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Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma.

Abstract

Dysregulation of long noncoding RNA (lncRNA) H19 has been implicated in hepatocellular carcinoma (HCC), but the concrete regulatory mechanism is lack of research. We mined gene expression profiles of 457 HCC samples from TCGA and TJMUCH cohorts and further validated in 64 FFPE HCC tissues. LncRNA H19 overexpression in situ was significantly correlated with poor prognosis of HCC patients, which induced EMT, promoted stemness and accelerated invasion of HCC cells in vitro. Co-expression network analysis indicated lncRNA H19 negatively correlated with miR-193b and positively correlated with MAPK1 gene, which implicated that lncRNA H19 served as a sponge molecule to hijack miR-193b and protect MAPK1. Forced overexpression of H19 attenuated miR-193b-mediated inhibition on multiple driver oncogenes (EGFR, KRAS, PTEN and IGF1R) and MAPK1 gene, thus triggered EMT and stem cell transformation in HCC. LncRNA H19 positively correlated with CD68 + TAMs in situ. TAMs-induced lncRNA H19 promotes HCC aggressiveness via triggering and activating the miR-193b/MAPK1 axis, mediates the crosstalk between HCC and immunological microenvironment, and causes poor clinical outcomes. LncRNA H19 is a valuable predictive biomarker and potential therapeutic target in HCC.

Authors+Show Affiliations

Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China. Electronic address: yeyingnan1001@163.com.School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, PR China; Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, PR China. Electronic address: guojincheng@gene.ac.Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China. Electronic address: xiaopei8836@163.com.Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China. Electronic address: 15032210069@163.com.Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China. Electronic address: zhangrui_rz@163.com.Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China. Electronic address: cgtwins@126.com.Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China. Electronic address: lyjunyi1212@163.com.Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, PR China. Electronic address: lyxu@stu.edu.cn.Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, State Key Laboratory of Computer Architecture, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, PR China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, PR China. Electronic address: biozy@ict.ac.cn.Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China. Electronic address: yujinpu@yahoo.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31705929

Citation

Ye, Yingnan, et al. "Macrophages-induced Long Noncoding RNA H19 Up-regulation Triggers and Activates the miR-193b/MAPK1 Axis and Promotes Cell Aggressiveness in Hepatocellular Carcinoma." Cancer Letters, 2019.
Ye Y, Guo J, Xiao P, et al. Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma. Cancer Lett. 2019.
Ye, Y., Guo, J., Xiao, P., Ning, J., Zhang, R., Liu, P., ... Yu, J. (2019). Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma. Cancer Letters, doi:10.1016/j.canlet.2019.11.001.
Ye Y, et al. Macrophages-induced Long Noncoding RNA H19 Up-regulation Triggers and Activates the miR-193b/MAPK1 Axis and Promotes Cell Aggressiveness in Hepatocellular Carcinoma. Cancer Lett. 2019 Nov 6; PubMed PMID: 31705929.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma. AU - Ye,Yingnan, AU - Guo,Jincheng, AU - Xiao,Pei, AU - Ning,Junya, AU - Zhang,Rui, AU - Liu,Pengpeng, AU - Yu,Wenwen, AU - Xu,Liyan, AU - Zhao,Yi, AU - Yu,Jinpu, Y1 - 2019/11/06/ PY - 2019/07/25/received PY - 2019/10/13/revised PY - 2019/11/01/accepted PY - 2019/11/11/pubmed PY - 2019/11/11/medline PY - 2019/11/10/entrez KW - Immunological microenvironment KW - Invasion KW - Predictive biomarker KW - ceRNA KW - lncRNA JF - Cancer letters JO - Cancer Lett. N2 - Dysregulation of long noncoding RNA (lncRNA) H19 has been implicated in hepatocellular carcinoma (HCC), but the concrete regulatory mechanism is lack of research. We mined gene expression profiles of 457 HCC samples from TCGA and TJMUCH cohorts and further validated in 64 FFPE HCC tissues. LncRNA H19 overexpression in situ was significantly correlated with poor prognosis of HCC patients, which induced EMT, promoted stemness and accelerated invasion of HCC cells in vitro. Co-expression network analysis indicated lncRNA H19 negatively correlated with miR-193b and positively correlated with MAPK1 gene, which implicated that lncRNA H19 served as a sponge molecule to hijack miR-193b and protect MAPK1. Forced overexpression of H19 attenuated miR-193b-mediated inhibition on multiple driver oncogenes (EGFR, KRAS, PTEN and IGF1R) and MAPK1 gene, thus triggered EMT and stem cell transformation in HCC. LncRNA H19 positively correlated with CD68 + TAMs in situ. TAMs-induced lncRNA H19 promotes HCC aggressiveness via triggering and activating the miR-193b/MAPK1 axis, mediates the crosstalk between HCC and immunological microenvironment, and causes poor clinical outcomes. LncRNA H19 is a valuable predictive biomarker and potential therapeutic target in HCC. SN - 1872-7980 UR - https://www.unboundmedicine.com/medline/citation/31705929/Macrophages-induced_Long_noncoding_RNA_H19_Up-regulation_Triggers_and_Activates_the_miR-193b/MAPK1_Axis_and_Promotes_Cell_Aggressiveness_in_Hepatocellular_Carcinoma L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(19)30556-7 DB - PRIME DP - Unbound Medicine ER -