<p>FOXA1 Promotes Cell Proliferation and Suppresses Apoptosis in HCC by Directly Regulating miR-212-3p/FOXA1/AGR2 Signaling Pathway</p>

Abstract

Background: Forkhead box protein A1 (FOXA1), acting as a transcriptional activator for liver-specific transcripts, plays a vital part in proliferation, apoptosis and cell cycle. Methods: The mRNA expression of FOXA1 in 90 HCC tissues and matched adjacent nontumor tissues was determined by qRT-PCR. The downstream and upstream regulators of FOXA1 were identified by bioinformatics analysis and experimental confirmation. Results: We found out that the expression of FOXA1 was obviously higher in hepatocellular carcinoma (HCC) tissues than that in matched non-tumor tissues. Similarly, FOXA1 is also highly expressed in HCC cell lines as compared with normal human hepatic cell line L02. Clinical association analysis indicated that high expression of FOXA1 was prominently correlated with high HBV level, large tumor size, high venous infiltration, high Edmondson-Steiner grading, and advanced tumor-node-metastasis tumor stage. Furthermore, the in vitro tests showed that ectopic expression of FOXA1 promoted HepG2 cell proliferation and suppressed apoptosis. In contrast, the downregulation of FOXA1 inhibited cell proliferation, and induced apoptosis in Hep3B cells. To investigate the functional mechanism of FOXA1, anterior gradient 2 (AGR2), an executor in proliferation and apoptosis, was identified as the direct target gene of FOXA1. Meanwhile, we also found the expression of FOXA1 could be inhibited by miR-212-3p, which working as a tumor suppressor downregulated in HCC. Conclusion: We revealed that FOXA1 exerted its biological function by regulating AGR2 expression, and its ectopic expression may be blamed for low expression of miR-212-3p.

Down-regulated HSA_circ_0003528 inhibits hepatocellular carcinoma aggressiveness via the miR-212-3p/XIAP axis

“…These studies revealed that miR-212-3p is an antitumor miRNA. Our data showed that downregulation of miR-212-3p reversed the antitumor effects of si-circ_0003528 in HCC cells, indicating the carcinostatic potential of miR-212-3p, which is in line with results of previous studies [ 6 , 35 ].…”

“…Li et al [ 31 ] found miR-212-3p served as a suppressor of breast cancer carcinogenesis via regulating VEGFA. Likewise, Yuan et al [ 35 ]reported that miR-212-3p had a cancer-inhibiting effect in HCC. These studies revealed that miR-212-3p is an antitumor miRNA.…”

MiR-212 value in prognosis and diagnosis of cancer and its association with patient characteristics: a systematic review and meta-analysis

“…2020 [ 50 ] miR-212 China 110 GC I-IV Serum Other individuals 53 RT-qPCR Median In vitro 10 OS Yuan, Z. 2020 [ 51 ] miR-212-3p China 90 HCC I-IV Tissue Normal tissue 60 RT-qPCR NR In vitro 9 OS Zhang, L. 2020 [ 52 ] miR-212-3p China 63 HGSOC I-IV Tissue NR 130 RT-qPCR Median - 9 OS, DFS B Studies included in diagnostic evaluation Study ID miR-212 type Country Cancer type Stage Normalizer Control source Assay Sample type AUC (95% CI) Cancer Miah, S. 2012 [ 53 ] miR-212 UK BC (UCC) pTa- pT4 NR Healthy individuals qRT-PCR …”

“…Dou et al found that HCC-related OS and DFS are predictable via miR-212 levels combined with Forkhead box protein-A1 (FOXA1), which was more reliable than each alone [ 21 ]. FOXA1 promotes cell proliferation and apoptosis with an established role in HCC development and post-transcriptionally down-regulated by miR-212-3p [ 21 , 24 ]. The miR-212 also suppresses the connective tissue growth factor (CTGF) (which promotes tumoral angiogenesis) and histone-H3 lysine-4 demethylase of RBP2 (which is upregulated in HCC) [ 20 , 22 , 23 ].…”

FOXA1 Can Be Modulated by HDAC3 in the Progression of Epithelial Ovarian Carcinoma

“…In pancreatic cancer, overexpression of FOXA1 promotes the invasion ability by affecting the progression of EMT 32 . FOXA1 also plays an important role in promoting cell proliferation and suppressing apoptosis in hepatocellular carcinoma 33 . In gastric carcinoma, FOXA1…”