Expression of Reg IV and Hath1 in neuroendocrine neoplasms.

Reg IV (RELP), a Regenerating protein family member, is constitutively expressed in neuroendocrine cells of the intestinal mucosa. The helix-loop-helix transcription factor Hath1 is the human homologue of murine Math1, which regulates the embryonic differentiation of neural and intestinal secretory lineage cells. Hath1 is constitutively expressed in a subset of mature secretory gastrointestinal cells. We investigated by immunohistochemistry the expression of Reg IV and Hath1 in 63 neuroendocrine tumors. Intestinal neuroendocrine neoplasms showed co-expression of Reg IV and Hath1, as did parathyroidal and Merkel cell tumors. Lung small-cell carcinoma and gastric mucocellular carcinoma expressed only Reg IV. Pancreatic islet-derived tumors, pheochromocytomas, and paragangliomas expressed only Hath1. Lymph node and liver metastases retained the tissue-specific expression patterns. These distinct expression profiles may be useful for differential diagnostics of metastatic lesions of neuroendocrine tumors. The dissimilar expression patterns suggest that the proteins belong to different signaling pathways and are activated at different stages of neuroendocrine differentiation. Local Reg IV expression may be influenced by the growth factors bFGF and HGF and/or their receptors CD138 and c-met, which were found to co-localize with Reg IV in intestinal neuroendocrine tumors.