Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity

  • Authors:
    • Susumu Nakata
    • Harunari Tanaka
    • Yuichi Ito
    • Masayasu Hara
    • Mitsugu Fujita
    • Eisaku Kondo
    • Yukihide Kanemitsu
    • Yasushi Yatabe
    • Hayao Nakanishi
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  • Published online on: July 8, 2014     https://doi.org/10.3892/ijo.2014.2538
  • Pages: 1583-1593
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Abstract

Poorly-differentiated colorectal cancers (PD-CRC) show high metastatic potential and poor prognosis. However, molecular characteristics of PD-CRC remain unknown to date, particularly in molecular targeting therapy for patients with PD-CRC. In this study, we examined the expression of EGFR, HER2 and HER3 in PD-CRC by immunohistochemical analysis of archived clinical specimens of primary tumors and investigated the sensitivity of PD-CRC cell lines to gefitinib, a tyrosine kinase inhibitor for EGFR in vitro. We found that HER3 expression of PD-CRC among members of the HER family was significantly lower than that of well to moderately differentiated CRC (WMD-CRC) and 37% of the PD cases showed a EGFR+/HER2+/HER3- expression pattern. COLM-5 cells, a PD-CRC-derived cell line, which exhibits EGFR+/HER2+/HER3- expression pattern and recapitulates the typical histology of PD-CRC in xenografted tumors, showed high gefitinib sensitivity both in vitro and in vivo, compared with WMD-CRC cell line (COLM-2). Treatment with gefitinib resulted in the upregulation of p27Kip1 expression and induction of G1 cell cycle arrest, concomitantly associated with inactivation of PI3K/Akt signaling in COLM-5 cells and marked inhibition of xenografted tumors in nude mice, but not evident in COLM-2 cells. Treatment with sodium butyrate, an HDAC inhibitor that induces differentiation, upregulated the expression of HER3 associated with enhancement of the PI3K/Akt signaling, attenuated gefitinib-mediated p27Kip1 upregulation and reduced gefitinib sensitivity in COLM-5 cells in vitro. Furthermore, enforced expression of HER3 in COLM-5 cells resulted in significant resistance to gefitinib treatment both in vitro and in vivo. These findings suggest that deficient HER3 expression plays an important role in gefitinib sensitivity and that a malignant subset of PD with EGFR+/HER2+/HER3- phenotype is a potential candidate for a target of anti-EGFR molecular therapy such as gefitinib.
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October 2014
Volume 45 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Nakata, S., Tanaka, H., Ito, Y., Hara, M., Fujita, M., Kondo, E. ... Nakanishi, H. (2014). Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity. International Journal of Oncology, 45, 1583-1593. https://doi.org/10.3892/ijo.2014.2538
MLA
Nakata, S., Tanaka, H., Ito, Y., Hara, M., Fujita, M., Kondo, E., Kanemitsu, Y., Yatabe, Y., Nakanishi, H."Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity". International Journal of Oncology 45.4 (2014): 1583-1593.
Chicago
Nakata, S., Tanaka, H., Ito, Y., Hara, M., Fujita, M., Kondo, E., Kanemitsu, Y., Yatabe, Y., Nakanishi, H."Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity". International Journal of Oncology 45, no. 4 (2014): 1583-1593. https://doi.org/10.3892/ijo.2014.2538