TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice

Lung adenocarcinoma, the most common type of human non-small cell lung cancer (NSCLC), frequently overexpresses epidermal growth factor receptor (EGFR). However, the mechanisms underlying EGFR overexpression are not completely understood. Recent studies have identified that decreased expression of TIP30 (30kDa HIV-1 Tat interacting protein) is associated with the metastasis of human NSCLCs, but a causative relationship between TIP30 deficiency and NSCLC development remains unclear. We show here that Tip30 deletion leads to spontaneous development of lung adenomas and adenocarcinomas in mice. Lung tumor development was preceded by aberrant expansion of bronchioalveolar stem/progenitor and alveolar type II (AT2) cells, and also increased expression of EGFR and its downstream signaling factors in the lung of Tip30(-/-) mice. Moreover, TIP30 knockdown in human lung adenocarcinoma cells resulted in prolonged EGFR activity in early endosomes, delayed EGFR degradation, increased EGFR nuclear localization, leading to upregulated pAKT and pERK1/2 expression. Importantly, in human lung adenocarcinomas, low TIP30 expression correlates with prolonged patient overall and post-progression survival times. Together, these results suggest that TIP30 functions as a tumor suppressor to inhibit EGFR cytoplasmic and nuclear signaling and suppress adenocarcinogenesis in the lung, and highlight the potential of therapeutic strategies aiming at inhibiting EGFR signaling for patients with low TIP30-expression lung adenocarcinoma.