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// Renato Franco 1, 2, * , Giosue Scognamiglio 1, * , Elena Valentino 1 , Michela Vitiello 3 , Antonio Luciano 4 , Giuseppe Palma 4 , Claudio Arra 4 , Elvira La Mantia 1 , Luigi Panico 5 , Valentina Tenneriello 5 , Antonello Pinto 6 , Ferdinando Frigeri 6 , Gaetana Capobianco 6 , Gerardo Botti 1 , Laura Cerchia 3 , Annarosaria De Chiara 1 , Monica Fedele 3 1 Surgical Pathology Unit, National Cancer Institute ‘Fondazione Giovanni Pascale’, IRCCS, Naples, Italy 2 Pathology Unit, Second University of Naples, Naples, Italy 3 Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Naples, Italy 4 Animal Facility, National Cancer Institute ‘Fondazione Giovanni Pascale’, IRCCS, Naples, Italy 5 Pathology Unit, Hospital ‘S.G. Moscati’, Avellino, Italy 6 Haematology-Oncology and Stem Cell Transplantation Unit, Department of Hematology, National Cancer Institute, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy * These authors share co-first authorship Correspondence to: Monica Fedele, email: mfedele@unina.it , monica.fedele@cnr.it Renato Franco, email: renato.franco@unina2.it , renfr@yahoo.com Keywords: non-Hodgkin lymphomas, prognostic marker, PATZ1, tissue-microarray, DLBCL Received: January 16, 2016 Accepted: July 18, 2016 Published: August 01, 2016 ABSTRACT Non-Hodgkin lymphomas (NHLs) include a heterogeneous group of diseases, which differ in both cellular origin and clinical behavior. Among the aggressive malignancies of this group, the diffuse large B-cell lymphomas (DLBCLs) are the most frequently observed. They are themselves clinically and molecularly heterogeneous and have been further sub-divided in three sub-types according to different cell of origin, mechanisms of oncogenesis and clinical outcome. Among them, the germinal center B-cell-like (GCB) derives from the germinal center and expresses the BCL6 oncogene. We have previously shown that Patz1-knockout mice develop B-cell neoplasias, suggesting a tumor suppressor role for PATZ1 in human NHLs. Here, by immunohistochemical analysis of a tissue-microarray including 170 NHLs, we found that PATZ1 nuclear expression is down-regulated in follicular lymphomas and DLBCLs. Moreover, consistent with our previous results showing a PATZ1-dependent regulation of BCL6 and BAX transcription, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs, and with low BAX expression, also considering separately follicular lymphomas and DLBCLs. Finally, by analyzing overall and progression-free survival in DLBCL patients that underwent rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, low levels of PATZ1 were significantly associated to a worst outcome and demonstrated an independent prognostic factor in multivariate analysis, including known prognostic factors of DLBCL, IPI score and cell of origin (GCB/non-GCB). Therefore, we propose PATZ1 as a new prognostic marker of DLBCLs, which may act as a tumor suppressor by enhancing apoptosis through inhibiting and enhancing transcription of BCL6 and BAX, respectively.

Obesity and type 2 diabetes, with associated chronic inflammation and metabolic syndrome, are important risk factors for malignancies. In particular, meta-analyses of clinical studies suggest that hyperinsulinemia is a major cancer risk factor. Increased levels of circulating insulin may promote tumor progression by activating insulin (INSR) and IGF1 (IGF1R) receptors, that are frequently overexpressed in cancer cells. Moreover, in obese patients insulin can synergize with inflammation to promote proliferation, survival, and dissemination of cancer cells. The kinase Akt/PKB is a key mediator of the proliferative and survival effects of insulin on tumor cells. In addition, Akt directly links hyperinsulinemia to inflammation through activation of NF-kB signaling. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), binds and inhibits PI3K-p85, limiting AKT activation in response to various stimuli. DAB2IP also binds directly to Akt1, possibly contributing to its inhibition. In addition to its action on AKT, DAB2IP modulates multiple extracellular signals involved in cancer progression, thus acting as a tumor suppressor. Its expression is frequently reduced by methylation in tumors, but other molecular mechanism of DAB2IP inactivation in cancer have been identified. One of such mechanisms is interaction with mutant p53 proteins. Point mutation of p53 is a frequent event and a significant factor in cancer development and progression. Mutant p53 proteins (mutp53) are very stable, and acquire oncogenic properties (gain of function) that can increase proliferation, survival and metastatic potential of tumor cells. In this thesis, I demonstrate that mutant p53, by binding DAB2IP, promotes insulin-induced AKT activation in triple negative breast cancer and androgen-independent prostate cancer cell lines, with cell-autonomous effects on proliferation and survival. Using a decoy protein to displace the mutp53-DAB2IP interaction, I showed that formation of this cytoplasmic complex is necessary for the enhanced response to insulin observed in mutant p53-bearing cancer cells. Together, the evidences reported in this Thesis underline a specific gain of function of mutp53 in the response of cancer cells to insulin stimulation, offering an additional perspective to understand the complex relationship between hyperinsulinemia and cancer evolution.

Arianna Bellazzo,1 Daria Sicari,1,2 Elena Valentino,1,2 Giannino Del Sal,1,2 Licio Collavin1,21National Laboratory CIB (LNCIB), AREA Science park, Trieste, Italy; 2Department of Life Sciences, University of Trieste, Trieste, ItalyAbstract: Breast cancer is the most frequently diagnosed malignancy in women, and mutations in the tumor suppressor p53 are commonly detected in the most aggressive subtypes. The majority of TP53 gene alterations are missense substitutions, leading to expression of mutant forms of the p53 protein that are frequently detected at high levels in cancer cells. P53 mutants not only lose the physiological tumor-suppressive activity of the wild-type p53 protein but also acquire novel powerful oncogenic functions, referred to as gain of function, that may actively confer a selective advantage during tumor progression. Some of the best-characterized oncogenic activities of mutant p53 are mediated by its ability to form aberrant protein complexes with other transcription factors or proteins not directly related to gene transcription. The set of cellular proteins available to interact with mutant p53 is dependent on cell type and extensively affected by environmental signals, so the prognostic impact of p53 mutation is complex. Specific functional interactions of mutant p53 can profoundly impact homeostasis of breast cancer cells, reprogramming gene expression in response to specific extracellular inputs or cell-intrinsic conditions. The list of protein complexes involving mutant p53 in breast cancer is continuously growing, as is the number of oncogenic phenotypes in which they could be involved. In consideration of the functional impact of such complexes, key interactions of mutant p53 may be exploited as potential targets for development of therapies aimed at defusing the oncogenic potential of p53 mutation. Keywords: protein–protein interactions, mutant p53 gain of function, targeted therapy, cancer-cell homeostasis

Le città sono l’espressione collettiva di una società e nelle città di mare questo fenomeno assume valenze particolari in quanto le comunità marittime condividono un’identità unitaria nel forte legame con la marineria, le navi e la navigazione. Il paesaggio urbano marittimo non può essere compreso pienamente se non dal mare e in navigazione, attraverso una percezione dinamica che ne restituisce la complessità. L’architettura delle città di mare ha nel mare l’elemento primario che sostanzia il paesaggio urbano, alimenta l’evoluzione culturale, influenza le dinamiche sociali e spinge le attività economiche. La crescita costante dei traffici marittimi indotti dalla globalizzazione dei mercati ha favorito lo sviluppo dei porti, che, se ben gestito può creare, ancora oggi, opportunità nelle città di mare. L’approccio ai temi della progettazione urbana incentrato su di una visione “dal mare” suggerisce di affrontare in modo integrato la dimensione portuale e la dimensione urbanistica. Attraverso un approccio "marecentrico" il porto può assumere una nuova centralità per la rigenerazione delle aree urbane costiere, diventando generatore del suo (auto)sviluppo e motore dello sviluppo locale urbano sostenibile. La relazione tra la città e il porto non è univoca ma, piuttosto, costituisce un processo continuo particolarmente complesso che prevede cambiamenti fisici e culturali spesso difficili da gestire e conseguire, ed in cui sono convolti soggetti e risorse differenti, spesso in conflitto. Questo significa affrontare in modo integrato la dimensione portuale e quella urbanistica, ricercando nell’identità marittima della città e della comunità urbana la continuità tra passato e futuro. Si propone il caso studio di Salerno dove, attraverso la continuità culturale della tradizione marittima, la crescita delle attività portuali è stata accompagnata da una vision urbana che ha il suo punto di forza nel ridisegno del waterfront urbano (Fig.1). Salerno ha individuato indirizzi, politiche e metodi per intraprendere la rigenerazione urbana, con la partecipazione dell’Amministrazione, dell’Autorità Portuale e dei privati, condividendo azioni e progetti per rendere più coerente e attraente il fronte a mare e per migliorare la qualità della vita urbana ed al tempo stesso per sfruttare economicamente il potenziale di queste aree preziose, garantendo una visione strategica e una prospettiva in cui sono state esaltate le caratteristiche locali, la vocazione dei luoghi, la memoria storica., Territorio della Ricerca su Insediamenti e Ambiente. Rivista internazionale di cultura urbanistica, No 11 (2013): Sea and the City

The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.

Breast cancer is the most frequently diagnosed malignancy in women, and mutations in the tumor suppressor p53 are commonly detected in the most aggressive subtypes. The majority of TP53 gene alterations are missense substitutions, leading to expression of mutant forms of the p53 protein that are frequently detected at high levels in cancer cells. P53 mutants not only lose the physiological tumor-suppressive activity of the wild-type p53 protein but also acquire novel powerful oncogenic functions, referred to as gain of function, that may actively confer a selective advantage during tumor progression. Some of the best-characterized oncogenic activities of mutant p53 are mediated by its ability to form aberrant protein complexes with other transcription factors or proteins not directly related to gene transcription. The set of cellular proteins available to interact with mutant p53 is dependent on cell type and extensively affected by environmental signals, so the prognostic impact of p53 mutation is complex. Specific functional interactions of mutant p53 can profoundly impact homeostasis of breast cancer cells, reprogramming gene expression in response to specific extracellular inputs or cell-intrinsic conditions. The list of protein complexes involving mutant p53 in breast cancer is continuously growing, as is the number of oncogenic phenotypes in which they could be involved. In consideration of the functional impact of such complexes, key interactions of mutant p53 may be exploited as potential targets for development of therapies aimed at defusing the oncogenic potential of p53 mutation.