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Loss of RUNX3 Expression Correlates with Differentiation, Nodal Metastasis, and Poor Prognosis of Gastric Cancer

  • Translational Research and Biomarkers
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Abstract

Background

RUNX3 is a major growth regulator of gastric epithelial cells that is involved in gastric tumorigenesis in both humans and mice. In this study, we investigated the involvement of RUNX3 in tumor progression, and in the prognosis of human gastric cancer.

Methods

We analyzed the extent of RUNX3 protein expression by immunohistochemistry in 95 primary gastric adenocarcinomas, and correlated expression levels with clinicopathological parameters. We examined the effects of pFlag/RUNX3 on cell growth, apoptosis, and caspase-3 expression in AGS and SNU1 gastric cancer cell lines by colony-forming assay, terminal deoxynucleotidyl transferase (TdT)-mediate deoxyuridine triphosphatase (dUTP) nick-end labeling (TUNEL) assay, and Western blot analysis, respectively. The pFlag/RUNX3 effects on AGS invasion and migration potentials were also evaluated.

Results

RUNX3 expression was lost in 37 (39%) cases of gastric cancer. The expression of RUNX3 in diffuse- and mixed-type cancers was less frequent than expression in intestinal-type cancer (P < 0.001 and P = 0.001, respectively). In addition, the loss of RUNX3 expression was associated with lymph node metastasis (P = 0.02), and correlated with poor gastric cancer survival (P = 0.018). The growth of gastric cancer cells was suppressed after pFlag/RUNX3 transfection. The re-expression of RUNX3 resulted in the upregulation of caspase-3 and promoted apoptosis. Furthermore, Re-expression of RUNX3 induced significant inhibitions of AGS cell invasion and migration in vitro.

Conclusions

This work shows that loss of RUNX3 expression is highly associated with lymph node metastasis and poor prognosis of gastric cancer. The re-expression of RUNX3 may induce apoptosis and inhibit the growth as well as invasion/migration of cancer cells. These results indicate that the targeting of the RUNX3 pathway could represent a potential modality for treating gastric cancer.

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Acknowledgement

This work was supported in part by grants from the National Science Council (to P. I.Hsu, P. J. Lu, and M. H.); and Academia Sinica (to M. H.).

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Authors and Affiliations

  1. Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan

    Ping-I. Hsu MD & Li-Fang Lin MS

  2. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Hsiao-Ling Hsieh PhD & Michael Hsiao DVM, PhD

  3. Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan

    Jihjong Lee DVM

  4. Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

    Hui-Chun Chen MD

  5. Institute of Clinical Medicine, School of Medicine, National Cheng-Kung University, Tainan, Taiwan

    Pei-Jung Lu PhD

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  1. Ping-I. Hsu MD
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  2. Hsiao-Ling Hsieh PhD
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  3. Jihjong Lee DVM
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  4. Li-Fang Lin MS
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Correspondence to Pei-Jung Lu PhD or Michael Hsiao DVM, PhD.

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Hsu, PI., Hsieh, HL., Lee, J. et al. Loss of RUNX3 Expression Correlates with Differentiation, Nodal Metastasis, and Poor Prognosis of Gastric Cancer. Ann Surg Oncol 16, 1686–1694 (2009). https://doi.org/10.1245/s10434-009-0428-2

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  • DOI: https://doi.org/10.1245/s10434-009-0428-2

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