Expression and regulation of c-erbB ligands in human head and neck squamous carcinoma cells

We recently reported that multiple c-erbB ligands differentially modulate i n vitro proliferation, invasion and expression of matrix metalloproteinases in human head and neck squamous carcinoma cells (HNSCC). In order to evalu ate further the importance of c-erbB ligands in tumor progression, the expr ession and regulation of this growth factor family in HNSCC cells was studi ed. We demonstrate that mRNAs for the 6 major c-erbB ligands, namely, epide rmal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) beta cellulin (BTC), heparin-binding epidermal growth factor-like growth factor (HB-EGF), amphiregulin (AR) and heregulin (HRG), are expressed in a large p anel of HNSCC cell lines. In addition to TGF-alpha, other ligands (notably ETC and HRG-betaI) are involved in the autocrine growth regulation of these cells. Each c-erbB ligand when applied exogenously, induced mRNA expressio n of both itself and the remaining family members and a differential respon se in the kinetics of induction was found. HB-EGF and HRG mRNAs were induce d rapidly (within I hr) and to a greater extent (3.2-6.2- and 4.8-7.3-fold increase) than TGF-alpha, ETC and AR mRNAs (1.6-2.7, 1.8-3.6- and 1.6-4.2-f old, respectively). This pattern was observed for all inducing ligands test ed. Analysis of mRNA stability, and concurrent treatment with ETC las an in ducing ligand) and cycloheximide (to inhibit protein synthesis) suggested b oth transcriptional and posttranscriptional regulatory mechanisms. These re sults support and extend previous observations of c-erbB receptor signaling as a critical element in the pathogenesis and progression of HNSCC, and em phasize the role of autocrine ligand production. (C) 2000 Wiley-Liss, Inc.