title: Interleukin-6-stimulated progranulin expression contributes to the malignancy of hepatocellular carcinoma cells by activating mTOR signaling.
abstract: This study aimed to determine the expression of progranulin (PGRN) in hepatocellular carcinoma (HCC) cells in response to interleukin 6 (IL-6), a non-cellular component of the tumor microenvironment, and the molecular mechanism of PGRN oncogenic activity in hepatocarcinogenesis. Levels of IL-6 and PGRN were increased and positively correlated in HCC tissues. IL-6 dose- and time-dependently increased PGRN level in HCC cells. IL-6-driven PGRN expression was at least in part mediated by Erk/C/EBPβ signaling, and reduced expression of PGRN impaired IL-6-stimulated proliferation, migration and invasion of HepG2 cells. PGRN activated mammalian target of rapamycin (mTOR) signaling, as evidenced by increased phosphorylation of p70S6K, 4E-BP1, and Akt-Ser473/FoxO1. Inhibition of mTOR signaling with rapamycin, an mTOR signaling inhibitor, disturbed PGRN- or IL-6-mediated proliferation, migration and invasion of HCC cells in vitro. Persistent activation of mTOR signaling by knockdown of TSC2 restored PGRN-knockdown-attenuated pro-proliferation effects of IL-6 in HepG2 cells. In addition, rapamycin treatment in vivo in mice slowed tumor growth stimulated by recombinant human PGRN. Our findings provide a better understanding of the biological activities of the IL-6/PGRN/mTOR cascade in the carcinogenesis of HCC, which may suggest a novel target in the treatment of HCC.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan 250012, China.|Department of Clinical Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D015850:Interleukin-6 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D000077153:Progranulins; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D000077153:Progranulins; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus