Forcella Matilde, Oldani Monica, Epistolio Samantha, Freguia Stefania, Monti Eugenio, Fusi Paola, Frattini Milo
Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milano, Italy.
Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
PLoS One. 2017 Oct 31;12(10):e0187289. doi: 10.1371/journal.pone.0187289. eCollection 2017.
Adenocarcinoma of Non-Small Cell Lung Cancer (NSCLC) is a severe disease. Patients carrying EGFR mutations may benefit from EGFR targeted therapies (e.g.: gefitinib). Recently, it has been shown that sialidase NEU3 directly interacts and regulates EGFR. In this work, we investigate the effect of sialidase NEU3 overexpression on EGFR pathways activation and EGFR targeted therapies sensitivity, in a series of lung cancer cell lines. NEU3 overexpression, forced after transfection, does not affect NSCLC cell viability. We demonstrate that NEU3 overexpression stimulates the ERK pathway but this activation is completely abolished by gefitinib treatment. The Akt pathway is also hyper-activated upon NEU3 overexpression, but gefitinib is able only to decrease, and not to abolish, such activation. These findings indicate that NEU3 can act directly on the ERK pathway through EGFR and both directly and indirectly with respect to EGFR on the Akt pathway. Furthermore, we provide evidence that a healthy mucosa cell line (with EGFR wild-type gene sequence) is slightly sensitive to gefitinib, especially in the presence of NEU3 overexpression, thus hypothesizing that NEU3 overexpressing patients may benefit from EGFR targeted therapies also in absence of EGFR point mutations. Overall, the expression of NEU3 may be a novel diagnostic marker in NSCLC because, by its ability to stimulate EGFR downstream pathways with direct and indirect mechanisms, it may help in the identification of patients who can profit from EGFR targeted therapies in absence of EGFR activating mutations or from new combinations of EGFR and Akt inhibitors.
非小细胞肺癌（NSCLC）腺癌是一种严重疾病。携带表皮生长因子受体（EGFR）突变的患者可能从EGFR靶向治疗中获益（例如：吉非替尼）。最近研究表明，唾液酸酶NEU3直接与EGFR相互作用并对其进行调节。在本研究中，我们在一系列肺癌细胞系中，研究了唾液酸酶NEU3过表达对EGFR通路激活及EGFR靶向治疗敏感性的影响。转染后强制实现的NEU3过表达，并不影响NSCLC细胞活力。我们证明，NEU3过表达刺激细胞外信号调节激酶（ERK）通路，但吉非替尼处理可完全消除这种激活。NEU3过表达时，蛋白激酶B（Akt）通路也被过度激活，但吉非替尼只能降低而不能消除这种激活。这些发现表明，NEU3可通过EGFR直接作用于ERK通路，并且在Akt通路上相对于EGFR既直接又间接起作用。此外，我们提供的证据表明，一个健康的黏膜细胞系（具有EGFR野生型基因序列）对吉非替尼轻度敏感，尤其是在存在NEU3过表达的情况下，因此推测NEU3过表达的患者在没有EGFR点突变时也可能从EGFR靶向治疗中获益。总体而言，NEU3的表达可能是NSCLC一种新的诊断标志物，因为其通过直接和间接机制刺激EGFR下游通路的能力，可能有助于识别那些在没有EGFR激活突变时可从EGFR靶向治疗中获益的患者，或那些可从EGFR与Akt抑制剂新组合中获益的患者。
