Yu Sun1, Qing Wang1, Yu Zhang2, Mengyuan Geng1, Yujuan Wei2, Yanrui Liu1, Shanshan Liu1, Robert B Petersen3, Junqiu Yue4, Kun Huang5, Ling Zheng6. 1. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China, 430072. 2. Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 430030. 3. Foundational Sciences, Central Michigan University College of Medicine, Mt. Pleasant, MI, USA, 48858. 4. Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 430030. 5. Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 430030. Electronic address: kunhuang@hust.edu.cn. 6. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China, 430072; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China, 430072. Electronic address: lzheng@whu.edu.cn.
Abstract
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.
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.
Authors: Ryan A Hlady; Xia Zhao; Louis Y El Khoury; Aesis Luna; Kien Pham; Qunfeng Wu; Jeong-Heon Lee; Nikolaos T Pyrsopoulos; Chen Liu; Keith D Robertson Journal: Hepatology Date: 2021-12-15 Impact factor: 17.298
Authors: Laís Vales Mennitti; Asha A M Carpenter; Elena Loche; Lucas C Pantaleão; Denise S Fernandez-Twinn; Josca M Schoonejans; Heather L Blackmore; Thomas J Ashmore; Luciana Pellegrini Pisani; John A Tadross; Iain Hargreaves; Susan E Ozanne Journal: Int J Obes (Lond) Date: 2021-10-18 Impact factor: 5.095