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The Significance of PITX2 Overexpression in Human Colorectal Cancer

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Abstract

Purpose

The paired-like homeodomain transcription factor 2 (PITX2) gene encodes a transcription factor controlled by the WNT/Dvl/CTNNB1 and Hedgehog/TGFB pathways in the pathogenesis of colorectal cancer (CRC). Although PITX2 is reportedly involved in various functions, including tissue development by controlling cell growth, its significance in CRC remains unclear. We report our findings regarding abnormal PITX2 expression in human CRC.

Methods

PITX2 expression was evaluated in 5 human CRC cell lines and 92 primary CRC samples. Cell growth was evaluated after inhibition of PITX2 expression or after exogenous introduction of PITX2.

Results

PITX2 expression was seen in all the five CRC cell lines. The study of tissue samples indicated that PITX2 expression was significantly higher in cancerous tissue than in paired control tissue (P = 0.0471). Patients with lower PITX2 expression showed a poorer overall survival rate than those with higher PITX2 expression (P = 0.0481). Multivariate analysis demonstrated that PITX2 expression was an independent prognostic factor. Experimental knockdown and introduction of PITX2 also demonstrated that the level of PITX2 expression is inversely associated with cell growth and invasion in vitro.

Conclusions

PITX2 expression is significantly related to the biological behavior of CRC cells and appears to be correlated with clinical survival. Thus, this study revealed a previously uncharacterized unique role and significance of PITX2 expression in CRC.

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Acknowledgment

We thank Dr. Miyoshi, Dr. Kim, Dr. Okano, and Dr. Uemura for their excellent advice and technical assistance. This work was supported in part by a grant from Core Research for Evolutional Science and Technology (CREST), a Grant-in-Aid for Scientific Research on Priority Areas (20012039), Grants-in-Aid for Scientific Research (S: 21229015 and C: 20590313) from the Ministry of Education, Culture, Sports, Science, and Technology, and a grant from the Tokyo Biochemical Research Foundation, Japan.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Hajime Hirose MD, Hideshi Ishii MD, PhD, Ichiro Takemasa MD, PhD, Tsunekazu Mizushima MD, PhD, Masataka Ikeda MD, PhD, Hirofumi Yamamoto MD, PhD, Mitsugu Sekimoto MD, PhD, Yuichiro Doki MD, PhD & Masaki Mori MD, PhD, FACS

  2. Division of Molecular and Surgical Oncology, Department of Molecular and Cellular Biology, Kyushu University, Medical Institute of Bioregulation, Beppu, Oita, Japan

    Hideshi Ishii MD, PhD, Koshi Mimori MD, PhD & Fumiaki Tanaka MD, PhD

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  1. Hajime Hirose MD
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  2. Hideshi Ishii MD, PhD
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Corresponding author

Correspondence to Masaki Mori MD, PhD, FACS.

Electronic supplementary material

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Supplementary Fig. 1

Quantitative RT-PCR analysis of PITX2 in CRC and matched normal tissue samples obtained from 5 patients. In 3 out of 5 tumor cases, PITX2 expression was higher than in the matched normal tissue. PC positive control, NC negative control (EPS 795 kb)

Supplementary Fig. 2

RT-PCR analysis of PITX2 in CRC cell lines. Study of the expression of PITX2 (normalized by GAPDH gene expression) indicated that Caco-2 and KM12SM cells had higher levels of expression than did the other CRC cell lines such as LoVo, HT29, and SW480. Values are mean ± SD from three independent experiments (EPS 826 kb)

Supplementary Fig. 3

Knockdown assessment of PITX2 by siRNA in the Caco-2 cell line. Confirmation of reduced PITX2 mRNA levels was by real-time monitoring RT-PCR (EPS 671 kb)

Supplementary Fig. 4

Knockdown assessment of PITX2 by siRNA in the Caco-2 cell line. Confirmation of increased MYC mRNA levels was by RT-PCR. There were significant differences between Neg and siRNA. a PITX2 transfection assessment by plasmid in the LoVo cell line. Confirmation of MYC mRNA levels was by RT-PCR. There were no significant differences between Mock and PITX2 (b). Values are mean ± SD from four independent experiments. Ctr a control without transfection, Neg transfection control of scramble sequence, siRNA PITX2 small interference RNA, Mock empty vector transfection control, PITX2 PITX2 plasmid-transfected cells) (EPS 671 kb)

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Hirose, H., Ishii, H., Mimori, K. et al. The Significance of PITX2 Overexpression in Human Colorectal Cancer. Ann Surg Oncol 18, 3005–3012 (2011). https://doi.org/10.1245/s10434-011-1653-z

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