Downregulation of Sef, an inhibitor of receptor tyrosine kinase signaling, is common to a variety of human carcinomas

Abstract

Carcinomas are tumors of epithelial origin accounting for over 80% of all human malignancies. A substantial body of evidence implicates oncogenic signaling by receptor tyrosine kinases (RTKs) in carcinoma development. Here we investigated the expression of Sef, a novel inhibitor of RTK signaling, in normal human epithelial tissues and derived malignancies. Human Sef (hSef) was highly expressed in normal epithelial cells of breast, prostate, thyroid gland and the ovarian surface. By comparison, substantial downregulation of hSef expression was observed in the majority of tumors originating from these epithelia. Among 186 primary carcinomas surveyed by RNA in situ hybridization, hSef expression was undetectable in 116 cases including 72/99 (73%) breast, 11/16 (69%) thyroid, 16/31 (52%) prostate and 17/40 (43%) ovarian carcinomas. Moderate reduction of expression was observed in 17/186, and marked reduction in 40/186 tumors. Only 13/186 cases including 12 low-grade and one intermediate grade tumor retained high hSef expression. The association of hSef downregulation and tumor progression was statistically significant (Po0.001). Functionally, ectopic expression of hSef suppressed proliferation of breast carcinoma cells, whereas inhibition of endogenous hSef expression accelerated fibroblast growth factor and epidermal growth factor-dependent proliferation of cervical carcinoma cells. The inhibitory effect of hSef on cell proliferation combined with consistent downregulation in human carcinoma indicates a tumor suppressor-like role for hSef, and implicates loss of hSef expression as a common mechanism in epithelial neoplasia.

Similar expression to FGF (Sef) inhibits fibroblast growth factor-induced tumourigenic behaviour in prostate cancer cells and is downregulated in aggressive clinical disease

“…The loss of hSef, therefore, is not in itself an oncogenic event but has an important permissive role in enhancing growth factor stimulation in prostate cancer. This hypothesis is supported by others who have similarly found that the loss of hSef can augment receptor tyrosine kinase signalling in cancer cells (Zisman-Rozen et al, 2007).…”

“…hSef has been reported to interact with both nerve growth factor (NGF) and epidermal growth factor (EGF) signalling (Xiong et al, 2003;Torii et al, 2004;Ziv et al, 2006). Silencing of hSef has further been shown to accelerate EGF-stimulated proliferation of cervical carcinoma cells in vitro (Zisman-Rozen et al, 2007). More recently, Ren et al (2008) reported evidence that hSef interacts and co-localises with the EGF receptor.…”

“…These act as feedback inhibitory checkpoints at key steps in the intracellular signalling cascade (Thisse and Thisse, 2005;Mason et al, 2006;Bundschu et al, 2007). The role of these regulators in malignancies has attracted much attention with reports of loss of expression in different tumour types (McKie et al, 2005;Fong et al, 2006;Yoshida et al, 2006;Zisman-Rozen et al, 2007).…”

Expression and regulation of the tumor suppressor, SEF, during folliculogenesis in humans and mice

“…Within the human reproductive system, SEF transcripts were detected in testes, ovarian surface epithelium (OSE), and mammary and prostate epithelium (Preger et al 2004, Zisman-Rozen et al 2007. SEF expression is downregulated in ovarian, breast and prostate carcinomas in a manner that correlates with tumor aggressiveness and poor prognosis, underscoring its role as a tumor suppressor (Darby et al 2006, Zisman-Rozen et al 2007, Murphy et al 2010.…”

“…SEF expression is downregulated in ovarian, breast and prostate carcinomas in a manner that correlates with tumor aggressiveness and poor prognosis, underscoring its role as a tumor suppressor (Darby et al 2006, Zisman-Rozen et al 2007, Murphy et al 2010. SEF inhibits FGF signaling also in cervical carcinoma and endometrial carcinoma cell lines (Torii et al 2004, Ziv et al 2006, Zisman-Rozen et al 2007, Zhang et al 2011. Thus far, SEF regulation in mammals was only demonstrated during wound healing in the model of rat nervous system (Grothe et al 2008), and nothing is known regarding SEF regulation in the reproductive system.…”