Nobiletin attenuates self-renewal in cervical cancer cells and spheres through miR-342-3p upregulation and FOXM1 downregulation.

Cervical cancer (CC) cells exhibiting self-renewal properties are regarded as the primary drivers of recurrence. Nobiletin (NOB), a polymethoxy flavonoid derived from citrus, demonstrates effective suppression of cancer stem cell characteristics through the regulation of multiple targets, including key signaling pathways and epigenetic mechanisms. This investigation seeks to evaluate the influence of NOB on self-renewal capabilities and to identify potential epigenetic mechanisms using spheroids derived from HeLa and SiHa cell lines as models for cancer stem-like cells (CCSLCs). The experimental findings demonstrated that NOB markedly diminished self-renewal capabilities, evidenced by reduced sphere formation and decreased protein expression of CD133, CD49f, Oct4, and Sox2 as well as in vivo tumor growth within CCSLCs. Analysis through quantitative polymerase chain reaction indicated NOB elevated miR-342-3p levels while suppressing FOXM1, its target gene expression. Luciferase-based experiments verified miR-342-3p's direct targeting of FOXM1 in CCSLCs obtained from NOB-treated HeLa cells. The alterations in miR-342-3p expression levels, whether through enhancement or suppression, showed corresponding changes in NOB's effectiveness. Moreover, alterations in FOXM1 expression, either via overexpression or knockdown, did not alter NOB-induced miR-342-3p levels but markedly impacted NOB's suppression of self-renewal in both HeLa cells and derived CCSLCs. Thus, NOB inhibits self-renewal by enhancing miR-342-3p levels and diminishing FOXM1 levels in CC cells and derived CCSLCs.