ABCG2, CD44 and SOX9 are increased with the acquisition of drug resistance and involved in cancer stem cell activities in head and neck squamous cell carcinoma cells

Koichi Murakami; Naoki Umemura; Makoto Adachi; Masahiro Motoki; Emika Ohkoshi

doi:10.3892/etm.2022.11658

ABCG2, CD44 and SOX9 are increased with the acquisition of drug resistance and involved in cancer stem cell activities in head and neck squamous cell carcinoma cells

Exp Ther Med. 2022 Oct 18;24(6):722. doi: 10.3892/etm.2022.11658. eCollection 2022 Dec.

Authors

Koichi Murakami¹, Naoki Umemura², Makoto Adachi³, Masahiro Motoki¹, Emika Ohkoshi¹

Affiliations

¹ Department of Natural Products Chemistry, Faculty of Pharmaceutical Sciences Aomori University, Aomori, Aomori 030-0943, Japan.
² Department of Oral Biochemistry, Asahi University School of Dentistry, Mizuho, Gifu 501-0296, Japan.
³ Department of Oral and Maxillofacial Surgery, Nagoya Tokushukai General Hospital, Kasugai, Aichi 487-0016, Japan.

Abstract

Cancer stem cells are a sub-population of cancer cells with self-renewal activity that play key roles in tumor resistance to chemotherapy and radiation. Several cancer stem cell markers have been identified to correlate with clinical prognosis. However, which marker is associated with which cancer stem cell characteristic is unclear. The present study aimed to clarify the relationship between cancer stem cell markers associated with drug resistance acquisition and the characteristics of cancer stem cells. We generated cisplatin-resistant head and neck squamous cell carcinoma cells by culturing cells in increasing concentrations of cisplatin. The cisplatin-resistant head and neck squamous cell carcinoma cells also acquired multidrug resistance and were named resistant HSC-3 (R HSC-3) cells. R HSC-3 showed no differences in cell proliferation or cell cycle distributions compared with parental cells. R HSC-3 cells showed increased drug excretion ability and elevated expression of ATP-binding cassette subfamily G member 2 (ABCG2), a drug excretion pump. R HSC-3 cells also highly expressed CD44, a cancer stem cell marker, and exhibited enhanced cell invasion and spheroid formation abilities. Furthermore, the stem cell-related factor SRY-box transcription factor 9 (SOX9) was identified as increased in R HSC-3 cells by microarray analysis. Knockdown experiments showed that SOX9 and ABCG2 were involved in the drug excretion ability of R HSC3 cells and ABCG2 was involved in the spheroid formation ability of R HSC-3 cells. These results indicate that CD44, SOX9 and ABCG2 expression levels were enhanced in head and neck squamous cell carcinoma cells that acquired multidrug resistance and that these molecules are important for maintaining cancer stem cell characteristics. Overall, regulating CD44, SOX9 and ABCG2 may be a strategy to inhibit cancer stem cells.

Keywords: ABCG2; CD44 antigen; SRY-box transcription factor 9; chemotherapeutic drug; cisplatin resistance; head and neck squamous cell carcinoma.

Grants and funding

Funding: This investigation was supported in part by JSPS KAKENHI (grant nos. 17K11691, 17K11890 and 20K09947).