Pingfu Hou1,2, Sen Meng1, Minle Li1, Tian Lin1, Sufang Chu1, Zhongwei Li1, Junnian Zheng3,4, Yuming Gu5, Jin Bai6,7. 1. Cancer Institute, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, Jiangsu Province, 221002, China. 2. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. 3. Cancer Institute, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, Jiangsu Province, 221002, China. jnzheng@xzhmu.edu.cn. 4. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. jnzheng@xzhmu.edu.cn. 5. Department of Interventional Radiography, Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu Province, 221002, China. guyumingxyfy@foxmail.com. 6. Cancer Institute, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, Jiangsu Province, 221002, China. bj@xzhmu.edu.cn. 7. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. bj@xzhmu.edu.cn.
Abstract
BACKGROUND: Increasing studies have shown that long noncoding RNAs (lncRNAs) are pivotal regulators participating in carcinogenic progression and tumor metastasis in colorectal cancer (CRC). Although lncRNA long intergenic noncoding RNA 460 (LINC00460) has been reported in CRC, the role and molecular mechanism of LINC00460 in CRC progression still requires exploration. METHODS: The expression levels of LINC00460 were analyzed by using a tissue microarray containing 498 CRC tissues and their corresponding non-tumor adjacent tissues. The correlations between the LINC00460 expression level and clinicopathological features were evaluated. The functional characterization of the role and molecular mechanism of LINC00460 in CRC was investigated through a series of in vitro and in vivo experiments. RESULTS: LINC00460 expression was increased in human CRC, and high LINC00460 expression was correlated with poor five-year overall survival and disease-free survival. LINC00460 overexpression sufficiently induced the epithelial-mesenchymal transition and promoted tumor cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. In addition, LINC00460 enhanced the protein expression of high-mobility group AT-hook 1 (HMGA1) by directly interacting with IGF2BP2 and DHX9 to bind the 3' untranslated region (UTR) of HMGA1 mRNA and increased the stability of HMGA1 mRNA. In addition, the N6-methyladenosine (m6A) modification of HMGA1 mRNA by METTL3 enhanced HMGA1 expression in CRC. Finally, it suggested that HMGA1 was essential for LINC00460-induced cell proliferation, migration, and invasion. CONCLUSIONS: LINC00460 may be a novel oncogene of CRC through interacting with IGF2BP2 and DHX9 and bind to the m6A modified HMGA1 mRNA to enhance the HMGA1 mRNA stability. LINC00460 can serve as a promising predictive biomarker for the diagnosis and prognosis among patients with CRC.
BACKGROUND: Increasing studies have shown that long noncoding RNAs (lncRNAs) are pivotal regulators participating in carcinogenic progression and tumor metastasis in colorectal cancer (CRC). Although lncRNA long intergenic noncoding RNA 460 (LINC00460) has been reported in CRC, the role and molecular mechanism of LINC00460 in CRC progression still requires exploration. METHODS: The expression levels of LINC00460 were analyzed by using a tissue microarray containing 498 CRC tissues and their corresponding non-tumor adjacent tissues. The correlations between the LINC00460 expression level and clinicopathological features were evaluated. The functional characterization of the role and molecular mechanism of LINC00460 in CRC was investigated through a series of in vitro and in vivo experiments. RESULTS:LINC00460 expression was increased in human CRC, and high LINC00460 expression was correlated with poor five-year overall survival and disease-free survival. LINC00460 overexpression sufficiently induced the epithelial-mesenchymal transition and promoted tumor cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. In addition, LINC00460 enhanced the protein expression of high-mobility group AT-hook 1 (HMGA1) by directly interacting with IGF2BP2 and DHX9 to bind the 3' untranslated region (UTR) of HMGA1 mRNA and increased the stability of HMGA1 mRNA. In addition, the N6-methyladenosine (m6A) modification of HMGA1 mRNA by METTL3 enhanced HMGA1 expression in CRC. Finally, it suggested that HMGA1 was essential for LINC00460-induced cell proliferation, migration, and invasion. CONCLUSIONS:LINC00460 may be a novel oncogene of CRC through interacting with IGF2BP2 and DHX9 and bind to the m6A modified HMGA1 mRNA to enhance the HMGA1 mRNA stability. LINC00460 can serve as a promising predictive biomarker for the diagnosis and prognosis among patients with CRC.
Authors: Ly P Vu; Brian F Pickering; Yuanming Cheng; Sara Zaccara; Diu Nguyen; Gerard Minuesa; Timothy Chou; Arthur Chow; Yogesh Saletore; Matthew MacKay; Jessica Schulman; Christopher Famulare; Minal Patel; Virginia M Klimek; Francine E Garrett-Bakelman; Ari Melnick; Martin Carroll; Christopher E Mason; Samie R Jaffrey; Michael G Kharas Journal: Nat Med Date: 2017-09-18 Impact factor: 53.440