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.