The SRCIN1/p140Cap adaptor protein negatively regulates the aggressiveness of neuroblastoma

Abstract

Neuroblastoma is the most common extra-cranial pediatric solid tumor, responsible for 13–15% of pediatric cancer death. Its intrinsic heterogeneity makes it difficult to target for successful therapy. The adaptor protein p140Cap/SRCIN1 negatively regulates tumor cell features and limits breast cancer progression. This study wish to assess if p140Cap is a key biological determinant of neuroblastoma outcome. RNAseq profiles of a large cohort of neuroblastoma patients show that SRCIN1 mRNA levels are an independent risk factor inversely correlated to disease aggressiveness. In high-risk patients, CGH+SNP microarray analysis of primary neuroblastoma identifies SRCIN1 as frequently altered by hemizygous deletion, copy-neutral loss of heterozygosity, or disruption. Functional experiments show that p140Cap negatively regulates Src and STAT3 signaling, affects anchorage-independent growth and migration, in vivo tumor growth and spontaneous lung metastasis formation. p140Cap also increases sensitivity of neuroblastoma cells to doxorubicin and etoposide treatment, as well as to a combined treatment with chemotherapy drugs and Src inhibitors. Our functional findings point to a causal role of p140Cap in curbing the aggressiveness of neuroblastoma, due to its ability to impinge on specific molecular pathways, and to sensitize cells to therapeutic treatment. This study provides the first evidence that the SRCIN1/p140Cap adaptor protein is a key player in neuroblastoma as a new independent prognostic marker for patient outcome and treatment. Altogether, these data highlight the potential clinical impact of SRCIN1/p140Cap expression in neuroblastoma tumors, in terms of reducing cytotoxic effects of chemotherapy, one of the main issues for pediatric tumor treatment.

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Acknowledgements

We thank Dr. Marta Gai for the confocal microscope analysis and Prof. Massimo Donadelli, University of Verona for the DRI50 analysis. This project has been approved by the Internal Bioethical Committee of the Department of Molecular Biotechnology and Health Sciences of the University of Torino and from the Ethical Committee of the Gaslini Institute in Genova. This work was supported by MIUR (Ministero Università Ricerca, PRIN 2015 to PD; FIRB 2012 grant RBFR12SOQ1 to CR), Ministero della Salute, AIRC (Associazione Italiana Ricerca Cancro) to PD (IG-15399 and IG-20107), to CR (IG-15232 and IG-21408), to LV (IG-17459) and to FDC (IG-17527); Compagnia San Paolo, Torino; Progetto d’Ateneo, Università di Torino 2011 to PD and ET; Fondazione CRT 2017.2954 to PD.

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Correspondence to Paola Defilippi.

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Edited by G. Del Sal

¥Dr. Luigi Varesio prematurely passed away in December 2017. The colleagues who had the privilege to collaborate with him dedicate this manuscript to his memory.

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