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Role of the YAP-1 Transcriptional Target cIAP2 in the Differential Susceptibility to Chemotherapy of Non-Small-Cell Lung Cancer (NSCLC) Patients with Tumor RASSF1A Gene Methylation from the Phase 3 IFCT-0002 Trial

Abstract : RASSF1 gene methylation predicts longer disease-free survival (DFS) and overall survival(OS) in patients with early-stage non-small-cell lung cancer treated using paclitaxel-based neoadjuvant chemotherapy compared to patients receiving a gemcitabine-based regimen, according tothe randomized Phase 3 IFCT (Intergroupe Francophone de Cancérologie Thoracique)-0002 trial. To better understand these results, this study used four human bronchial epithelial cell (HBEC) models(HBEC-3, HBEC-3-RasV12, A549, and H1299) and modulated the expression of RASSF1A or YAP1. Wound healing, invasion, proliferation and apoptosis assays were then carried out and the expression of YAP-1 transcriptional targets was quantified using a quantitative polymerase chain reaction. This study reports herein that gemcitabine synergizes with RASSF1A, silencing to increase the IAP-2 expression, which in turn not only interferes with cell proliferation but also promotes cell migration. This contributes to the aggressive behavior of RASSF1A-depleted cells, as confirmed by a combined knockdown of IAP-2 and RASSF1A. Conversely, paclitaxel does not increase the IAP-2 expression but limits the invasiveness of RASSF1A-depleted cells, presumably by rescuing microtubule stabilization. Overall, these data provide a functional insight that supports the prognostic value of RASSF1 gene methylation on survival of early-stage lung cancer patients receiving perioperative paclitaxel-based treatment compared to gemcitabine-based treatment, identifying IAP-2 as a novel biomarker indicative of YAP-1-mediated modulation of chemosensitivity in lung cancer.
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Submitted on : Tuesday, November 26, 2019 - 2:45:53 PM
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Fatéméh Dubois, Maureen Keller, Julien Hoflack, Elodie Maille, Martine Antoine, et al.. Role of the YAP-1 Transcriptional Target cIAP2 in the Differential Susceptibility to Chemotherapy of Non-Small-Cell Lung Cancer (NSCLC) Patients with Tumor RASSF1A Gene Methylation from the Phase 3 IFCT-0002 Trial. Cancers, MDPI, 2019, 11 (12), pp.1835. ⟨10.3390/cancers11121835⟩. ⟨hal-02373638⟩

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