Lung cancer is the most common cancer and is the leading cause of cancer death [
1]. Despite rapid advances in cancer treatment, the prognosis of lung cancer patients remains less than optimal. The 5-year survival rate in lung cancer patients is 4–17%, depending on tumor stage and region [
2,
3]. Cancer stem cells (CSCs), a small population of cancer cells that retain stem cell properties [
4,
5], play an essential role in tumor initiation, progression and therapy. The self-renewal and differentiation of CSCs are responsible for tumor initiation and maintenance. CSCs also act as tumorigenic cells in metastasis. Moreover, CSCs exhibit resistance to anticancer drugs, and CSCs remaining after therapy lead to cancer recurrence. Because of the conspicuous role of CSCs in tumor initiation, maintenance, metastasis, drug resistance and recurrence, inhibiting CSCs by targeting signaling pathways that regulate these cells is an effective anti-lung cancer strategy [
6].
Forkhead box (FOX) proteins, characterized by a winged helix DNA-binding domain [
7], are important transcription factors [
8,
9], and many FOX family members play a critical role in cancer progression [
10‐
13]. Previous studies have proven that FOX proteins are strongly associated with CSCs. For example, downregulation of FOXA1 expression promotes CSC-like properties in breast cancer cells, leading to tamoxifen resistance [
14]. FOXM1 increases the CSC population and induces endocrine resistance in breast cancer [
15], and FOXQ1 inhibition with diallyl disulfide is a novel strategy for suppressing breast CSCs [
16]. Forkhead box C1 (FOXC1), a member of the FOX protein family, acts as an oncogene in various cancers [
17]. For instance, FOXC1 mRNA and protein levels are upregulated in 60% and 63.3%, respectively, of patients with non-small cell lung cancer (NSCLC), which is the main type of lung cancer, and FOXC1 knockdown inhibits proliferation and metastasis in NSCLC [
18‐
20]. FOXC1 also promotes proliferation, migration, invasion and drug resistance in hepatocellular carcinoma [
21,
22] and breast cancer [
23‐
26]. Recently, several studies have shown that FOXC1 governs hair follicle stem cell quiescence to maintain regenerating potential [
27,
28]. Hedgehog and Notch are essential pathways in CSC regulation [
29]. FOXC1 activates Notch pathway by directly regulating Dll4 in endothelial cells [
30] and enhances Hedgehog signaling activity via Gli2 binding in basal-like breast cancer [
31]. Moreover, FOXC2 has been shown to enhance CSC-like properties in breast cancer and prostate cancer [
32,
33]. These findings emphasize the role of FOX proteins in regulating CSCs.
Nonetheless, there is no report on the function of FOXC1 in the regulation of CSCs in NSCLC. This study is the first to investigate FOXC1 induction of CSC-like properties in NSCLC, and we hope that the findings will provide a foundation for NSCLC therapy via CSC eradication.