AUF1 promotes hepatocellular carcinoma progression and chemo-resistance by post-transcriptionally upregulating alpha-fetoprotein expression

Background: The target genes of AU-rich Element RNA-binding Protein 1 (AUF1), which is an RNA binding protein, and its role in the progression of hepatocellular carcinoma (HCC) is still elusive. This study aims to investigate the biological function and the underlying target genes of AUF1 in HCC.

Methods: RNA sequencing data and the Liver Cancer Institute (LCI) database were used to screen candidate targets of AUF1. LCI database, TCGA database, and a retrospective HCC cohort were used to investigate the correlation between AUF1 and alpha-fetoprotein (AFP) and their prognostic values in HCC patients. Huh-7, HepG2, and HepAD38 cell lines were used to investigate the underlying mechanism of AUF1 regulating the AFP expression. Cell Counting Kit-8, colony formation, EdU incorporation, and flow cytometry assays were performed to detect the effect of AUF1-AFP axis on the progression and doxorubicin resistance of HCC cells.

Results: A combined analysis of the transcriptome data from Huh-7 cells after knockdown of AUF1 and gene expression data from LCI database revealed that AFP was the most significantly downregulated gene after AUF1 depletion. AUF1 expression was positively associated with AFP expression in HCC tissues and the high expression of both AUF1 and AFP were correlated with a worse prognosis in HCC patients of LCI and TCGA databases, as well as our retrospective cohort. Mechanistically, AUF1 bound to the 3' untranslation region (UTR) of AFP mRNA to enhance the mRNA stability of AFP, thereby upregulating AFP. Functional tests showed that AFP knockdown inhibited tumor growth and doxorubicin resistance of HCC cells induced by AUF1.

Conclusions: AFP may be an important target gene of AUF1. AUF1 promoted HCC progression and doxorubicin resistance by upregulating AFP expression via increasing its mRNA stability.