Abstract 2690: The role of musashi-1 in tumor progression in non-small cell lung cancer.

Abstract

Abstract We have previously developed an in vivo mouse model of metastatic lung adenocarcinoma by combining a mutant p53 allele (p53R175HΔG) with a KrasG12D allele (KrasLA1). From the tumors arising in KrasLA1/+; p53R172HΔG/+ mice, we have established lung adenocarcinoma cell lines (KP cells) with high (344SQ) or low (393P) metastatic potential. The metastatic potential of KP cells is governed by Zeb-1 and the microRNA-200 family, which interact through a double-negative feedback loop. Given that metastatic KP cells exhibit the capacity to form polarized epithelial spheres in Matrigel and undergo epithelial-to-mesenchymal transition (EMT) in response to extracellular cues, we hypothesized that stem cell factors serve as drivers of tumor cell invasion and metastasis in this model. We examined the expression of 13 stem cell factors in metastatic and non-metastatic KP cell lines using qPCR and found that Musashi-1 (Msi-1) was more highly expressed in metastatic KP cells, which was confirmed by western analysis. Msi1 is an RNA-binding protein that plays a central role during nervous system development, stem cell maintenance, and tumorigenesis. High levels of Msi1 have been reported in several malignancies including brain tumors, colon and breast cancer, and associate with poor survival in patients with breast and colon cancer. We have used a panel of human lung cancer cell lines and found Msi-1 protein to be expressed in lung adenocarcinoma and squamous carcinoma cell lines. Further analysis revealed that Msi-1 expression is up-regulated by Zeb-1 and down-regulated by miR-200, raising the possibility that Msi-1 functions as a downstream mediator of the Zeb-1/miR-200 axis, which we are currently investigating by carrying out Msi-1 loss-of-function and gain-of-function experiments and by analyzing human tissue microarrays to determine whether Msi-1 has prognostic value in patients. Our data suggests that Msi-1 is a candidate driver of tumor progression in NSCLC. Citation Format: Yanis Boumber, Alexander Kudinov, Xin Liu, Young-Ho Ahn, Jaime Rodriguez, Ignacio Wistuba, Don Gibbons, Jonathan Kurie. The role of musashi-1 in tumor progression in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2690. doi:10.1158/1538-7445.AM2013-2690