title: Human leptin protein activates the growth of HepG2 cells by inhibiting PERK‑mediated ER stress and apoptosis.
abstract: Current treatment modalities for various types of hepatic cancer, which has an increasing incidence rate, are inadequate and novel therapies are required. Therefore, identifying targets for liver cancer is becoming increasingly valuable to develop novel methods for therapy. The aim of the present study was to examine the growth activation mechanism of the leptin protein in the liver cancer cell line HepG2. The effects of the leptin protein on cell death were investigated by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide analysis. DNA fragmentation and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis were also performed to detect cell apoptosis. The expression of leptin and three endoplasmic reticulum (ER) stress unfolded protein response (UPR) proteins, including activating transcription factor 6, phosphorylated‑PKR‑like ER kinase (p‑PERK) and inositol requiring protein 1, were investigated for the examination of ER stress. The mRNA UPR proteins were also detected by reverse transcription polymerase chain reaction. The apoptosis‑associated caspase 12 and C/EBP homologous protein (CHOP) was detected by western blot analysis. The expression of or incubation with the leptin protein was able to activate cell growth and inhibit cell death and apoptosis. In cells that expressed leptin or were incubated with leptin protein (pep-LPT), cisplatin‑induced ER stress‑associated mRNA transcription and protein activation were inhibited. Levels of the ER stress UPR pathway protein, PERK, increased significantly in leptin‑silenced cells when treated with cisplatin as compared with those in the leptin‑expressing or pep-LPT cells. Furthermore, caspase 12 activation was inhibited in ex‑LPT, pep‑LPT and HepG2 cells. In conclusion, human leptin protein is involved in promoting the proliferation of HepG2 cells through inhibiting the ER stress‑associated apoptotic pathway. The PERK UPR pathway and the apoptotic factor caspase 12 were found to be involved in the inhibition of apoptosis and enhancement of proliferation.
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Plastic and Cosmetic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Man
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Anorectal, The Affiliated Hospital of Jiangxi Traditional Chinese Medicine University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Mingwei
authors.initials: M
authors.lastname: An
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lei
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Wuhua
authors.initials: W
authors.lastname: Guo
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D053938:DNA Fragmentation; D059865:Endoplasmic Reticulum Stress; D056945:Hep G2 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: C084104:APLP2 protein, human; C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D016564:Amyloid beta-Protein Precursor; D020738:Leptin; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; C506444:CASP12 protein, human; D053454:Caspase 12; D002945:Cisplatin