Research Papers:

Collagen type IV alpha 1 (COL4A1) and collagen type XIII alpha 1 (COL13A1) produced in cancer cells promote tumor budding at the invasion front in human urothelial carcinoma of the bladder

Makito Miyake _, Shunta Hori, Yosuke Morizawa, Yoshihiro Tatsumi, Michihiro Toritsuka, Sayuri Ohnishi, Keiji Shimada, Hideki Furuya, Vedbar S. Khadka, Youping Deng, Kenta Ohnishi, Kota Iida, Daisuke Gotoh, Yasushi Nakai, Takeshi Inoue, Satoshi Anai, Kazumasa Torimoto, Katsuya Aoki, Nobumichi Tanaka, Noboru Konishi and Kiyohide Fujimoto

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Oncotarget. 2017; 8:36099-36114. https://doi.org/10.18632/oncotarget.16432

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Makito Miyake1, Shunta Hori1, Yosuke Morizawa1, Yoshihiro Tatsumi1,2, Michihiro Toritsuka3, Sayuri Ohnishi1, Keiji Shimada4, Hideki Furuya5, Vedbar S. Khadka6, Youping Deng6, Kenta Ohnishi1, Kota Iida1, Daisuke Gotoh1, Yasushi Nakai1, Takeshi Inoue1, Satoshi Anai1, Kazumasa Torimoto1, Katsuya Aoki1, Nobumichi Tanaka1, Noboru Konishi2, Kiyohide Fujimoto1

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

2Department of Pathology, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan

3Department of Psychiatry, Nara Medical University, Kashihara-shi, Nara 634-8522, Japan

4Department of Pathology, Nara City Hospital, Nara-shi, Nara 630-8305, Japan

5Clinical and Translational Research Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA

6Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA

Correspondence to:

Makito Miyake, email: [email protected]

Keywords: bladder cancer, tumor budding, invasion, collagen

Received: February 22, 2017     Accepted: March 15, 2017     Published: March 21, 2017


Current knowledge of the molecular mechanism driving tumor budding is limited. Here, we focused on elucidating the detailed mechanism underlying tumor budding in urothelial cancer of the bladder. Invasive urothelial cancer was pathologically classified into three groups as follows: nodular, trabecular, and infiltrative (tumor budding). Pathohistological analysis of the orthotopic tumor model revealed that human urothelial cancer cell lines MGH-U3, UM-UC-14, and UM-UC-3 displayed typical nodular, trabecular, and infiltrative patterns, respectively. Based on the results of comprehensive gene expression analysis using microarray (25 K Human Oligo chip), we identified two collagens, COL4A1 and COL13A1, which may contribute to the formation of the infiltrative pattern. Visualization of protein interaction networks revealed that proteins associated with connective tissue disorders, epithelial-mesenchymal transition, growth hormone, and estrogen were pivotal factors in tumor cells. To evaluate the invasion pattern of tumor cells in vitro, 3-D collective cell invasion assay using Matrigel was performed. Invadopodial formation was evaluated using Gelatin Invadopodia Assay. Knockdown of collagens with siRNA led to dramatic changes in invasion patterns and a decrease in invasion capability through decreased invadopodia. The in vivo orthotopic experimental model of bladder tumors showed that intravesical treatment with siRNA targeting COL4A1 and COL13A1 inhibited the formation of the infiltrative pattern. COL4A1 and COL13A1 production by cancer cells plays a pivotal role in tumor invasion through the induction of tumor budding. Blocking of these collagens may be an attractive therapeutic approach for treatment of human urothelial cancer of the bladder.

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