MiR-129-5p exerts Wnt signaling-dependent tumor-suppressive functions in hepatocellular carcinoma by directly targeting hepatoma-derived growth factor HDGF.

Autor: Huge N; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Reinkens T; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Buurman R; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Sandbothe M; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Bergmann A; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Wallaschek H; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Vajen B; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Stalke A; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Decker M; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Eilers M; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Schäffer V; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Dittrich-Breiholz O; Research Core Unit Genomics, Hannover Medical School, Hannover, Germany., Gürlevik E; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany., Kühnel F; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany., Schlegelberger B; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany., Illig T; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.; Hannover Unified Biobank (HUB), Hannover Medical School, Hannover, Germany., Skawran B; Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany. skawran.britta@mh-hannover.de.
Jazyk: angličtina
Zdroj: Cancer cell international [Cancer Cell Int] 2022 May 16; Vol. 22 (1), pp. 192. Date of Electronic Publication: 2022 May 16.
DOI: 10.1186/s12935-022-02582-2
Abstrakt: Background: In hepatocellular carcinoma (HCC), histone deacetylases (HDACs) are frequently overexpressed. This results in chromatin compaction and silencing of tumor-relevant genes and microRNAs. Modulation of microRNA expression is a potential treatment option for HCC. Therefore, we aimed to characterize the epigenetically regulated miR-129-5p regarding its functional effects and target genes to understand its relevance for HCC tumorigenesis.
Methods: Global miRNA expression of HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B) and normal liver cell lines (THLE-2, THLE-3) was analyzed after HDAC inhibition by miRNA sequencing. An in vivo xenograft mouse model and in vitro assays were used to investigate tumor-relevant functional effects following miR-129-5p transfection of HCC cells. To validate hepatoma-derived growth factor (HDGF) as a direct target gene of miR-129-5p, luciferase reporter assays were performed. Survival data and HDGF expression were analyzed in public HCC datasets. After siRNA-mediated knockdown of HDGF, its cancer-related functions were examined.
Results: HDAC inhibition induced the expression of miR-129-5p. Transfection of miR-129-5p increased the apoptosis of HCC cells, decreased proliferation, migration and ERK signaling in vitro and inhibited tumor growth in vivo. Direct binding of miR-129-5p to the 3'UTR of HDGF via a noncanonical binding site was validated by luciferase reporter assays. HDGF knockdown reduced cell viability and migration and increased apoptosis in Wnt-inactive HCC cells. These in vitro results were in line with the analysis of public HCC datasets showing that HDGF overexpression correlated with a worse survival prognosis, primarily in Wnt-inactive HCCs.
Conclusions: This study provides detailed insights into the regulatory network of the tumor-suppressive, epigenetically regulated miR-129-5p in HCC. Our results reveal for the first time that the therapeutic application of mir-129-5p may have significant implications for the personalized treatment of patients with Wnt-inactive, advanced HCC by directly regulating HDGF. Therefore, miR-129-5p is a promising candidate for a microRNA replacement therapy to prevent HCC progression and tumor metastasis.
(© 2022. The Author(s).)
Databáze: MEDLINE
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