<scp>circPVT1</scp>and<scp><i>PVT1/AKT3</i></scp>show a role in cell proliferation, apoptosis, and tumor subtype‐definition in small cell lung cancer
Doron Tolomeo, Debora Traversa, Santina Venuto, Karoline K. Ebbesen, Juan L. García‐Rodríguez, Grazia Tamma, Marianna Ranieri, Giorgia Simonetti, Martina Ghetti, Matteo Paganelli, Grazia Visci, Arcangelo Liso, Klaas Kok, Lucia Anna Muscarella, Federico Pio Fabrizio, Maria Antonia Frassanito, Aurelia Lamanuzzi, Ilaria Saltarella, Antonio Giovanni Solimando, Alessandro Fatica, Zaira Ianniello, Renè Massimiliano Marsano, Antonio J. Palazzo, Amalia Azzariti, Vito Longo, Stefania Tommasi, Domenico Galetta, Annamaria Catino, Alfredo Zito, Tommaso Mazza, Alessandro Napoli, Giovanni Martinelli, Jørgen Kjems, Lasse S. Kristensen, Angelo Vacca, Clelia Tiziana Storlazzi
Abstract
Small cell lung cancer (SCLC) is treated as a homogeneous disease, although the expression of NEUROD1, ASCL1, POU2F3, and YAP1 identifies distinct molecular subtypes. The MYC oncogene, amplified in SCLC, was recently shown to act as a lineage-specific factor to associate subtypes with histological classes. Indeed, MYC-driven SCLCs show a distinct metabolic profile and drug sensitivity. To disentangle their molecular features, we focused on the co-amplified PVT1, frequently overexpressed and originating circular (circRNA) and chimeric RNAs. We analyzed hsa_circ_0001821 (circPVT1) and PVT1/AKT3 (chimPVT1) as examples of such transcripts, respectively, to unveil their tumorigenic contribution to SCLC. In detail, circPVT1 activated a pro-proliferative and anti-apoptotic program when over-expressed in lung cells, and knockdown of chimPVT1 induced a decrease in cell growth and an increase of apoptosis in SCLC in vitro. Moreover, the investigated PVT1 transcripts underlined a functional connection between MYC and YAP1/POU2F3, suggesting that they contribute to the transcriptional landscape associated with MYC amplification. In conclusion, we have uncovered a functional role of circular and chimeric PVT1 transcripts in SCLC; these entities may prove useful as novel biomarkers in MYC-amplified tumors.