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Cancers 2018, 10(8), 269; https://doi.org/10.3390/cancers10080269

4-Acetyl-Antroquinonol B Suppresses SOD2-Enhanced Cancer Stem Cell-Like Phenotypes and Chemoresistance of Colorectal Cancer Cells by Inducing hsa-miR-324 re-Expression

1
Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
2
Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
3
Division of Colorectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei City 110, Taiwan
4
School of Life Sciences, The Chinese University of Hong Kong, Hong Kong 153254, China
5
Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
6
Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
7
Department of Appiled Chemistry, Chaoyang University of Technology, Taichung 41147, Taiwan
8
Beijing Bioprocess Key Laboratory, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
9
Amoy-BUCT Industrial Bio-Technovation Institute, Amoy 361022, China
10
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
11
Department of Pathology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
12
Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 12 July 2018 / Revised: 4 August 2018 / Accepted: 7 August 2018 / Published: 10 August 2018
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Abstract

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit the niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite the accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored. Experimental approach: In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, Western blot, real-time polymerase chain reaction (RT-PCR), and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2. Results: This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-acetylantroquinonol B (4-AAQB), as evidenced by inhibited cell viability and proliferation, as well as attenuated migration, invasion, and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. Interestingly, 4-AAQB did not affect the viability and proliferation of normal colon cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA, reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates the FOLFOX (folinate (leucovorin), fluorouracil (5FU), and oxaliplatin) anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324, and inhibiting SOD2-mediated tumorigenicity. Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients. View Full-Text
Keywords: 4-AAQB; SOD2; hsa-miR-324; colon cancer stem cells; chemoresistance; chemosensitivity 4-AAQB; SOD2; hsa-miR-324; colon cancer stem cells; chemoresistance; chemosensitivity
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Bamodu, O.A.; Yang, C.-K.; Cheng, W.-H.; Tzeng, D.T.; Kuo, K.-T.; Huang, C.-C.; Deng, L.; Hsiao, M.; Lee, W.-H.; Yeh, C.-T. 4-Acetyl-Antroquinonol B Suppresses SOD2-Enhanced Cancer Stem Cell-Like Phenotypes and Chemoresistance of Colorectal Cancer Cells by Inducing hsa-miR-324 re-Expression. Cancers 2018, 10, 269.

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