FOXM1-CD44 Signaling Is Critical for the Acquisition of Regorafenib Resistance in Human Liver Cancer Cells

Kenly Wuputra; Pi-Jung Hsiao; Wen-Tsan Chang; Po-Hsuan Wu; Lin-Ann Chen; Jian-Wei Huang; Wen-Lung Su; Ya-Han Yang; Deng-Chyang Wu; Kazunari K Yokoyama; Kung-Kai Kuo

doi:10.3390/ijms23147782

FOXM1-CD44 Signaling Is Critical for the Acquisition of Regorafenib Resistance in Human Liver Cancer Cells

Int J Mol Sci. 2022 Jul 14;23(14):7782. doi: 10.3390/ijms23147782.

Authors

Kenly Wuputra^{1

2

3}, Pi-Jung Hsiao⁴, Wen-Tsan Chang^{5

6

7}, Po-Hsuan Wu⁶, Lin-Ann Chen^{6

8}, Jian-Wei Huang⁹, Wen-Lung Su¹⁰, Ya-Han Yang^{2

3

6}, Deng-Chyang Wu^{2

3

11}, Kazunari K Yokoyama^{1

2

3}, Kung-Kai Kuo^{2

3

6

7}

Affiliations

¹ Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
² Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
³ Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan.
⁴ Department of Internal Medicine, Division of Endocrinology and Metabolism, EDA Hospital, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan.
⁵ Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁶ Division of General & Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan.
⁷ Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁸ Department of Surgery, Ministry of Health and Welfare Pingtung Hospital, Pingtung 900027, Taiwan.
⁹ Department of Surgery, Kaohsiung Municipal Siaogang Hospital, Kaohsiung 812, Taiwan.
¹⁰ Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan.
¹¹ Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan.

Abstract

Regorafenib is a multikinase inhibitor that was approved by the US Food and Drug administration in 2017. Cancer stem cells (CSCs) are a small subset of cancer-initiating cells that are thought to contribute to therapeutic resistance. The forkhead box protein M1 (FOXM1) plays an important role in the regulation of the stemness of CSCs and mediates resistance to chemotherapy. However, the relationship between FOXM1 and regorafenib resistance in liver cancer cells remains unknown. We found that regorafenib-resistant HepG2 clones overexpressed FOXM1 and various markers of CSCs. Patients with hepatocellular carcinoma also exhibited an upregulation of FOXM1 and resistance to regorafenib, which were correlated with a poor survival rate. We identified a close relationship between FOXM1 expression and regorafenib resistance, which was correlated with the survival of patients with hepatocellular carcinoma. Thus, a strategy that antagonizes FOXM1-CD44 signaling would enhance the therapeutic efficacy of regorafenib in these patients.

Keywords: CD44; FOXM1; cancer stem cell lines; hepatocellular carcinoma; regorafenib.

MeSH terms

Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / metabolism
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
Forkhead Box Protein M1 / genetics
Forkhead Box Protein M1 / metabolism
Gene Expression Regulation, Neoplastic
Humans
Hyaluronan Receptors / metabolism
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Liver Neoplasms* / metabolism
Phenylurea Compounds
Pyridines

Substances

CD44 protein, human
FOXM1 protein, human
Forkhead Box Protein M1
Hyaluronan Receptors
Phenylurea Compounds
Pyridines
regorafenib

Grants and funding

MOST108-2314-B-037-100-MY2, MOST 110-2314-B-037-141 and MOST 110-2320-B-037-028/Ministry of Science Technology