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PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells

Oncogene volume 31, pages 5090–5098 (2012)Cite this article

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Abstract

One of the key drivers for squamous cell carcinoma (SCC) proliferation is activation of the epidermal growth factor receptor (EGFR), a known proto-oncogene. However, the mechanism of EGFR-dependent SCC proliferation remains unclear. Our previous studies indicate that epidermal growth factor (EGF)-induced SCC cell proliferation requires the SH3 domain of phospholipase C-γ1 (PLC-γ1), but not its catalytic activity. The SH3 domain of PLC-γ1 is known to activate the short form of nuclear phosphatidylinositol 3-kinase enhancer (PIKE) that enhances the activity of nuclear class Ia phosphatidylinositol 3-kinase (PI3K) required for proliferation. However, PIKE has been described for more than a decade to be present exclusively in neuronal cells. In the present study, we found that PIKE was highly expressed in malignant human keratinocytes (SCC4 and SCC12B2) but had low expression in normal human keratinocytes. Immunohistochemical analysis showed strong nuclear staining of PIKE in human epidermal and tongue SCC specimens but little staining in the adjacent non-cancerous epithelium. Treatment of SCC4 cells with EGF-induced translocation of PLC-γ1 to the nucleus and binding of PLC-γ1 to the nuclear PIKE. Knockdown of PLC-γ1 or PIKE blocked EGF-induced activation of class Ia PI3K and protein kinase C-ζ and phosphorylation of nucleolin in the nucleus as well as EGF-induced SCC cell proliferation. However, inhibition of the catalytic activity of PLC-γ1 had little effect. These data suggest that PIKE has a critical role in EGF-induced SCC cell proliferation and may function as a proto-oncogene in SCC.

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Acknowledgements

This work was supported by the grant 81072219 from the National Natural Science Foundation of China and grants 1R03DE018001 and 1R21DE019529 from the US National Institutes of Health. We thank Drs Daniel D Bikle, Chia-Ling Tu and Yongmei Wang for helpful discussions. We also thank Dr Larry L Wang (Department of Pathology, Children Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles) for reviewing pathological slides.

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Authors and Affiliations

  1. Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Z Xie, E-Y Liao & J Peng

  2. Endocrine Unit, Veterans Affairs Medical Center, Northern California Institute for Research and Education and University of California, San Francisco, CA, USA

    Z Xie, S D Pennypacker & S M Chang

  3. Department of Pathology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, China

    Y Jiang

  4. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

    Y Chen

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  1. Z Xie
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Correspondence to Z Xie.

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Xie, Z., Jiang, Y., Liao, EY. et al. PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells. Oncogene 31, 5090–5098 (2012). https://doi.org/10.1038/onc.2012.10

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