The Japanese Herbal Medicine Hangeshashinto Induces Oral Keratinocyte Migration by Mediating the Expression of CXCL12 Through the Activation of Extracellular Signal-Regulated Kinase

Kanako Miyano; Seiya Hasegawa; Noriho Asai; Miaki Uzu; Wakako Yatsuoka; Takao Ueno; Miki Nonaka; Hideaki Fujii; Yasuhito Uezono

doi:10.3389/fphar.2021.695039

The Japanese Herbal Medicine Hangeshashinto Induces Oral Keratinocyte Migration by Mediating the Expression of CXCL12 Through the Activation of Extracellular Signal-Regulated Kinase

Front Pharmacol. 2022 Jan 18:12:695039. doi: 10.3389/fphar.2021.695039. eCollection 2021.

Authors

Kanako Miyano^{1

2}, Seiya Hasegawa³, Noriho Asai^{2

3}, Miaki Uzu⁴, Wakako Yatsuoka⁵, Takao Ueno⁵, Miki Nonaka², Hideaki Fujii³, Yasuhito Uezono^{2

6}

Affiliations

¹ Division of Cancer Pathophysiology, National Cancer Research Institute, Tokyo, Japan.
² Department of Pain Control Research, The Jikei University School of Medicine, Tokyo, Japan.
³ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo, Japan.
⁴ Vitrigel Project Research Team, Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan.
⁵ Dental Division, National Cancer Center Hospital, 5-1-1, Tsukiji, Japan.
⁶ Supportive and Palliative Care Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan.

Abstract

Several clinical studies have reported that Japanese herbal medicine Hangeshashinto (HST) has beneficial effects on chemotherapy-induced oral ulcerative mucositis (OUM). Our previous research demonstrated that HST improves chemotherapy-induced OUM through human oral keratinocyte (HOK) migration, which was suppressed by mitogen-activated protein kinase (MAPK) and C-X-C chemokine receptor 4 (CXCR4) inhibitors. However, the association between these molecules and HOK migration was unclear. Here, we examined the effects of HST on the expression of CXCR4/CXCR7 and C-X-C motif chemokine ligands 11 and 12 (CXCL11/CXCL12) in HOKs. Our results indicated that HST upregulated CXCL12, but not CXCR4, CXCR7, nor CXCL11 in HOKs. HST-induced expression of CXCL12 was significantly suppressed by an inhibitor of extracellular signal-regulated kinase (ERK), but not of p38 and c-Jun N-terminal kinase (JNK). In addition, HST induced phosphorylation of ERK in HOKs. These findings suggest that HST enhances HOK migration by upregulating CXCL12 via ERK.

Keywords: CXCL12; extracellular signal-regulated kinase; hangeshashinto; oral keratinocytes; oral ulcerative mucositis.