Diffuse Large B-cell lymphoma (DLBCL) is the most common adult non-Hodgkin lymphoma, whose standard of care is the immunochemotherapy R-CHOP. Chemorefractory patients, still approximately 40%, represent an unmet medical need, requiring novel targets for innovative treatments. One potential target is cyclin-dependent kinase 5 (CDK5), a serine/threonine protein kinase that has been recently linked to tumor development and progression. Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39 and it is mostly active in the nervous system, regulating several processes. In the past few years, novel roles for Cdk5 have been proposed in many pathological conditions and cancer, even if its role in DLBCL remains uninvestigated to date. For the first time, we showed that Cdk5 and p35 are both overexpressed in DLBCL cell lines. Moreover, we highlighted that proliferation and apoptosis are regulated by Cdk5 activity in loss-of-function experiments. MicroRNAs (miRNAs) are a class of highly conserved short RNAs that regulate diverse cellular processes by degradation or translation inhibition of mRNA targets. Numerous reports have shown that miRNA dysfunction is involved in the development and progression of various human cancers (4). In particular, miR26a has a tumor suppressor role in different cancers, such as nasopharyngeal carcinoma (5) breast cancer (6) and gastric carcinoma (7), but its role in DLBCL remains still unclear. In this study we demonstrated that mir-R26 regulates p35 expression and that it involves Cdk5/p35 pathway directly affecting DLBCL cells proliferation and apoptosis. Thus, the clarification of the molecular mechanisms at the base of Cdk5/p35 expression and their role on DLBCL tumor cell proliferation could lead to the identification of innovative therapeutic targets for treatments of DLBCL.

CDK5 PLAYS A KEY ROLE IN PROLIFERATION, APOPTOSIS, AND IN VIVO TUMOR GROWTH OF DIFFUSE LARGE B-CELL LYMPHOMA / A. Inguscio ; relatore: C. Carlo-Stella ; correlatore: M. Quintavalle. - : . DIPARTIMENTO DI BIOTECNOLOGIE MEDICHE E MEDICINA TRASLAZIONALE, 2015 Jan 12. ((27. ciclo, Anno Accademico 2014. [10.13130/inguscio-alessandra_phd2015-01-12].

CDK5 PLAYS A KEY ROLE IN PROLIFERATION, APOPTOSIS, AND IN VIVO TUMOR GROWTH OF DIFFUSE LARGE B-CELL LYMPHOMA

A. Inguscio
2015

Abstract

Diffuse Large B-cell lymphoma (DLBCL) is the most common adult non-Hodgkin lymphoma, whose standard of care is the immunochemotherapy R-CHOP. Chemorefractory patients, still approximately 40%, represent an unmet medical need, requiring novel targets for innovative treatments. One potential target is cyclin-dependent kinase 5 (CDK5), a serine/threonine protein kinase that has been recently linked to tumor development and progression. Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39 and it is mostly active in the nervous system, regulating several processes. In the past few years, novel roles for Cdk5 have been proposed in many pathological conditions and cancer, even if its role in DLBCL remains uninvestigated to date. For the first time, we showed that Cdk5 and p35 are both overexpressed in DLBCL cell lines. Moreover, we highlighted that proliferation and apoptosis are regulated by Cdk5 activity in loss-of-function experiments. MicroRNAs (miRNAs) are a class of highly conserved short RNAs that regulate diverse cellular processes by degradation or translation inhibition of mRNA targets. Numerous reports have shown that miRNA dysfunction is involved in the development and progression of various human cancers (4). In particular, miR26a has a tumor suppressor role in different cancers, such as nasopharyngeal carcinoma (5) breast cancer (6) and gastric carcinoma (7), but its role in DLBCL remains still unclear. In this study we demonstrated that mir-R26 regulates p35 expression and that it involves Cdk5/p35 pathway directly affecting DLBCL cells proliferation and apoptosis. Thus, the clarification of the molecular mechanisms at the base of Cdk5/p35 expression and their role on DLBCL tumor cell proliferation could lead to the identification of innovative therapeutic targets for treatments of DLBCL.
CARLO STELLA, CARMELO
DLBCL; CDK5; miR-26a; proliferation; apoptosis; tumor growth
Settore BIO/13 - Biologia Applicata
CDK5 PLAYS A KEY ROLE IN PROLIFERATION, APOPTOSIS, AND IN VIVO TUMOR GROWTH OF DIFFUSE LARGE B-CELL LYMPHOMA / A. Inguscio ; relatore: C. Carlo-Stella ; correlatore: M. Quintavalle. - : . DIPARTIMENTO DI BIOTECNOLOGIE MEDICHE E MEDICINA TRASLAZIONALE, 2015 Jan 12. ((27. ciclo, Anno Accademico 2014. [10.13130/inguscio-alessandra_phd2015-01-12].
Doctoral Thesis
File in questo prodotto:
File Dimensione Formato  
phd_unimi_R09800.pdf

embargo fino al 16/12/2015

Tipologia: Tesi di dottorato completa
Dimensione 11.53 MB
Formato Adobe PDF
11.53 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/250916
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact