MicroRNA-449a 通过抑制 KDM3A/HIF-1α 轴延缓肺癌的发展。

MicroRNA-449a delays lung cancer development through inhibiting KDM3A/HIF-1α axis.

机构信息

Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Qiaokou District, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, 430030, Hubei, China.

出版信息

J Transl Med. 2021 May 27;19(1):224. doi: 10.1186/s12967-021-02881-8.

BACKGROUND

It has been established that microRNA (miR)-449a is anti-tumorigenic in cancers, including lung cancer. Therefore, this study further explored miR-449a-mediated mechanism in lung cancer, mainly focusing on lysine demethylase 3A/hypoxia-induced factor-1α (KDM3A/HIF-1α) axis.

METHODS

miR-449a, KDM3A and HIF-1α levels in lung cancer tissues and cell lines (A549, H1299 and H460) were measured. Loss- and gain-of-function assays were performed and then cell proliferation, cell cycle, apoptosis, invasion and migration were traced. The relationship between KDM3A, miR-449a and HIF-1α was verified. Tumor growth in vivo was also monitored.

RESULTS

Both lung cancer tissues and cells exhibited reduced miR-449a and raised KDM3A and HIF-1α levels. miR-449a interacted with KDM3A; HIF-1α could bind with KDM3A. Up-regulating miR-449a hindered while suppressing miR-449a induced lung cancer development via mediating HIF-1α. Elevating KDM3A promoted cellular aggression while down-regulating KDM3A had the opposite effects. Up-regulating KDM3A or HIF-1α negated up-regulated miR-449a-induced effects on cellular growth in lung cancer. Restoring miR-449a impaired tumorigenesis in vivo in lung cancer.

CONCLUSION

It is eventually concluded that miR-449a delays lung cancer development through suppressing KDM3A/HIF-1α axis.

背景

已有研究证实，微小 RNA（miR）-449a 在包括肺癌在内的多种癌症中具有抗肿瘤作用。因此，本研究进一步探讨了 miR-449a 在肺癌中的介导机制，主要集中在赖氨酸去甲基酶 3A/缺氧诱导因子-1α（KDM3A/HIF-1α）轴上。

方法

检测肺癌组织和细胞系（A549、H1299 和 H460）中 miR-449a、KDM3A 和 HIF-1α 的水平。进行了失活和功能获得实验，然后追踪细胞增殖、细胞周期、凋亡、侵袭和迁移。验证了 KDM3A、miR-449a 和 HIF-1α 之间的关系。还监测了体内肿瘤的生长。

结果

肺癌组织和细胞均表现出 miR-449a 水平降低和 KDM3A 和 HIF-1α 水平升高。miR-449a 与 KDM3A 相互作用；HIF-1α 可以与 KDM3A 结合。上调 miR-449a 抑制而下调 miR-449a 则通过调节 HIF-1α 促进肺癌的发展。上调 KDM3A 促进细胞侵袭，而下调 KDM3A 则产生相反的效果。上调 KDM3A 或 HIF-1α 则可消除 miR-449a 对肺癌细胞生长的上调作用。恢复 miR-449a 则可破坏肺癌体内的肿瘤发生。