Oncotarget

Research Papers:

Oncogenic function of the homeobox A13-long noncoding RNA HOTTIP-insulin growth factor-binding protein 3 axis in human gastric cancer

Sophie S.W. Wang, Kenly Wuputra, Chung-Jung Liu, Yin-Chu Lin, Yi-Ting Chen, Chee-Yin Chai, Chen-Lung Steve Lin, Kung-Kai Kuo, Ming-Ho Tsai, Shin-Wei Wang, Ker-Kong Chen, Hiroyuki Miyoshi, Yukio Nakamura, Shigeo Saito, Tadashi Hanafusa, Deng-Chyang Wu, Chang-Shen Lin and Kazunari K. Yokoyama _

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Oncotarget. 2016; 7:36049-36064. https://doi.org/10.18632/oncotarget.9102

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Abstract

Sophie S.W. Wang1,2, Kenly Wuputra3, Chung-Jung Liu1,2, Yin-Chu Lin4, Yi-Ting Chen5, Chee-Yin Chai5, Chen-Lung Steve Lin3,6, Kung-Kai Kuo6, Ming-Ho Tsai3, Shin-Wei Wang1,2, Ker-Kong Chen4, Hiroyuki Miyoshi7, Yukio Nakamura8, Shigeo Saito9,10, Tadashi Hanafusa11, Deng-Chyang Wu1,2,12,13,14, Chang-Shen Lin3,15, Kazunari K. Yokoyama2,3,16,17,18

1Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

2Center for Stem Cell Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

3Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

4School of Dentistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan

5Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

6Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

7Department of Physiology, Keio University School of Medicine, Shinanomachi, Tokyo 160-8582, Japan

8Cell Engineering Division, BioResource Center, RIKEN, Tsukuba, Ibaraki 305-0074, Japan

9School of Science and Engineering, Teikyo University, Utsunomia, Tochigi 329-2192, Japan

10Saito Laboratory of Cell Technology, Yaita, Tochigi 329-2192, Japan

11Advanced Science Research Center, Okayama University, Okayama, Okayama 700-8558, Japan

12Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

13Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 807, Taiwan

14Center of Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan

15Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan

16Center of Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

17Faculty of Science and Engineering, Tokushima Bunri University, Sanuki 763-2193, Japan

18Department of Molecular Preventive Medicine, Graduate School of medicine, The University of Tokyo, Tokyo 113-0033, Japan

Correspondence to:

Chang-Shen Lin, email: [email protected]

Kazunari K Yokoyama, email: [email protected]

Keywords: gastric cancer cells, HOTTIP, HoxA13, IGFBP-3, p53-E2F signaling

Received: January 30, 2016     Accepted: April 11, 2016     Published: April 29, 2016

ABSTRACT

To study the mechanisms of gastric tumorigenesis, we have established CSN cell line from human normal gastric mucosa, and CS12, a tumorigenic and invasive gastric cancer cell line from CSN passages. Many stem cell markers were expressed in both CSN and CS12 cells, but LGR5 and NANOG were expressed only in CS12 cells. Increased expression of homeobox A13 (HoxA13) and its downstream cascades was significant for the tumorigenic activity of CS12 cells, and was associated with recruitment of E2F-1 to HoxA13 promoter accompanied with increased trimethylation of histone H3 lysine 4 (H3K4me3) at the hypomethylated E2F motifs. Knockdown of HoxA13 caused the downregulation of long non-coding RNA HOTTIP and insulin growth factor-binding protein 3 (IGFBP-3) genes, indicating that both were targets of HoxA13. Concurrent regulation of HoxA13-HOTTIP was mediated by the mixed lineage leukemia-WD repeat domain 5 complex, which caused the trimethylation of H3K4 and then stimulated cell proliferation. HoxA13 transactivated the IGFBP-3 promoter through the HOX-binding site. Activation of IGFBP-3 stimulated the oncogenic potential and invasion activity. Increased expression of HoxA13 (63.2%) and IGFBP-3 (28.6%) was detected in human gastric cancer tissues and was found in the gastric cancer data of The Cancer Genome Atlas. Taken together, the HoxA13–HOTTIP–IGFBP-3 cascade is critical for the carcinogenic characteristics of CS12 cells.


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