title: The role of neuregulin4 and HER4 in gastrointestinal malignant lymphoma.
abstract: The human epidermal growth factor (EGF) receptor (HER) family consists of four receptors that bind to ligands sharing an EGF-like motif. The HER family of receptor tyrosine kinases and their ligands (EGF family) are known to play a significant role in gastrointestinal cancer. In particular, the EGF receptor, HER1, is one of the main candidates for the molecular-targeted therapy of colon cancer, and HER2 is a candidate for the treatment of gastric cancer which overexpresses HER2. In contrast, the role of the HER and EGF families in malignant lymphoma has not been fully elucidated. In this study, we investigated the expression and function of the HER and EGF families in lymphoma cell lines and tumor samples. Reverse transcription polymerase chain reaction revealed that the ligands for HER1 were mainly expressed in gastric cancer and colon cancer cell lines, but not in lymphoma cell lines. On the other hand, the EGF family member, neuregulin (NRG) 4, was highly expressed in lymphoma cell lines. Immunohistochemical analyses of malignant lymphoma clinical samples revealed that NRG4 and HER4 were mainly expressed in mucosa-associated lymphoid tissue (MALT) and follicular lymphoma. Immunoprecipitation of Raji and Daudi cell lines revealed that recombinant NRG4 induced the tyrosine phosphorylation of HER4. Additionally, recombinant NRG4 activated the proliferation of lymphoma cell lines. These findings suggest that the NRG4-HER4 axis plays a major role in the proliferation of malignant lymphoma cells in the gastrointestinal tract.
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Ebi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Takaya
authors.initials: T
authors.lastname: Shimura
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Takashi
authors.initials: T
authors.lastname: Mizushima
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Mizoshita
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tanaka
authors.forename: Hironobu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Keiji
authors.initials: K
authors.lastname: Ozeki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kamiya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inagaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D005770:Gastrointestinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000378:metabolism* / Q000473:pathology; D008224:Lymphoma, Follicular / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D020880:Neuregulins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020880:Neuregulins; D011994:Recombinant Proteins; C467747:neuregulin-4; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4