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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Integrin α4 up-regulation activates the hedgehog pathway to promote arsenic and benzo[α]pyrene co-exposure-induced cancer stem cell-like property and tumorigenesis.

Authors: Xie, Jie; Yang, Ping; Lin, Hsuan-Pei; Li, Yunfei; Clementino, Marco; Fenske, William; Yang, Chengfeng; Wang, Chunhong; Wang, Zhishan

Published In Cancer Lett, (2020 11 28)

Abstract: Arsenic and benzo[α]pyrene (BaP) are widespread carcinogens and important etiology factors for lung cancer. Moreover, arsenic and BaP co-exposure displays a significantly stronger effect in inducing lung cancer than arsenic or BaP exposure alone. This study was performed to investigate the basic mechanism of the synergistic carcinogenic effect of arsenic and BaP co-exposure. It was found that integrin α4 (ITGA4) expression levels are significantly up-regulated and the Hedgehog pathway is highly activated in arsenic plus BaP co-exposure-transformed human bronchial epithelial cells. Either ITGA4 downregulation or Hedgehog pathway inhibition in the co-exposure-transformed cells significantly reduced their cancer stem cell (CSC)-like property and tumorigenicity. It was determined that ITGA4 downregulation leads to the inhibition of the Hedgehog pathway activation, which is achieved by increasing suppressor of fused (SUFU) protein stability through reducing the PI3K/Akt signaling. Moreover, stably overexpressing SUFU in the co-exposure-transformed cells significantly reduces their CSC-like property and tumorigenicity. These findings indicate that ITGA4 up-regulation activates the Hedgehog pathway to enhance the CSC-like property and tumorigenicity of arsenic and BaP co-exposure-transformed cells, offering new mechanistic insight for the synergistic carcinogenic effect of arsenic and BaP co-exposure.

PubMed ID: 32860851 Exiting the NIEHS site

MeSH Terms: Animals; Arsenic/adverse effects*; Benzo(a)pyrene/adverse effects*; Cell Line; Cell Transformation, Neoplastic/chemically induced*; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/pathology; Gene Expression Regulation, Neoplastic; Hedgehog Proteins/metabolism; Humans; Integrin alpha4/genetics*; Integrin alpha4/metabolism; Lung Neoplasms/chemically induced; Lung Neoplasms/genetics; Lung Neoplasms/metabolism; Lung Neoplasms/pathology*; Mice; Neoplastic Stem Cells/drug effects; Protein Stability; Repressor Proteins/chemistry; Repressor Proteins/metabolism; Signal Transduction/drug effects; Up-Regulation*

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