Colorectal cancer (CRC) is one of the most common cancers in the digestive tract [1]. It ranks third in terms of incidence and second in terms of mortality, with approximately 1.8 million new CRC cases and 881,000 deaths in 2018 worldwide [2]. Approximately, 25% of patients with CRC present with distant metastases at diagnosis, most to the liver, and half of the patients with CRC will develop metastatic diseases [3], [4], [5]. A variety of factors involved in CRC pathogenesis have been reported, including protein-coding and noncoding genes, but many unknown factors that need to be identified and further studied remained.

The forkhead box (Fox) proteins are transcription factors that are involved in embryonic development and organogenesis. FOXA subfamily is the most widely studied subfamily, and it consists of 3 members, including FOXA1, FOXA2, and FOXA3. Members of the FOXA subfamily are necessary for endoderm formation and some organ development, such as the liver, pancreas, lung, and prostate. Also, they regulate energy metabolism by regulating multiple target genes in the liver, pancreas, and adipose tissues, thereby participating in the pathological process of many diseases, including the metastasis of malignant tumors [6], [7], [8]. FOXA2 is a winged-helix transcription factor known to interact with chromosome protein and deoxyribonucleic acid (DNA), opening the compacted chromatin for other proteins [9]. Dysregulation of FOXA2 has been reported in multiple cancers, such as breast, lung, and gastric cancers [10], [11], [12]. Shang et al. evaluated the expression of FOXA2 in a variety of cancers in The Cancer Genome Atlas database and found that FOXA2 gene upregulation is related to the overall survival improvement in patients with ovarian cancer [13]. Teng et al. found that the liver-specific transcription factors FOXA2 and HNF1A bind to the enhancer and activate liver-specific gene transcription, thereby driving the liver metastasis of CRC [14]. Recently, Wang et al. revealed that the FOXA2 expression was elevated in colon cancer tissues and correlated with colon cancer clinical staging and metastasis [15]. However, the reports about the role of FOXA2 in CRC are rare, and the related mechanisms remain unclear.

MicroRNAs (miRs) are a large family of noncoding RNAs with a length of 22–25 nt. They can regulate gene expression by binding to the 3′-UTR of target mRNAs [16], [17]. Increasing evidence shows that miRNAs can regulate cell proliferation, invasion, and migration [18], [19], and some miRNAs play crucial roles in CRC development. miR-144 can inhibit CRC cell proliferation and migration through GSPT1 inhibition [20]. miR-195-5p mediates the downregulation of YAP1, leading to reduced tumor development in a mouse CRC xenograft model [21]. miR-let-7 g (let-7 g), a member of the let-7 miRNA family, plays important biological functions in various diseases including cancer [22], [23], [24]. Bioinformation analysis (http://www.cuilab.cn/transmir) showed that FOXA2 could bind to the promoter region of hsa-let-7 g and promote its transcription.

This study aimed to examine the role of FOXA2 in hypoxia-induced metastasis and epithelial-mesenchymal transition (EMT) in CRC and explore the molecular mechanisms by which FOXA2 regulates EMT.