Oncotarget

Research Papers:

Gamma-Klotho exhibits multiple roles in tumor growth of human bladder cancer

Shunta Hori, Makito Miyake, Yoshihiro Tatsumi, Yosuke Morizawa, Yasushi Nakai, Sayuri Onishi, Kenta Onishi, Kota Iida, Daisuke Gotoh, Nobumichi Tanaka and Kiyohide Fujimoto _

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Oncotarget. 2018; 9:19508-19524. https://doi.org/10.18632/oncotarget.24628

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Abstract

Shunta Hori1, Makito Miyake1, Yoshihiro Tatsumi1, Yosuke Morizawa1, Yasushi Nakai1, Sayuri Onishi1, Kenta Onishi1, Kota Iida1, Daisuke Gotoh1, Nobumichi Tanaka1 and Kiyohide Fujimoto1

1Department of Urology, Nara Medical University, Kashihara-Shi, Nara 634-8522, Japan

Correspondence to:

Kiyohide Fujimoto, email: [email protected]

Keywords: urothelial carcinoma; gamma-Klotho; apoptosis; epithelial-mesenchymal transition; cancer prognosis

Received: October 02, 2017     Accepted: February 24, 2018     Published: April 13, 2018

ABSTRACT

Alpha-Klotho (KLα) and beta-Klotho (KLβ) have recently been reported to correlate with cancer prognosis in some malignancies and we previously reported the association between KLα, KLβ, and urothelial carcinoma of the bladder (UCB), indicating that KLβ acts as a tumor promoter. However, the association between gamma-Klotho (KLγ) and cancer prognosis remains unclear. In the present study, we evaluated the association between KLγ and UCB. To evaluate the effect of KLγ on human bladder cancer cell lines in vitro assays were performed. Exogenous KLγ increased the ability of human bladder cancer cells to proliferate, migrate, invade, form colonies, and provide anchorage-independent growth potential. In in vivo assays, eighteen mice bearing xenografts inoculated using UM-UC-3, were randomly divided into three groups and treated with a small interfering RNA (siRNA) by intratumoral administration once a week for four weeks. Knockdown of KLγ with siRNA led to a dramatic change in tumor growth and suggested that KLγ had effects on tumor growth, including promotion of cell proliferation, inhibition of apoptosis, and enhancement of the epithelial-mesenchymal transition. To confirm the study, human tissue samples were used and patients were divided into two groups according to KLγ expression level. High expression of KLγ was significantly associated with higher stage and grade cancer and the presence of lymphovascular invasion compared to patients with lower expression of KLγ. Our results suggest that KLγ plays an important role in tumor invasion and progression and these results may lead to the development of new therapies and diagnostic methods for UCB.


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