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Multigenerational maternal obesity increases the incidence of HCC in offspring via miR-27a-3p

      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

      Keywords

      Linked Article

      • Maternal obesity: A severe risk factor in hepatocarcinogenesis?
        Journal of HepatologyVol. 73Issue 3
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          While one third of the world's population is overweight or obese, the impact of obesity as an epigenetic trait affecting not only people's health but also the health of unborn children is highly questionable. Obesity confers a higher risk of developing metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC).1 Besides that, the offspring of obese mothers are known to be more susceptible to NAFLD, but no relationship has been established between obesity in mothers and the risk of their progeny developing HCC.
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