Highlights
- •Multi-generational maternal exposure to high-fat diet causes increased incidence of DEN-induced HCC in offspring.
- •Gradually downregulated Acsl1 and Aldh2 are found in the offspring over generations, which promote tumor growth in synergy.
- •miR-27a-3p negatively regulates Acsl1 and Aldh2 in mouse and human HCC samples.
- •Increased serum miR-27a-3p is found in mothers fed a high-fat diet.
- •Offspring of miR-27a-3p agomir-injected mothers show increased HCC susceptibility.
Background & Aims
Obesity is an independent risk factor for malignancies, including hepatocellular carcinoma
(HCC). However, it remains unknown whether maternal obesity affects the incidence
of HCC in offspring. Thus, we aimed to investigate this association and its underlying
mechanisms.
Methods
Diethylnitrosamine (DEN) was used to induce HCC in a high-fat diet (HFD)-induced multigenerational
obesity model. RNA-sequencing was performed to identify the genes and microRNAs (miRNAs)
that were altered over generations. The role of the miR-27a-3p-Acsl1/Aldh2 axis in
HCC was evaluated in cell lines and HCC-bearing nude mice, and its intergenerational
impact was studied in pregnant mice and their offspring.
Results
Under HFD stress, maternal obesity caused susceptibility of offspring to DEN-induced
HCC, and such susceptibility was cumulative over generations. We identified that Acsl1 and Aldh2, direct targets of miR-27a-3p, were gradually changed over generations. Under hyperlipidemic
conditions, downregulation of Acsl1 and Aldh2 increased cell proliferation (in vitro) or tumor growth (in vivo) in synergy. Intratumor injection of an miR-27a-3p agomir exacerbated tumor growth
by downregulating Acsl1 and Aldh2; while intratumor injection of an miR-27a-3p antagomir had the opposite effect. Moreover,
serum miR-27a-3p levels gradually increased in the HFD-fed maternal lineage over generations.
Injecting pregnant mice with an miR-27a-3p agomir not only upregulated hepatic miR-27a-3p
and downregulated Acsl1/Aldh2 in offspring (fetus, young and adult stages), but also
exacerbated HCC development in DEN-treated offspring. In human HCC, upregulated miR-27a-3p
and downregulated Acsl1/Aldh2 were negatively correlated with survival on TCGA analysis;
while, hepatic miR-27a-3p was negatively correlated with Acsl1/Aldh2 expression in
tumor/non-tumor tissues from fatty/non-fatty livers.
Conclusions
Maternal obesity plays a role in regulating cumulative susceptibility to HCC development
in offspring over multiple generations through the miR-27a-3p-Acsl1/Aldh2 axis.
Lay summary
It is not currently known how maternal obesity affects the incidence of liver cancer
in offspring. In this study, we identified a microRNA (miR-27a-3p) that was upregulated
in obese mothers and could be passed on to their offspring. This microRNA enhanced
the risk of liver cancer in offspring by regulating 2 genes (Acsl1 and Aldh2). This mechanism could be a future therapeutic target.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 25, 2020
Accepted:
March 20,
2020
Received in revised form:
March 19,
2020
Received:
October 11,
2019
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
