title: Malignant transformation of human gastric epithelium cells via reactive oxygen species production and Wnt/β-catenin pathway activation following 40-week exposure to ochratoxin A.
abstract: Ochratoxin A (OTA), one of the most abundant food-contaminating mycotoxins, is a possible carcinogenic to humans. We previously demonstrated that OTA treatment induced oxidative damage in human gastric epithelium cells (GES-1) in vitro. In this study, we found that long-term OTA treatment could result in increased proliferation, migration, and invasion abilities of GES-1 cells and induce anchorage-independent growth of cells in soft agar. Inoculation of OTA-treated GES-1 cells resulted in the formation of tumor xenografts in Balb/c nude mice in vivo, confirming that long-term OTA treatment can induce the malignant transformation of GES-1 cells. In addition, we found that long-term OTA treatment induced oxidative stress and activated the Wnt/β-catenin pathway, including the nuclear transition of β-catenin and the upregulation of the downstream molecules of the pathway. Finally, pretreatment with the antioxidant N-acetyl-L-cysteine (NAC) inhibited ROS formation and activation of the Wnt pathway in OTA-transformed GES-1 cells, which decreased the tumor formation abilities of these cells after inoculation in nude mice. These findings suggest that long-term OTA exposure induces the malignant transformation of GES-1 cells via intracellular ROS production and activation of the Wnt/β-catenin signaling pathway.
authors.affiliation: Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Cui
authors.affiliation: Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Xinxing
authors.initials: X
authors.lastname: Meng
authors.affiliation: Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Xing
authors.affiliation: Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Lian
authors.affiliation: Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China; Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China. Electronic address: zhangxianghong2008@163.com.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009793:Ochratoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; C495270:CTNNB1 protein, human; D002273:Carcinogens; D009793:Ochratoxins; D017382:Reactive Oxygen Species; D051176:beta Catenin; C025589:ochratoxin A
keywords: Malignant transformation; Ochratoxin A; Oxidative stress; Wnt/β-catenin signaling pathway; Xenografts