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, Kazunari K. Yokoyama

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30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)36049-36064
Number of pages16
JournalOncotarget
Volume7
Issue number24
DOIs
Publication statusPublished - 2016

Keywords

  • Gastric cancer cells
  • HOTTIP
  • HoxA13
  • IGFBP-3
  • P53-E2F signaling

ASJC Scopus subject areas

  • Oncology

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    Wang, S. S. W., Wuputra, K., Liu, C. J., Lin, Y. C., Chen, Y. T., Chai, C. Y., Lin, C. L. S., Kuo, K. K., Tsai, M. H., Wang, S. W., Chen, K. K., Miyoshi, H., Nakamura, Y., Saito, S., Hanafusa, T., Wu, D. C., Lin, C. S., & Yokoyama, K. K. (2016). Oncogenic function of the homeobox A13-long noncoding RNA HOTTIP-insulin growth factor-binding protein 3 axis in human gastric cancer. Oncotarget, 7(24), 36049-36064. https://doi.org/10.18632/oncotarget.9102