Betacellulin promotes tumor development and EGFR mutant lung cancer growth by stimulating the EGFR pathway and suppressing apoptosis

Suresh Chava; Suresh Bugide; Xuchen Zhang; Romi Gupta; Narendra Wajapeyee

doi:10.1016/j.isci.2022.104211

Betacellulin promotes tumor development and EGFR mutant lung cancer growth by stimulating the EGFR pathway and suppressing apoptosis

iScience. 2022 Apr 6;25(5):104211. doi: 10.1016/j.isci.2022.104211. eCollection 2022 May 20.

Authors

Suresh Chava¹, Suresh Bugide¹, Xuchen Zhang², Romi Gupta^{1

3}, Narendra Wajapeyee^{1

3}

Affiliations

¹ Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
² Department of Pathology, Yale University, New Haven, CT 06510, USA.
³ O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.

Abstract

Oncogenic mutations in the EGFR gene account for 15-20% of lung adenocarcinoma (LUAD) cases. However, the mechanism for EGFR driven tumor development and growth is not fully understood. Here, using an mRNA expression profiling-based approach we identified betacellulin (BTC) as one the gene upregulated by oncogenic EGFR in an MAP kinase-dependent manner. BTC protein expression was markedly increased in LUAD patient samples compared to normal lung tissue, with higher expression in EGFR-mutant LUAD. BTC was sufficient to transform immortalized mouse cells, initiate tumor development in mice, and promote the survival of immortalized human lung epithelial cells. Conversely, knockdown of BTC inhibited the growth of EGFR-mutant human LUAD cells in culture and their tumor-forming ability in mice. Mechanistically, BTC knockdown resulted in attenuated EGFR signaling and apoptosis induction. Collectively, these results demonstrate a key role of BTC in EGFR-mutant LUAD, with potential therapeutic implications in LUAD and other EGFR-mutant cancers.

Keywords: Cancer; Cell biology; Transcriptomics.

Grants and funding

P30 CA013148/CA/NCI NIH HHS/United States