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Phosphorylation of HSF1 at serine 326 residue is related to the maintenance of gynecologic cancer stem cells through expression of HSP27

Kazuyo Yasuda, Yoshihiko Hirohashi, Tasuku Mariya, Aiko Murai, Yuta Tabuchi, Takafumi Kuroda, Hiroki Kusumoto, Akari Takaya, Eri Yamamoto, Terufumi Kubo, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Yasuaki Tamura, Hiroshi Hirano, Tadashi Hasegawa, Tsuyoshi Saito, Noriyuki Sato and Toshihiko Torigoe _

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Oncotarget. 2017; 8:31540-31553. https://doi.org/10.18632/oncotarget.16361

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Abstract

Kazuyo Yasuda1, Yoshihiko Hirohashi1, Tasuku Mariya1,2, Aiko Murai1, Yuta Tabuchi1,2, Takafumi Kuroda2, Hiroki Kusumoto1, Akari Takaya1, Eri Yamamoto1, Terufumi Kubo1, Munehide Nakatsugawa1, Takayuki Kanaseki1, Tomohide Tsukahara1, Yasuaki Tamura1, Hiroshi Hirano3, Tadashi Hasegawa3, Tsuyoshi Saito2, Noriyuki Sato1, Toshihiko Torigoe1

1Department of Pathology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan

2Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan

3Department of Surgical Pathology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan

Correspondence to:

Toshihiko Torigoe, email: torigoe@sapmed.ac.jp

Yoshihiko Hirohashi, email: hirohash@sapmed.ac.jp

Keywords: gynecological cancer, cancer stem cell, stress response, HSP27, HSF1

Received: February 10, 2016     Accepted: March 10, 2017     Published: March 18, 2017

ABSTRACT

Cancer stem-like cells (CSCs)/ cancer-initiating cells (CICs) are defined by their higher tumor-initiating ability, self-renewal capacity and differentiation capacity. CSCs/CICs are resistant to several therapies including chemotherapy and radiotherapy. CSCs/CICs thus are thought to be responsible for recurrence and distant metastasis, and elucidation of the molecular mechanisms of CSCs/CICs are essential to design CSC/CIC-targeting therapy. In this study, we analyzed the molecular aspects of gynecological CSCs/CICs. Gynecological CSCs/CICs were isolated as ALDH1high cell by Aldefluor assay. The gene expression profile of CSCs/CICs revealed that several genes related to stress responses are preferentially expressed in gynecological CSCs/CICs. Among the stress response genes, a small heat shock protein HSP27 has a role in the maintenance of gynecological CSCs/CICs. The upstream transcription factor of HSP27, heat shock factior-1 (HSF1) was activated by phosphorylation at serine 326 residue (pSer326) in CSCs/CICs, and phosphorylation at serine 326 residue is essential for induction of HSP27. Immunohistochemical staining using clinical ovarian cancer samples revealed that higher expressions of HSF1 pSer326 was related to poorer prognosis. These findings indicate that activation of HSF1 at Ser326 residue and transcription of HSP27 is related to the maintenance of gynecological CSCs/CICs.


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