Presence of spontaneous epithelial-mesenchymal plasticity in esophageal cancer

Kenji Tsuchihashi; Yuki Hirata; Juntaro Yamasaki; Kentaro Suina; Kenro Tanoue; Toshifumi Yae; Kenta Masuda; Eishi Baba; Koichi Akashi; Yuko Kitagawa; Hideyuki Saya; Osamu Nagano

doi:10.1016/j.bbrep.2022.101246

Presence of spontaneous epithelial-mesenchymal plasticity in esophageal cancer

Biochem Biophys Rep. 2022 Mar 19:30:101246. doi: 10.1016/j.bbrep.2022.101246. eCollection 2022 Jul.

Authors

Kenji Tsuchihashi^{1

2}, Yuki Hirata³, Juntaro Yamasaki², Kentaro Suina², Kenro Tanoue¹, Toshifumi Yae^{2

4}, Kenta Masuda⁵, Eishi Baba⁶, Koichi Akashi¹, Yuko Kitagawa³, Hideyuki Saya², Osamu Nagano²

Affiliations

¹ Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
² Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan.
³ Department of Surgery, School of Medicine, Keio University, Tokyo, 160-8582, Japan.
⁴ Department of Respiratory Medicine, Juntendo University Graduate School of Medicine 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
⁵ Department of Obstetrics and Gynecology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan.
⁶ Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Abstract

Epithelial-mesenchymal plasticity (EMP) refers to the reversible cellular transition between epithelial and mesenchymal status. Spontaneous EMP is also reported in breast and prostate cancer, leading to the acquisition of stem-cell properties and chemoresistance. However, the presence of spontaneous EMP is still not reported in esophageal cancer. We screened 11 esophageal squamous cancer cell (ESCC) cell lines by CD44 isoform expression. KYSE520 was found to comprise heterogenous populations consisting of CD44v⁺ and CD44v^- subpopulations. CD44v⁺ and CD44v^- cells showed the expression of epithelial and mesenchymal markers, respectively. Single-cell sorting of CD44v⁺ and CD44v^- cells revealed both cells gave rise to cell populations consisting of CD44v⁺ and CD44v^- cells, indicating CD44v⁺ epithelial-like and CD44v^- mesenchymal-like cells can generate counterparts, respectively. The ablation of Epithelial splicing regulatory protein 1 (ESRP1), a major regulator of CD44 mRNA splicing, resulted in the shift from CD44v+ to CD44v- cells in KYSE520. However, the expression of epithelial-mesenchymal transition (EMT)-related markers or transcriptional factors were almost not affected, suggesting ESRP1 functions downstream of EMP. Our results revealed the presence of spontaneous EMP in esophageal cancer and KYSE520 is useful model to understand spontaneous EMP.

Keywords: Alternative splicing; CD44; ESRP1; Epithelial-mesenchymal plasticity; Esophageal squamous cell carcinoma.