Role of heparin‐binding EGF‐related peptides in proliferation and apoptosis of activated ras ‐stimulated intestinal epithelial cells

Abstract

The ras mutation is a common and critical step in carcinogenesis. Autocrine growth factors are also known to play an important role in cancer cell growth and transformation. However, the contribution of autocrine growth factors in regulation of proliferation and apoptosis of activated ras‐stimulated intestinal epithelium is not fully understood. Therefore, we constructed activated ras‐transfected intestinal epithelial cell clones (IEC‐ras) to examine the role of epidermal growth factor (EGF)‐related peptides in the behavior of IEC‐ras. Overexpression of EGF family growth factors (transforming growth factor α, heparin‐binding EGF‐like growth factor, amphiregulin and betacellulin) and stronger phosphorylation of the EGF receptor was observed in IEC‐ras compared with control cells. IEC‐ras proliferated more rapidly than control cells, and a specific EGF receptor kinase inhibitor, AG1478, abolished the increased proliferation of IEC‐ras. Heparitinase and chlorate also prevented increased proliferation of IEC‐ras. Additionally, IEC‐ras expressed more bcl‐2 and was more resistant to apoptosis induction by UV radiation and mitomycin C. AG1478 suppressed bcl‐2 expression and inhibited resistance to apoptosis of IEC‐ras. Heparitinase and chlorate had effects similar to those of AG1478. Our data indicate that heparin‐binding EGF family growth factors play an important role in both increased proliferation and resistance to apoptosis of ras‐stimulated intestinal epithelial cells. Int. J. Cancer 73:917–923, 1997. © 1997 Wiley‐Liss, Inc.

Intestinal phenotype in mice overexpressing a heparin-binding EGF-like growth factor transgene in enterocytes

“…The proliferative effects of overexpressed HB-EGF are present in a dose-dependent manner, since the effects were more prominent in high expression TG mice compared to low expression TG mice. The mitogenic activity of overexpressed HB-EGF on IEC is consistent with a substantial body of previous studies, particularly with sHB-EGF, in the intestine and other cell types (Zushi et al 1997; Xia et al 2002; El-Assal and Besner 2005; Feng and Besner 2007; Wang et al 2007; Zhuang et al 2008). Intestinal renewal involves crypt epithelial cell proliferation and migration of crypt cells to the luminal surface (Freeman 2008).…”

Inhibition of Apoptosis by Amphiregulin via an Insulin-like Growth Factor-1 Receptor-dependent Pathway in Non-small Cell Lung Cancer Cell Lines

“…Our results showed also here that AR stimulated the IGF1-R, which in turn induced the release of AR, an amplification phenomenon that could also explain the high levels of AR secreted by H358 cells. Furthermore, H358 cells express a mutated constitutively active Ras protein (59), and Ras activation has been shown to increase the production of EGF-related peptides (60,61). Accordingly, H322 cells, which did not secrete AR, express a wild-type Ras protein (59).…”

Cell Surface Ectodomain Cleavage of Human Amphiregulin Precursor Is Sensitive to a Metalloprotease Inhibitor

“…In addition, AR mRNA and protein have been detected in normal human mammary epithelial cell and normal human keratinocyte cultures (6,13,14). AR has been shown to act as an autocrine factor for human colon carcinoma cell lines, normal human mammary epithelial cell lines, and normal human keratinocytes (9,(13)(14)(15)(16)(17)(18). Recent studies indicate that AR may be involved in upregulation of matrix metalloproteases, invasion by tumor cells, as well as hyperproliferation and inflammation observed with psoriasis (19 -21).…”