Int J Biol Sci 2022; 18(11):4301-4315. doi:10.7150/ijbs.66224 This issue

Research Paper

YY1-induced DLEU1/miR-149-5p Promotes Malignant Biological Behavior of Cholangiocarcinoma through Upregulating YAP1/TEAD2/SOX2

Jinglin Li*, Xingming Jiang*, Yi Xu*, Pengcheng Kang*, Peng Huang, Nanfeng Meng, Hang Wang, Wangyang Zheng, Hao Wang, Zhidong Wang, Xiangyu Zhong, Yunfu Cui

Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China.
*These authors contributed equally to this work.

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Citation:
Li J, Jiang X, Xu Y, Kang P, Huang P, Meng N, Wang H, Zheng W, Wang H, Wang Z, Zhong X, Cui Y. YY1-induced DLEU1/miR-149-5p Promotes Malignant Biological Behavior of Cholangiocarcinoma through Upregulating YAP1/TEAD2/SOX2. Int J Biol Sci 2022; 18(11):4301-4315. doi:10.7150/ijbs.66224. Available from https://www.ijbs.com/v18p4301.htm

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Abstract

Graphic abstract

Cholangiocarcinoma is an extremely malignant cancer with poor prognosis. Finding efficient diagnosis and treatment is the indispensable way to improve the prognosis of CCA patients. Therefore, exploring molecular abnormalities in CCA development is urgently needed. DLEU1 is a potential tumor-related lncRNA and abnormally expressed in multiple cancers. In this study, TCGA data analysis showed upregulation of DLEU1 expression in CCA. Furthermore, we confirmed that DLEU1 expression was increased in CCA tissues and cells compared with corresponding controls. Upregulated DLEU1 was related to poor clinicopathological characteristics. Functionally, silencing DLEU1 inhibited CCA proliferation, invasion, stemness maintenance and chemo-resistance, whereas amplifying DLEU1 promoted malignant biological behavior of CCA cells. Mechanistically, DLEU1 expression was transcriptionally facilitated by transcription factor YY1. Moreover, DLEU1 promoted oncogene YAP1 expression by functioning as a sponge to competitively bind to miR-149-5p. YAP1 promoted CCA proliferation, invasion and stemness maintenance, whereas miR-149-5p inhibited malignant biological behavior of CCA. Rescue experiments confirmed that the cancer-promoting effect of DLEU1 was saved by interfering miR-149-5p or YAP1. Furthermore, YAP1 promoted tumor stemness maintenance partly by acting as a transcriptional coactivator to promote TEAD2-induced SOX2 expression. These findings indicated that YY1-induced DLEU1 played a crucial role in CCA progression via miR-149-5p/YAP1/TEAD2/SOX2 axis.

Keywords: cholangiocarcinoma, prognosis, DLEU1, miR-149-5p, YAP1