Abstract 2975: The pluripotency factor LIN28 promotes colorectal tumorigenesis and tumor progression

Abstract

Abstract LIN28A and LIN28B are RNA-binding protein paralogs expressed in embryonic stem cells and in early developing tissues. Through blocking the terminal processing of let-7 miRNAs and regulating the translation of a number of mRNA binding targets, LIN28 controls an array of targets that mediate proliferation, pluripotency, differentiation and metabolism. While highly expressed in the early embryos, the levels of LIN28A/B are downregulated as differentiation and development proceed. However, aberrant overexpression of LIN28 is often observed in human malignancies especially those with poor prognosis. We have demonstrated that LIN28 promotes cellular transformation in vitro, yet it is unknown how LIN28 regulates tumorigenesis in vivo. Here, we investigate the role of LIN28 in colorectal cancer (CRC) in humans and in mouse models. We first investigated the status of LIN28A/B in 1000 CRC patients and observed 35-60% of the cancer samples express LIN28A and/or LIN28B. Furthermore, we generated intestinal-specific LIN28 overexpressing mice, and observed intestinal adenoma as well as invasive adenocarcinoma that highly resemble the histology of human CRCs. Moreover, in Apcmin/+ animals, additional LIN28 expression significantly increased tumor incidence and accelerated disease onset, as their tumors are poorly differentiated and more invasive compared with Apcmin/+ tumors. Together, our study shows that LIN28 drives intestinal tumorigenesis and further promotes tumor progression in vivo. CRC is one of the major contributors to cancer-related mortality; however, current mouse models seldom progress to later stages of the disease, which greatly impedes efforts to developing more effective therapies. Based on the knowledge gained from this research, we hope to provide novel insights into designing therapeutics targeting late-stage CRC. Citation Format: Sarah Schwitalla, Ho-Chou Tu, Srinivas Viswanathan, Hao Zhu, Zhirong Qian, Samar Shah, Shuji Ogino, George Q. Daley. The pluripotency factor LIN28 promotes colorectal tumorigenesis and tumor progression. [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 2975. doi:10.1158/1538-7445.AM2014-2975