FOXA1 activates NOLC1 transcription through NOTCH pathway to promote cell stemness in lung adenocarcinoma.

Abstract

Tumor cell stemness plays a pivotal role in generating functional heterogeneity within tumors and is implicated in essential processes such as drug resistance, metastasis, and cell proliferation. Therefore, creating novel tumor diagnostic techniques and therapeutic plans requires a knowledge of the possible processes that preserve the stem cell-like qualities of cancers. Bioinformatics analysis of NOLC1 expression in lung adenocarcinoma (LUAD) and prediction of its upstream transcription factors and their binding sites were completed. RT-qPCR detection of NOLC1 and FOXA1 expression, colony formation assay of cell proliferation, Transwell assay of cell invasion, sphere formation assay of cell stemness, western blot detection of CD133, OCT4, GLI1, NOTCH1 and Hes1 expression, CCK-8 assay of IC₅₀ value of cisplatin, and ChIP and dual-luciferase reporter validation of binding relationship between NOLC1 and FOXA1 were done. NOLC1 expression was elevated in LUAD cells and tissues. Decreased NOLC1 expression inhibited the proliferation and invasive capacity of LUAD cells, prevented LUAD cells from becoming stem cells, and suppressed cisplatin resistance in the cells. Rescue tests demonstrated that NOLC1 activated the NOTCH pathway to increase the stemness of LUAD cells and promoted cisplatin resistance in LUAD cells. The activation of NOLC1 transcription by FOXA1 was validated by bioinformatics prediction and molecular verification, and the FOXA1/NOLC1 axis enhanced the stemness of LUAD cells. Activation of NOLC1 transcription by FOXA1 through NOTCH pathway promoted stemness of LUAD. FOXA1/NOLC1 axis is expected to become a new target for inhibiting stemness of LUAD cells.