Researchers in China have identified a microRNA in obese mouse mothers that is passed on to their pups, increasing susceptibility to liver cancer and elevating the odds of hepatocellular carcinoma (HCC) developing in offspring, down multiple generations. The study found that the maternal microRNA, miR-27a-3p, acted to increase the risk of liver cancer in offspring by regulating two genes, Acsl1 and Aldh2. The investigators say their findings could point to a future therapeutic target.

“Epidemiological studies show that obesity is an independent risk factor for liver cancer,” stated lead investigators Ling Zheng, PhD, at the College of Life Sciences, Wuhan University, and Kun Huang, PhD, at the Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology. “Maternal obesity, which directly affects the health of the offspring, plays a critical role in the obesity epidemic and metabolic diseases. Our study provides insights into the question of whether and how maternal obesity affects tumor incidence in offspring.”

The researchers reported their findings in the Journal of Hepatology, in a paper titled, “Multigenerational maternal obesity increases the incidence of HCC in offspring via miR-27a-3p.”

About a third of people are overweight or obese, and studies indicate that obesity confers a higher risk of developing metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Up to 50% of recently diagnosed HCC in the United States is the result of hepatic metabolic disorders such as NAFLD.

graphical abstract
Source: Journal of Hepatology

Studies have also uncovered a connection between maternal obesity and liver disease in the offspring of obese mothers. “Offspring of obese mothers are at increased risk of developing metabolic diseases, including NAFLD, independent of the body weight of their fathers, indicating that maternal factors play a major role in the inheritance of obesity,” the researchers continued. Their prior research had shown that the offspring of mothers exposed to high-fat diet (HFD) over multiple generations showed gradual increases in obesity and NAFLD. However, they wrote, “… whether the offspring of obese mothers are more prone to develop malignant tumors, such as HCC, is currently unknown.”

There are indications from existing research that noncoding RNAs can be passed to offspring. “Epigenetic mechanisms are involved in multigenerational obesity,” the scientists continued. “Growing evidence suggests that noncoding RNAs mediate heritable phenotypes in their offspring, for example, maternal circulating microRNAs (mRNAs) have been suggested to cross the placenta and affect the phenotype of offspring.” Yet despite this evidence, “… the links between maternal noncoding RNAs and disease development in offspring have not been established.”

To look at this more closely in the context of maternal obesity and HCC risk in offspring, the investigators administered diethylnitrosamine (DEN) to induce liver cancer in obese mice that had been fed a high-fat diet. RNA sequencing was carried out to identify the genes and microRNAs that altered over generations. The results indicated that injecting pregnant mice with the microRNA miR-27a-3p increased hepatic miR-27a-3p and reduced the expression of two genes, Acsl1 and Aldh2 in the offspring—at fetus, young, and adult stage. Injecting the mothers with the microRNA also exacerbated HCC development in DEN-treated offspring.

The results indicated that high-fat diet-induced maternal obesity caused the susceptibility of offspring to DEN-induced HCC. Interestingly, serum miR-27a-3p levels increased over generations in response to obesity in the maternal line. The investigators established that the odds for developing liver cancer similarly increased intergenerationally. So, risk severity in the offspring of an obese mother and an obese grandmother was higher than risk levels in offspring that had an obese mother but a normal weight grandmother.

The investigators also analyzed human samples of liver tumors, including 27 fatty liver-associated HCCs, and 27 non-fatty liver-associated HCCS. They found that miR-27a-3p was negatively correlated with Ascl1 and Aldh2 in the HCC patients, with or without fatty liver disease.

In vivo experiments showing that (A) HFD-fed female mice secrete miR-27a-3p and this increases with the generations (G0 to G2), leading to a higher HCC burden in G3 male mice compared to G1; (B) miR-27a-3p represses the expression of Acsl1 and Aldh2, responsible for this increased tumor burden; (C) Injection of miR-27a-3p agomir to pregnant female mice leads to the same phenotypic consequences in the offspring. [Journal of Hepatology]
“The levels of Acsl1 or Aldh2 in tumors were significantly lower compared to those in non-tumor tissues, and their levels in fatty liver samples were also significantly lower compared to those in non-fatty liver,” they wrote. “Consistently, the miR-27a-3p levels in tumors were significantly higher compared with those in non-tumor tissues, while its levels were significantly higher in fatty liver samples compared to those in non-fatty liver. Correlation analysis further revealed a negative correlation between the expression of miR-27a-3p and Ascl1 or Aldh2.”

“Our findings provide a mechanistic link between maternal obesity and the development of diseases in offspring, which will be helpful in exploring therapies and preventions for fetal- and developmental-originated diseases,” noted Huang. Added Zheng, “For pregnant mothers, the serum level of miR-27a-3p is critical for the offspring’s health and may be used in the future as a diagnostic or predictive biomarker. We would, therefore, like to call for a global effort on maternal multigenerational obesity in humans to better address this common problem we are facing.”

The team concluded, “Since maternal obesity is an independent contributing factor to metabolic diseases in offspring, and HCC is closely associated with metabolic diseases, our animal studies reveal a mechanistic link between maternal obesity and the development of cancer in offspring. Further clinical and epidemiological investigations will help to link our findings in humans … Attention should be paid to the potential clinical impacts of intergenerational and multigenerational phenomena.”

In an accompanying editorial in the same issue of the Journal of Hepatology, Sabine Colnot, PhD, at the Cordeliers Research Center, INSERM, and André Lechel, PhD, at University Hospital Ulm, commented, “This study opens a new avenue for cancer research at the crossroads of metabolism and epigenetics. It brings new information on how maternal stress could influence its progeny, with consequences for HCC development. The mode of inheritance is not a classical intergenerational one. It is multigenerational, as the susceptibility to HCC gradually increases over generations.”

They noted that there are still unknowns, however, including the mechanism of inheritance of mir-27a-3p. “In the mother, which cell type is the target of HFD to impact on miR-27a-3p synthesis and secretion?” They wrote, “The transportation of miR-27a-3p from the mother to the fetus by small extracellular vesicles also remains to be identified.”

A second question that will need addressing is whether the findings in mice can be extrapolated directly to humans “… to what extent is the maternal transmission of the miR-27a-3p-Acsl1/Aldh2 axis conserved between mice and humans?” As Colnot and Lechel pointed out, “If it is, the need for efficient prevention against junk food consumption gains a new argumentation.”

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