Long Noncoding Rna Lnc01534 Regulates Cancer Stem Cells In Colorectal Cancer

Introduction The clinical importance of cancer stem cells (CSCs) has been widely reported, and clinical studies targeting CSCs are in progress. Additionally, accumulating evidence suggests that long noncoding RNAs (lncRNAs) have essential roles in cancer initiation and progression, while deregulated lncRNA expression is found in a variety of cancer types. In this study, we focused on lncRNAs regulating CSCs in colorectal cancer (CRC). Objectives To identify the lncRNAs associated with CSCs and to evaluate their clinical relevance and function. Materials and Methods We separated CSCs and other cells in CRC using the ornithine decarboxylase (ODC) degron system to visualize CSCs based on the correlation between low proteasome activity and CSC properties. We performed comprehensive gene analysis comparing CSCs and other cells to identify a candidate lncRNA that regulates the stemness of CRC cells. Finally, we analyzed the clinical relevance and function of the lncRNA. Results The lncRNA LNC01534 showed high expression in CSCs compared with the level in other CRC cells. Using gene expression and clinical data from the Cancer Genome Atlas Project for CRC patients, we showed that LNC01534 was associated with overall survival in CRC. LNC01534 was also associated with overall survival and disease-free survival in 187 separate CRC samples. Functional studies revealed that the loss of LNC01534 function reduced proliferation and arrested the cell cycle in CRC cells. Furthermore, genes that underwent expression changes upon the knockdown of LNC01534 were evaluated by RNA-seq. This showed that the knockdown of LNC01534 affected the expression of genes related to endoplasmic reticulum (ER) stress and autophagy. Specifically, the expression levels of HSPA5, LC3-I, p62, and Beclin-1–genes related to ER stress and autophagy–increased upon suppressing LNC01534. Conclusions We demonstrated the clinical and biological relevance of LNC01534 in association with CSCs, and discovered the effect of LNC01534 on ER stress and autophagy to maintain stemness in CRC. Citation Format: Masahisa Ohtsuka, Wu Xin, Momoko Ichihara, Haruka Hirose, Hidekazu Takahashi, Chu Matsuda, Hiroki Akamatsu, Tsunekazu Mizushima, Yuichiro Doki, Hirofumi Yamamoto. Long noncoding RNA LNC01534 regulates cancer stem cells in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 264.