Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development, Dali University, Dali, Yunnan, 671000, China; The Libraries of Dali University, Dali, Yunnan, 671003, China.
Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical Research and Development, Dali University, Dali, Yunnan, 671000, China.
Biomed Pharmacother. 2018 Aug;104:94-101. doi: 10.1016/j.biopha.2018.05.015. Epub 2018 May 14.
Colorectal cancer (CRC) is one of the most common malignancies with high morbidity and mortality rates worldwide. This study aimed to investigate whether miR-3666 was involved in inhibitory effects of all-transretinoic acid (ATRA) on the development of colorectal cancer (CRC).
Surgical specimens of CRC tissues and adjacent non-tumor mucosa were collected for determining miR-3666 expression. Human CRC HCT116 cells were treated with different doses of ATRA (10, 20, 40, and 60 μM, respectively) and/or transfected with miR-3666 mimic, miR-3666 inhibitor, E2F7 siRNAs or their controls, respectively. After different treatments, cell viability, apoptosis, migration and invasion were detected. The regulatory relationship between miR-3666 and E2F7 was investigated. Furthermore, the association between MAPK/ERK pathway and ATRA or miR-3666/E2F7 was explored.
The miR-3666 was lowly expressed in CRC tissues, while E2F7 was highly expressed. ATRA decreased HCT116 cell viability, migration, and invasion, and induced apoptosis, indicating that ATRA inhibited the malignant behaviors of HCT116 cells. Moreover, ATRA increased miR-3666 expression, and effects of ATRA on the malignant behaviors of HCT116 cells were achieved by positive regulating miR-3666 expression. Furthermore, E2F7 was a target gene of miR-3666, and knockdown of E2F7 reversed the combined effects of ATRA and miR-3666 inhibitor on the malignant behaviors of HCT116 cells. Besides, ATRA inhibited the activation of MAPK/ERK signaling pathway, which was reversed by inhibition of miR-3666.
Our results reveal that ATRA protects against CRC development possible via increasing miR-3666 expression and decreasing E2F7 expression. MiR-3666/E2F7 may play a key role in regulating the inhibitory effects of ATRA on HCT116 cells via suppressing the activation of MAPK/ERK signaling pathway.
结直肠癌（CRC）是全球发病率和死亡率较高的最常见恶性肿瘤之一。本研究旨在探讨 miR-3666 是否参与全反式维甲酸（ATRA）对结直肠癌（CRC）发展的抑制作用。
收集 CRC 组织和相邻非肿瘤黏膜的手术标本，用于检测 miR-3666 的表达。分别用不同浓度的 ATRA（分别为 10、20、40 和 60 μM）和/或 miR-3666 模拟物、miR-3666 抑制剂、E2F7 siRNA 及其对照处理人 CRC HCT116 细胞。经不同处理后，检测细胞活力、凋亡、迁移和侵袭。探讨 miR-3666 与 E2F7 的调控关系。此外，还探讨了 MAPK/ERK 通路与 ATRA 或 miR-3666/E2F7 的关系。
miR-3666 在 CRC 组织中低表达，而 E2F7 高表达。ATRA 降低 HCT116 细胞活力、迁移和侵袭，并诱导细胞凋亡，表明 ATRA 抑制 HCT116 细胞的恶性行为。此外，ATRA 增加 miR-3666 的表达，通过正向调节 miR-3666 的表达来实现 ATRA 对 HCT116 细胞恶性行为的作用。此外，E2F7 是 miR-3666 的靶基因，E2F7 的敲低逆转了 ATRA 和 miR-3666 抑制剂对 HCT116 细胞恶性行为的联合作用。此外，ATRA 抑制 MAPK/ERK 信号通路的激活，而 miR-3666 的抑制则逆转了这一作用。
本研究结果表明，ATRA 通过增加 miR-3666 的表达和降低 E2F7 的表达来保护 CRC 的发生发展。miR-3666/E2F7 可能通过抑制 MAPK/ERK 信号通路的激活，在调节 ATRA 对 HCT116 细胞抑制作用中发挥关键作用。
