Nrf2 signaling promotes cancer stemness, migration, and expression of ABC transporter genes in sorafenib-resistant hepatocellular carcinoma cells.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Gene Expression* ; Gene Expression Regulation, Neoplastic*; ATP-Binding Cassette Transporters/*genetics ; Antineoplastic Agents/*pharmacology ; Carcinoma, Hepatocellular/*metabolism ; Cell Movement/*genetics ; Drug Resistance, Neoplasm/*drug effects ; Liver Neoplasms/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Protein Kinase Inhibitors/*pharmacology ; Signal Transduction/*genetics ; Sorafenib/*pharmacology; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Cell Survival/drug effects ; Cell Survival/genetics ; Drug Resistance, Neoplasm/genetics ; Gene Knockdown Techniques ; Humans ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; NF-E2-Related Factor 2/genetics ; Signal Transduction/drug effects ; Transfection

Background and Aim: As a multiple tyrosine kinase inhibitor, sorafenib is widely used to treat hepatocellular carcinoma (HCC), but patients frequently face resistance problems. Because the mechanism controlling sorafenib-resistance is not well understood, this study focused on the connection between tumor characteristics and the Nrf2 signaling pathway in a sorafenib-resistant HCC cell line.
Methods: A sorafenib-resistant HCC cell line (Huh7) was developed by increasing the dose of sorafenib in the culture medium until the target concentration was reached. Cell morphology, migration/invasion rates, and expression of stemness-related and ATP-binding cassette (ABC) transporter genes were compared between sorafenib-resistant Huh7 cells and parental Huh7 cells. Next, a small interfering RNA was used to knock down Nrf2 expression in sorafenib-resistant Huh7 cells, after which cell viability, stemness, migration, and ABC transporter gene expression were examined again.
Results: Proliferation, migration, and invasion rates of sorafenib-resistant Huh7 cells were significantly increased relative to the parental cells with or without sorafenib added to the medium. The expression levels of stemness markers and ABC transporter genes were up-regulated in sorafenib-resistant cells. After Nrf2 was knocked down in sorafenib-resistant cells, cell migration and invasion rates were reduced, and expression levels of stemness markers and ABC transporter genes were reduced.
Conclusion: Nrf2 signaling promotes cancer stemness, migration, and expression of ABC transporter genes in sorafenib-resistant HCC cells.
Competing Interests: We state the potential conflicts of interest with regard to our study as follows: Mitsuo Shimada declares receiving unrestricted research grant from Bayer Yakuhin, CO. LTD., Japan. All other authors report no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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0 (ATP-Binding Cassette Transporters)
0 (Antineoplastic Agents)
0 (NF-E2-Related Factor 2)
0 (NFE2L2 protein, human)
0 (Protein Kinase Inhibitors)
9ZOQ3TZI87 (Sorafenib)

Date Created: 20210902 Date Completed: 20211117 Latest Revision: 20211117

20240829

PMC8412368

10.1371/journal.pone.0256755

34473785