RNA-binding protein AUF1 suppresses miR-122 biogenesis by down-regulating Dicer1 in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the common cancers worldwide, especially in developing countries. Although the chronic infections of hepatitis B and C viruses have been established as the etiological factors of HCC, the mechanism for the tumorigenesis and development of HCC is still unclear. The liver-specific microRNA-122 (miR-122), an established tumor-suppressor miRNA, is often down-regulated in HCC, while the underlying mechanism is not well understood. Here we report that the AU-rich element-binding factor AUF1 suppresses the expression of Dicer1, the type III RNase that is required for microRNA maturation, leading to the inhibited biogenesis of miR-122. Overexpression of AUF1 led to the decreased expression of Dicer1 and miR-122, while the level of the miR-122 precursor (pre-miR-122) was increased. On the other hand, siRNA of AUF1 (siAUF1) increased the levels of Dicer1 mRNA and miR-122, but it reduced the abundance of pre-miR-122. Consistent with the reported data, this study demonstrated that AUF1 and Dicer1 showed opposite expression pattern in both human HCC tissues and cell lines. In addition, AUF1 inhibited the expression of Dicer1 by interacting with the 3′ untranslated region (3′UTR) and coding region of DICER1 mRNA. Moreover, the knockdown of AUF1 by siRNA altered the expression of other miRNAs and promoted HCC cell death. In conclusion, AUF1 down-regulates the expression miR-122 by interacting with the 3′UTR and coding region of DICER1 mRNA and suppressing Dicer1 expression. The AUF1/Dicer1/miR-122 pathway might play a critical role in the development of HCC.

DICER1 Syndrome: DICER1 Mutations in Rare Cancers

“…Mice treated with metformin showed reduced tumor growth and an upregulation of miRNAs and an increase in DICER1 gene expression. A similar, recent experiment confirmed these results, as metformin was found to induce higher Dicer levels in mouse models and human patients by altering the localization of AUF1, a DICER1 mRNA binding protein that down-regulates DICER1 , leading to increased DICER1 mRNA stability [ 98 , 99 ]. While the treatments described in these experiments may not be beneficial to patients with biallelic DICER1 mutations, those with a single, functional DICER1 allele might benefit from metformin and compounds similar to it, as this single allele could hypothetically be targeted and upregulated to achieve increased Dicer protein production.…”

The Role of RNA Splicing Factors in Cancer: Regulation of Viral and Human Gene Expression in Human Papillomavirus-Related Cervical Cancer

“…Indeed, the hnRNP A1 has been shown to interact with pri-miR-18a conserved terminal loop and to induce a relaxation in the stem loop that facilitates the cleavage by Drosha and production of mature miR-18a in prostate, esophageal, pancreatic, hepatocellular, and colorectal cancer (Guil and Caceres, 2007;Komatsu et al, 2014;Kooshapur et al, 2018). Moreover, the hnRNP D reduces the Dicer1 levels by targeting the 3 -UTR of DICER1 mRNA, causing downregulation of tumor suppressor miR-122 and increased viability of PLC/PRF/5 hepatoma as well as Huh7 liver derived cell lines (Wu et al, 2018). Among SRSF proteins, the SRSF3 was demonstrated to enhance the processing of miR-16-1, miR-30a and miR-223 through the binding of a CNNC motif located 17-18 nucleotides downstream the Drosha cleavage signal (Auyeung et al, 2013).…”

DICER1 Syndrome and Cancer Predisposition: From a Rare Pediatric Tumor to Lifetime Risk

“…Some studies explored the use of metformin to upregulate DICER1 and linked proteins in mice, to counter the DICER1 syndrome's effects (74)(75)(76)(77). Despite patients affected by biallelic DICER1 mutations may not benefit from this treatment, metformin will be may proposed to patients with a single allele alteration, to try to augment DICER1 protein production and compensate the deficit, preventing the oncogenetic cascade.…”