals. miRNAs exhibit a developmental stage- and tissue-specific expression and are present in critical regulatory pathways to regulate stem cells function, cell lineage specification/differentiation, maintenance of cell identity and tissue induction, growth and morphogenesis. The identification of the molecular pathways involving miRNAs and specific RNA-binding proteins, responsible for the regulation of their production, localization, stability and activity, is gaining crucial importance for the characterization of physiological and pathological processes of human development.
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