Morra, Francesco (2014) New Therapeutic Perspective in CCDC6 Deficient Lung Cancer Cells. [Tesi di dottorato]
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| Tipologia del documento: | Tesi di dottorato | ||||
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| Lingua: | English | ||||
| Titolo: | New Therapeutic Perspective in CCDC6 Deficient Lung Cancer Cells | ||||
| Autori: |
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| Data: | 30 Marzo 2014 | ||||
| Numero di pagine: | 62 | ||||
| Istituzione: | Università degli Studi di Napoli Federico II | ||||
| Dipartimento: | Medicina Molecolare e Biotecnologie Mediche | ||||
| Scuola di dottorato: | Medicina molecolare | ||||
| Dottorato: | Genetica e medicina molecolare | ||||
| Ciclo di dottorato: | 26 | ||||
| Coordinatore del Corso di dottorato: |
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| Data: | 30 Marzo 2014 | ||||
| Numero di pagine: | 62 | ||||
| Parole chiave: | CCDC6, Lung Cancer, NSCLC | ||||
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/03 - Genetica medica Area 06 - Scienze mediche > MED/04 - Patologia generale Area 06 - Scienze mediche > MED/06 - Oncologia medica |
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| Aree tematiche (7° programma Quadro): | SALUTE e TUTELA DEL CONSUMATORE > Biotecnologie, strumenti e tecnologie generiche per la salute umana | ||||
| Depositato il: | 10 Apr 2014 10:20 | ||||
| Ultima modifica: | 28 Gen 2015 09:30 | ||||
| URI: | http://www.fedoa.unina.it/id/eprint/9840 |
Abstract
Non-small cell lung cancer (NSCLC) is the main cause of cancer-related deaths worldwide and new therapeutic approaches for NSCLC are urgently needed. The role of CCDC6 in cancer induction and progression still remains largely unexplored, despite its emerging role as a tumour suppressor and its involvement in apoptosis and DNA damage response. In this study we have characterized a panel of nine NSC lung cancer cell lines for CCDC6 expression in order to evaluate their response to conventional treatments. In the NCI-H460 cells, a weak response to DNA damage and a low number of Rad51 positive foci are associated to low levels of the CCDC6 protein. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. The CCDC6 attenuation while conferring resistance to cisplatinum sensitizes these cells to the small molecule inhibitors of PARP1/2, such as olaparib. The combination of the two drugs is more effective than each agent individually, according to the combination index (CI < 1). Stable silencing of CCDC6 in the profoundly olaparib-resistant H1975 lung adenocarcinoma cell line increases sensitivity to olaparib alone and in combination with cisplatin, showing the relationship between CCDC6 and PARP1/2 inhibitor sensitivity. Besides the low penetrance of CCDC6 somatic mutations or the CCDC6-RET rearrangements, TMA immunostaining for CCDC6 revealed a low expression in about 30% of the NSCL tumours analyzed (45 out of 138). Compared to the stroma, the weak CCDC6 protein staining significantly correlated with the presence of lymph node metastasis (chi-squared test: p ≤ 0,02). Moreover, the CCDC6 low phenotype was negatively correlated to the Disease Free Survival (p ≤ 0.01) and the Overall Survival (p ≤ 0.05). We believe that the inclusion of CCDC6 in NSCLC clinical studies should provide an additional prognostic biomarker for the overall survival (OS) with also a predictive value for the resistance to conventional treatments in NSCLC patients.
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