title: Overexpression of variant PNPLA3 gene at I148M position causes malignant transformation of hepatocytes via IL-6-JAK2/STAT3 pathway in low dose free fatty acid exposure: a laboratory investigation in vitro and in vivo.
abstract: Epidemiological survey identified that the variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene at I148M position exerts direct effect in promoting hepatocellular carcinoma (HCC) under extraneous oxidative stress by interaction with obesity. However, the mechanism is still unknown. HepG2 cells were overexpressed by transinfection of PNPLA3 with wild-type 148I (PNPLA3(WT)) and mutant 148M (PNPLA3(I148M)), respectively. Variation in metabolic indicators, hepatic steatosis, biological behaviors and signaling molecules related to cancer promotion was measured in hepatocytes using low-dose free fatty acid (FFA) exposure. Effect of PNPLA3(I148M) on xenograft biology and its interaction with dietary obesity were also evaluated in animal study. Cells overexpresssing PNPLA3(I148M) in low-dose FFA incubation showed more proliferation, migration, invasion, and less apoptosis (P<0.05). Low-dose FFA specifically activated JAK2/STAT3 phosphorylation of PNPLA3(I148M) cells via upregulation of interleukin-6. Animal study showed high-fat diet accelerated growth of xenografts derived from PNPLA3(I148M) cells incubated in low-dose FFA. In low oxidative stress, PNPLA3(I148M) initiated the hepatocyte malignant transformation through the activation of inflammation-mediated JAK/STAT pathway. Dietary obesity amplified the growth of tumor from PNPLA3(I148M) cells by interaction with local FFA incubation. Anti-inflammation and weight loss might be potential approaches for preventing HCC in high-risk population carrying PNPLA3 variant.
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang ProvinceHangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesHangzhou 310003, China.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang ProvinceHangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesHangzhou 310003, China.
authors.forename: Tianchi
authors.initials: T
authors.lastname: Chen
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang ProvinceHangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesHangzhou 310003, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Lu
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang ProvinceHangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesHangzhou 310003, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang ProvinceHangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesHangzhou 310003, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang ProvinceHangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesHangzhou 310003, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhou 310003, China.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
keywords: PNPLA3; hepatocellular carcinoma; inflammation; obesity