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p53-dependent upregulation of miR-16-2 by sanguinarine induces cell cycle arrest and apoptosis in hepatocellular carcinoma.
Cancer Lett. 2019 09 10; 459:50-58.CL

Abstract

MicroRNAs (miRNAs) were involved in cancer progression, and the targeting of miRNAs by natural agents has opened avenues for cancer treatment and drug development. miR-16 functions as a tumor suppressor and is frequently deleted or downregulated in various human cancers, including hepatocellular carcinoma (HCC). In the present study, we employed a miR-16-responsive luciferase reporter to screen candidate compounds that modulate miR-16 expression from a natural product library. One compound, sanguinarine (SG), was capable of activating miR-16 in HCC cells with wildtype or mutated p53 expression but not in p53-deleted HCC cells. Mechanistic investigations revealed that SG increased p53 occupancy on the miR-16-2 promoter and decreased the expression of miR-16 target genes, including Bcl-2 and cyclin D1. Moreover, SG significantly inhibited HCC cell proliferation in a p53-dependent manner by inducing cell cycle arrest and reactive oxygen species (ROS)-associated apoptosis. Silencing miR-16 by treatment with anti-miR16 miRNA inhibitors rescued the cell viability repression effect caused by SG. Importantly, SG dramatically suppressed tumor growth in an HCC xenograft model, with little cytotoxicity. Taken together, our results provide a preclinical proof-of-concept for SG as a potential strategy for HCC treatment based on the restoration of miR-16 tumor suppressor function.

Authors+Show Affiliations

Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710071, China; Department of Gynecology and Obstetrics, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710038, China.Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710071, China.School of Ocean Science and Biochemistry Engineering, Fujian Normal University Fuqing Branch, Fuqing, Fujian, 350300, China.Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710071, China.Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710071, China.Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710071, China; CAS Key Laboratory of Molecular Imaging, Institute of Automation Chinese Academy of Sciences, Beijing, 100190, China; Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine, Beihang University, Beijing, 100190, China. Electronic address: jie.tian@ia.ac.cn.Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710071, China. Electronic address: fwang@xidian.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31163195

Citation

Zhang, Beilei, et al. "P53-dependent Upregulation of miR-16-2 By Sanguinarine Induces Cell Cycle Arrest and Apoptosis in Hepatocellular Carcinoma." Cancer Letters, vol. 459, 2019, pp. 50-58.
Zhang B, Wang X, Deng J, et al. P53-dependent upregulation of miR-16-2 by sanguinarine induces cell cycle arrest and apoptosis in hepatocellular carcinoma. Cancer Lett. 2019;459:50-58.
Zhang, B., Wang, X., Deng, J., Zheng, H., Liu, W., Chen, S., Tian, J., & Wang, F. (2019). P53-dependent upregulation of miR-16-2 by sanguinarine induces cell cycle arrest and apoptosis in hepatocellular carcinoma. Cancer Letters, 459, 50-58. https://doi.org/10.1016/j.canlet.2019.05.042
Zhang B, et al. P53-dependent Upregulation of miR-16-2 By Sanguinarine Induces Cell Cycle Arrest and Apoptosis in Hepatocellular Carcinoma. Cancer Lett. 2019 09 10;459:50-58. PubMed PMID: 31163195.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - p53-dependent upregulation of miR-16-2 by sanguinarine induces cell cycle arrest and apoptosis in hepatocellular carcinoma. AU - Zhang,Beilei, AU - Wang,Xinan, AU - Deng,Jiacong, AU - Zheng,Haifeng, AU - Liu,Wei, AU - Chen,Si, AU - Tian,Jie, AU - Wang,Fu, Y1 - 2019/06/01/ PY - 2018/11/21/received PY - 2019/05/26/revised PY - 2019/05/29/accepted PY - 2019/6/5/pubmed PY - 2020/6/11/medline PY - 2019/6/5/entrez KW - Apoptosis KW - Cell cycle KW - Sanguinarine KW - miRNA-16 KW - p53 SP - 50 EP - 58 JF - Cancer letters JO - Cancer Lett. VL - 459 N2 - MicroRNAs (miRNAs) were involved in cancer progression, and the targeting of miRNAs by natural agents has opened avenues for cancer treatment and drug development. miR-16 functions as a tumor suppressor and is frequently deleted or downregulated in various human cancers, including hepatocellular carcinoma (HCC). In the present study, we employed a miR-16-responsive luciferase reporter to screen candidate compounds that modulate miR-16 expression from a natural product library. One compound, sanguinarine (SG), was capable of activating miR-16 in HCC cells with wildtype or mutated p53 expression but not in p53-deleted HCC cells. Mechanistic investigations revealed that SG increased p53 occupancy on the miR-16-2 promoter and decreased the expression of miR-16 target genes, including Bcl-2 and cyclin D1. Moreover, SG significantly inhibited HCC cell proliferation in a p53-dependent manner by inducing cell cycle arrest and reactive oxygen species (ROS)-associated apoptosis. Silencing miR-16 by treatment with anti-miR16 miRNA inhibitors rescued the cell viability repression effect caused by SG. Importantly, SG dramatically suppressed tumor growth in an HCC xenograft model, with little cytotoxicity. Taken together, our results provide a preclinical proof-of-concept for SG as a potential strategy for HCC treatment based on the restoration of miR-16 tumor suppressor function. SN - 1872-7980 UR - https://www.unboundmedicine.com/medline/citation/31163195/p53_dependent_upregulation_of_miR_16_2_by_sanguinarine_induces_cell_cycle_arrest_and_apoptosis_in_hepatocellular_carcinoma_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(19)30343-X DB - PRIME DP - Unbound Medicine ER -