Abstract 1460: Tumor suppressor miR-137 inhibits colorectal cancer progression by negatively regulating cancer stem cell marker, Musashi-1

Abstract

Abstract Colorectal cancer is the 3rd most common cause of cancer-related deaths for men and women in the United States. Understanding the mechanisms involved in colon cancer initiation and progression requires immediate attention. Multiple regulatory processes are required to maintain normal cell homeostasis, including microRNA (miRNA) regulation. miRNAs are predicted to target 60% of all mRNAs, therefore, providing substantial regulatory power of many cellular processes. The goal of this project is to identify and characterize dysregulated miRNAs in colorectal cancer. We previously demonstrated that the colon cancer stem cell marker, Musashi1 (Msi1), is negatively regulated by miR-137. Msi1 is an RNA binding protein over-expressed in a variety of cancers, including colon cancer. Msi1 promotes tumor growth by positively regulating both Notch and Wnt signaling. Notch and Wnt signaling play important roles in colorectal cancer initiation and progression. We hypothesize that miR-137 acts as a tumor suppressive miRNA by negatively regulating Msi1 and subsequent Notch and Wnt signaling. Using Taqman miRNA assay, we discovered that miR-137 expression is decreased in approximately 84% of rectal tumor samples as compared to paired normal rectal mucosal samples (n=68). Consistent with the clinical data, our colon cancer cell lines have decreased expression of miR-137 as compared to a normal colon epithelial cell line. Restoration of miR-137 reduced colon cancer proliferation, measured by colony formation and tumorsphere assays. Furthermore, miR-137 restoration decreased Msi1 which resulted in subsequent decreased Notch and Wnt signaling, measured by quantitative Real-Time PCR and Western blotting. In order to understand the effect of miR-137 on tumor growth, HCT-116 colon cancer cells were stably transduced with a doxycycline-inducible miR-137 lentiviral expression vector. In vivo studies were carried out whereby athymic nude mice were subcutaneously injected with either negative control miRNA or miR-137 stable cell lines. After tumors reached approximately 50 mm3 in size, mice were fed doxycycline to induce expression of miR-137 or negative control miRNA. Induction of miR-137 expression significantly decreased tumor growth in our xenograft model by approximately 50% (n=10). In conclusion, our research demonstrates miR-137 as a potent tumor suppressive miRNA that is lost in colorectal cancer and negatively regulates the colon cancer stem cell marker, Musashi-1. Citation Format: Amber R. Smith, Rebecca Marquez, Bryan Tsao, Lan Lan, Surajit Pathak, Xiao-Feng Sun, Kristi Neufeld, Liang Xu. Tumor suppressor miR-137 inhibits colorectal cancer progression by negatively regulating cancer stem cell marker, Musashi-1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1460. doi:10.1158/1538-7445.AM2014-1460