Description:
<jats:title>Abstract</jats:title>
<jats:p>Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) involved in cell growth and differentiation. Recent studies have revealed important roles for ERK3 in promoting cancer cell migration and invasion. In addition, ERK3 was shown to be highly upregulated in human lung cancers and to be associated with tumor metastasis. Altogether, these findings suggest an important role for ERK3 in lung tumor formation and progression. However, no in vivo study of ERK3 in lung tumorigenesis has been reported. For this purpose, a transgenic mouse model conditionally overexpressing ERK3 in lung bronchial epithelial cells was generated. First, a transgenic mouse line harboring ERK3 transgene under the control of a ubiquitous promoter and a STOP sequence flanked by two Lox P sites (LSL-ERK3) was generated. The obtained LSL-ERK3 mice were then crossed with a mouse line harboring the Cre recombinase transgene driven by a Clara cell secretory protein gene promoter (CCSP-Cre), resulting in CCSP-Cre/LSL-ERK3 transgenic mice that show ERK3 overexpression in Clara cells, the non-ciliated epithelial cells lining the bronchioles of lung. No clear phenotype, however, was observed in CCSP-Cre/LSL-ERK3 transgenic mice. As lung tumorigenesis usually requires multiple genetic alterations, the CCSP-Cre/LSL-ERK3 transgenic mice were then crossed with a PTENFlox/Flox mouse line in which the exon 5 of the tumor suppressor gene PTEN (Phosphatase and Tensin homolog) is flanked by two Lox P sites. These crossings led to the generation of CCSP-Cre/LSL-ERK3/PTENFlox/Flox mice which display PTEN deletion and ERK3 overexpression in the Clara cells of lung. Thus, four transgenic mouse groups were included in the study and monitored on daily basis: 1) LSL-ERK3; 2) CCSP-Cre/LSL-ERK3; 3) CCSP-Cre/PTENFlox/Flox; 4) CCSP-Cre/LSL-ERK3/PTENFlox/Flox. Tumor growth or other abnormalities in the lungs were analyzed by examining the whole lungs for surface tumors and by histological examination of lung tissue sections. As reported in previous studies, PTEN deletion alone resulted in lung hyperplasia. Interestingly, while ERK3 overexpression alone didn't cause clear phenotype, a combination of ERK3 overexpression with PTEN deletion in CCSP-Cre/LSL-ERK3/ PTENFlox/Flox mice induced lung tumorigenesis as demonstrated by the formation of surface tumors in lungs. Tumor formation in these CCSP-Cre/LSL-ERK3/PTENFlox/Flox mice was confirmed by hematoxylin and eosin (HE) staining of lung sections. Further, immunohistochemical analysis of differential biomarkers suggested that these tumors correspond to lung adenocarcinomas. Taken together, our study demonstrates a promoting role of ERK3 in lung tumor formation in vivo.</jats:p>
<jats:p>Citation Format: Sreeram Vallabhaneni, Marion Morel, Ming-Jer Tsai, Francesco J. Demayo, Weiwen Long. Conditional ERK3 overexpression and PTEN deletion induce lung tumors in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5098.</jats:p>