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Expression of Wnt4 in Human Pituitary Adenomas Regulates Activation of the β-Catenin-Independent Pathway

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Abstract

The Wnt signaling pathway has been implicated in the genesis of numerous human cancers. A member of the Wnt family of genes, Wnt4, has been known to regulate proliferation of anterior pituitary cell types in the mouse during embryonic development. In order to elucidate the roles of Wnt signaling in human pituitary adenomas, we examined the expression of Wnt4 and its putative receptor Frizzled6 (Fzd6) by immunohistochemistry in pituitary adenomas and normal pituitaries. Expression of Wnt4 was higher in growth hormone-producing adenomas (GHomas), prolactin-producing adenomas (PRLomas), and thyroid-stimulating hormone-producing adenomas (TSHomas) than in the normal pituitary. Fzd6 was widely expressed in GHomas, PRLomas, TSHomas, and gonadotropin subunit (GnSU)-positive adenomas. In normal pituitary glands, Wnt4 and Fzd6 were colocalized predominantly in follicle-stimulating hormone-, luteinizing hormone-, and α-subunits of glycoprotein hormone-positive cells. The canonical Wnt/β-catenin signaling pathway was analyzed by β-catenin immunohistochemistry. β-Catenin was localized at the cell membrane in all pituitary adenomas, but not in the nuclei. On the other hand, Erk1/2 was highly activated in GHomas and TSHomas. These results suggested that activation of Wnt4/Fzd6 signaling through a “β-catenin-independent” pathway played a role in proliferation and survival of the pituitary adenoma cells. Detailed involvement of transcription factors including Pit-1 remains to be further investigated.

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Acknowledgements

The authors thank Hideaki Hasegawa and Hideo Tsukamoto from the Teaching and Research Support Center, Tokai University School of Medicine for their technical support. This work was supported by Grants-in-Aid for Scientific Research Projects (#19390105) from the Ministry of Education Culture, Sports, Science, and Technology, Japan, and by the Research on Measures for Intractable Diseases Project of the Hypothalamo-Pituitary Dysfunction Research Group of the Ministry of Health, Labor, and Welfare, Japan.

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  1. Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan

    Takashi Miyakoshi, Hanako Kajiya, Noboru Egashira, Susumu Takekoshi & Robert Yoshiyuki Osamura

  2. Department of Neurosurgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan

    Mao Takei & Akira Teramoto

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  1. Takashi Miyakoshi
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  2. Mao Takei
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Correspondence to Robert Yoshiyuki Osamura.

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Miyakoshi, T., Takei, M., Kajiya, H. et al. Expression of Wnt4 in Human Pituitary Adenomas Regulates Activation of the β-Catenin-Independent Pathway. Endocr Pathol 19, 261–273 (2008). https://doi.org/10.1007/s12022-008-9048-9

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