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HOXB7 overexpression in lung cancer is a hallmark of acquired stem-like phenotype

Oncogene volume 37, pages 3575–3588 (2018)Cite this article

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Abstract

HOXB7 is a homeodomain (HOX) transcription factor involved in regional body patterning of invertebrates and vertebrates. We previously identified HOXB7 within a ten-gene prognostic signature for lung adenocarcinoma, where increased expression of HOXB7 was associated with poor prognosis. This raises the question of how HOXB7 overexpression can influence the metastatic behavior of lung adenocarcinoma. Here, we analyzed publicly available microarray and RNA-seq lung cancer expression datasets and found that HOXB7-overexpressing tumors are enriched in gene signatures characterizing adult and embryonic stem cells (SC), and induced pluripotent stem cells (iPSC). Experimentally, we found that HOXB7 upregulates several canonical SC/iPSC markers and sustains the expansion of a subpopulation of cells with SC characteristics, through modulation of LIN28B, an emerging cancer gene and pluripotency factor, which we discovered to be a direct target of HOXB7. We validated this new circuit by showing that HOXB7 enhances reprogramming to iPSC with comparable efficiency to LIN28B or its target c-MYC, which is a canonical reprogramming factor.

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Acknowledgements

We thank Bruno Amati for kindly providing the pBABE-MYC plasmid. We are indebted to Giuseppina Bonizzi, Giovanna Jodice, Elena Belloni, Elena Marino, Francesca De Santis, Stefania Pirroni, Pietro Vella, Valentina Melocchi, Davide Disalvatore and Stefano Freddi for technical support. We thank Ugo Cavallaro for inspiring discussions and comments on the paper. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) (MFAG17568 to FB; IG 10349 and 14040 and MCO 10.000 to PPDF) and from the Monzino Foundation (to PPDF).

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  1. Simona Monterisi

    Present address: Humanitas Clinical and Research Center, 20089 Rozzano (MI), Italy

Authors and Affiliations

  1. Molecular Medicine Program, European Institute of Oncology, 20141, Milan, Italy

    Simona Monterisi, Giovanni Bertalot, Pier Paolo Di Fiore & Fabrizio Bianchi

  2. IFOM, The FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy

    Simona Monterisi, Karin Russo, Manuela Vecchi & Pier Paolo Di Fiore

  3. Department of Experimental Oncology, European Institute of Oncology, 20141, Milan, Italy

    Pietro Lo Riso & Giuseppe Testa

  4. DIPO, Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, Italy

    Giuseppe Testa & Pier Paolo Di Fiore

  5. ISBREMIT, Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies, IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo (FG), Italy

    Fabrizio Bianchi

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Monterisi, S., Lo Riso, P., Russo, K. et al. HOXB7 overexpression in lung cancer is a hallmark of acquired stem-like phenotype. Oncogene 37, 3575–3588 (2018). https://doi.org/10.1038/s41388-018-0229-9

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