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1.
J Transl Med ; 20(1): 467, 2022 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224560

RESUMO

BACKGROUND: Immunotherapy has dramatically improved cancer treatment by inhibiting or activating specific cell receptors, thus unleashing the host anti-tumor response. However, the engagement of the three main immune checkpoints so far identified, CTLA4, PD-1 and PD-L1, is effective in a fraction of patients, therefore novel targets must be identified and tested. METHODS: We focused our attention on the following nine highly relevant immune checkpoint (ICR) receptors: CTLA4, PD1, PD-L1, LAG3, TIM3, OX40, GITR, 4-1BB and TIGIT. All of them are targets of existing drugs currently under clinical scrutiny in several malignancies. Their expression levels were evaluated in patient tissues of 31 different cancer types vs. proper controls, in a total of 15,038 individuals. This analysis was carried out by interrogating public databases available on GEPIA2 portal and UALCAN portal. By the Principal Component Analysis (PCA) their ability to effectively discriminate patients form controls was then investigated. Expression of the nine ICRs was also related to overall survival in 31 cancer types and expressed as Hazard Ratio, on the GEPIA2 portal and validated, for melanoma patients, in patients-datasets available on PROGgene V2 portal. RESULTS: Significant differential expression was observed for each ICR molecule in many cancer types. A 7-molecules profile was found to specifically discriminate melanoma patients from controls, while two different 6-molecules profiles discriminate pancreatic cancer patients and Testicular Germ Cell Tumors from matched controls. Highly significant survival improvement was found to be related to the expression levels of all nine ICRs in a wide spectrum of malignancies. For melanoma analysis, the relation with survival observed in TCGA datasets was validated in independent GSE melanoma datasets. CONCLUSION: Analysis the nine ICR molecules demonstrates that their expression patterns may be considered as markers of disease and strong survival predictors in a variety of malignancies frequently associated to poor prognosis. Thus, the present findings are strongly advocating that exploratory clinical trials are worth to be performed, using available drugs, targeting these molecules.


Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Antígeno B7-H1 , Antígeno CTLA-4 , Expressão Gênica , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Fatores Imunológicos , Imunoterapia , Melanoma/genética , Melanoma/terapia , Prognóstico , Receptores Imunológicos
2.
Cells ; 9(2)2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041138

RESUMO

The microtubule-associated protein TPX2 is a key mitotic regulator that contributes through distinct pathways to spindle assembly. A well-characterised function of TPX2 is the activation, stabilisation and spindle localisation of the Aurora-A kinase. High levels of TPX2 are reported in tumours and the effects of its overexpression have been investigated in cancer cell lines, while little is known in non-transformed cells. Here we studied TPX2 overexpression in hTERT RPE-1 cells, using either the full length TPX2 or a truncated form unable to bind Aurora-A, to identify effects that are dependent-or independent-on its interaction with the kinase. We observe significant defects in mitotic spindle assembly and progression through mitosis that are more severe when overexpressed TPX2 is able to interact with Aurora-A. Furthermore, we describe a peculiar, and Aurora-A-interaction-independent, phenotype in telophase cells, with aberrantly stable microtubules interfering with nuclear reconstitution and the assembly of a continuous lamin B1 network, resulting in daughter cells displaying doughnut-shaped nuclei. Our results using non-transformed cells thus reveal a previously uncharacterised consequence of abnormally high TPX2 levels on the correct microtubule cytoskeleton remodelling and G1 nuclei reformation, at the mitosis-to-interphase transition.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Núcleo Celular/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Mitose , Aurora Quinase A/metabolismo , Linhagem Celular , Cromatina/metabolismo , Citoesqueleto/metabolismo , Complexo de Golgi/metabolismo , Humanos , Lamina Tipo B/metabolismo , Metáfase , Ligação Proteica , Telófase
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