Dihydroartemisinin suppresses the tumorigenesis of esophageal carcinoma by elevating DAB2IP expression in a NFIC-dependent manner

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 397; no. 10; pp. 8117 - 8128
• Main Authors: Yang, Chao, Wei, Wei, Hu, Fen, Zhao, Xing, Yang, Hanxue, Song, Xiujun, Sun, Zhihua
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2024; Springer Nature B.V
• Subjects: Angiogenesis; Animals; Antineoplastic Agents - pharmacology; Antitumor activity; Artemisinins - pharmacology; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Carcinogenesis - drug effects; Carcinogenesis - genetics; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Dihydroartemisinin; Disabled-2 protein; Esophageal cancer; Esophageal carcinoma; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic - drug therapy; Neurosciences; Nuclear factor I; Pharmacology/Toxicology; ras GTPase-Activating Proteins - genetics; ras GTPase-Activating Proteins - metabolism; Tumor suppressor genes; Tumorigenesis; Western blotting; Dihydroartemisinin; DAB2IP; Stemness; Angiogenesis; ESCA; NFIC
• ISSN: 0028-1298; 1432-1912; 1432-1912
• DOI: 10.1007/s00210-024-03163-y

Dihydroartemisinin (DHA) has been identified to have the anticancer and anti-inflammatory activities. Disabled homolog 2 interacting protein (DAB2IP) is a well-recognized tumor suppressor. Both DHA and DAB2IP were proven to have suppressing effects on esophageal carcinoma (ESCA) tumorigenesis. However, whether DHA regulated ESCA cells via DAB2IP and its mechanism are still vague. Functional analyses were conducted using MTT, tube formation, sphere formation, and transwell assays in vitro as well as Tumor formation experiments in mice. Levels of genes and proteins were assayed by qRT-PCR and western blotting analyses. The interaction between DAB2IP and Nuclear Factor I C (NFIC) was confirmed using bioinformatics analysis and dual-luciferase reporter assay. DHA treatment suppressed ESCA cell angiogenesis, stemmess, migration, and invasion. DAB2IP level was decreased in ESCA tissues and cells, and DHA elevated DAB2IP expression in ESCA cells. Functionally, DAB2IP overexpression impaired ESCA cell angiogenesis, stemmess, migration and invasion. Mechanistically, NFIC had binding sites on the promoter region and directly targeted DAB2IP. DHA could up-regulate DAB2IP expression via NFIC. Moreover, NFIC was also decreased in ESCA tissues and cells, and its overexpression had anticancer activity in ESCA cells. In addition, DAB2IP knockdown reversed the anticancer effects of NFIC or DHA on ESCA cells. In further in vivo analysis, DHA also suppressed ESCA growth by regulating DAB2IP expression. DHA suppressed the tumorigenesis of ESCA by elevating DAB2IP expression in an NFIC-dependent manner, suggesting the potential clinical application of DHA in ESCA treatment.