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Homeobox C10 Influences on the Malignant Phenotype of Gastric Cancer Cell Lines and its Elevated Expression Positively Correlates with Recurrence and Poor Survival

  • Takashi Miwa
  • Mitsuro KandaEmail author
  • Shinichi Umeda
  • Haruyoshi Tanaka
  • Chie Tanaka
  • Daisuke Kobayashi
  • Masaya Suenaga
  • Masamichi Hayashi
  • Suguru Yamada
  • Goro Nakayama
  • Masahiko Koike
  • Yasuhiro Kodera
Translational Research and Biomarkers

Abstract

Background

The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa.

Methods

Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer.

Results

PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis.

Conclusions

Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy.

Notes

Disclosure

Takashi Miwa, Mitsuro Kanda, Shinichi Umeda, Haruyoshi Tanaka, Chie Tanaka, Daisuke Kobayashi, Masaya Suenaga, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Masahiko Koike, and Yasuhiro Kodera have no conflicts of interest to declare.

Supplementary material

10434_2019_7166_MOESM1_ESM.tif (5 mb)
Supplementary Figure 1 (a) Cell adhesion assays. Adhesion to collagens I and IV by HOXC10 knockout cells was slightly reduced compared with the parental MKN1 cells. (b) Cell cycle assay. The cell cycle of HOCX10 knockout MKN1 cells was not significantly altered. (c) Phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells compared with control MKN1 cells. (d) Receiver operating characteristic curve analysis of predicting recurrence after curative gastrectomy indicated that the cut-off value of HOXC10 mRNA levels of gastric cancer tissues was 0.005 (AUC 0.605). (e) Kaplan–Meier survival analysis of overall survival of stage I–III patients with gastric cancer with high and low HOXC10 mRNA levels of the institutional and validation cohorts. mRNA messenger RNA, AUC area under the curve, HR hazard ratio, CI confidence interval (TIFF 5140 kb)
10434_2019_7166_MOESM2_ESM.doc (40 kb)
Supplementary Table 1 (DOC 40 kb)
10434_2019_7166_MOESM3_ESM.doc (41 kb)
Supplementary Table 2 (DOC 41 kb)

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Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Takashi Miwa
    • 1
  • Mitsuro Kanda
    • 1
    Email author
  • Shinichi Umeda
    • 1
  • Haruyoshi Tanaka
    • 1
  • Chie Tanaka
    • 1
  • Daisuke Kobayashi
    • 1
  • Masaya Suenaga
    • 1
  • Masamichi Hayashi
    • 1
  • Suguru Yamada
    • 1
  • Goro Nakayama
    • 1
  • Masahiko Koike
    • 1
  • Yasuhiro Kodera
    • 1
  1. 1.Department of Gastroenterological Surgery (Surgery II)Nagoya University Graduate School of MedicineNagoyaJapan

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