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circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in Small Cell Lung Cancer

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  • Doron Tolomeo, University of Bari
  • ,
  • Debora Traversa, University of Bari
  • ,
  • Santina Venuto
  • ,
  • Karoline Ebbesen
  • Juan Luis Garcia Rodriguez
  • Grazia Tamma, University of Bari, Italy
  • Marianna Ranieri, University of Bari
  • ,
  • Giorgia Simonetti, IRCCS Istituto scientifico romagnolo per lo studio e la cura dei tumori - Meldola (FC)
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  • Martina Ghetti, IRCCS Istituto scientifico romagnolo per lo studio e la cura dei tumori - Meldola (FC)
  • ,
  • Matteo Paganelli
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  • Grazia Visci, University of Bari
  • ,
  • Arcangelo Liso
  • ,
  • Klaas Kok
  • ,
  • Lucia Anna Muscarella
  • ,
  • Federico Pio Fabrizio
  • ,
  • Maria Antonia Frassanito
  • ,
  • Aurelia Lamanuzzi
  • ,
  • Ilaria Saltarella
  • ,
  • Antonio Giovanni Solimando
  • ,
  • Alessandro Fatica
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  • Zaira Ianiello
  • ,
  • René Massimiliano Marsano
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  • Antonio Palazzo, University of Bari
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  • Amalia Azzariti
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  • Vito Longo
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  • Stefania Tommasi, IRCCS Istituto Tumori Bari Giovanni Paolo II, Ist Nazl Tumori Giovanni Paolo II
  • ,
  • Domenico Galetta
  • ,
  • Annamaria Catino
  • ,
  • Alfredo ZIto
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  • Tommaso Mazza, European XFEL
  • ,
  • Alessandro Napoli
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  • G Martinelli, Denmark
  • Jørgen Kjems
  • Lasse Sommer Kristensen
  • Angelo Vacca
  • ,
  • Clelia Tiziana Storlazzi, University of Bari
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.
Original languageEnglish
JournalGenes, Chromosomes & Cancer
ISSN1045-2257
Publication statusAccepted/In press - 22 Dec 2022

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