Hepatoma‐derived growth factor regulates breast cancer cell invasion by modulating epithelial–mesenchymal transition

Abstract

Hepatoma-derived growth factor (HDGF) participates in tumourigenesis but its role in breast cancer is unclear. We set out to elucidate the expression profile and function of HDGF during breast carcinogenesis. Immunoblot and immunohistochemical studies revealed elevated HDGF expression in human breast cancer cell lines and tissues. Nuclear HDGF labelling index was positively correlated with tumour grade, stage and proliferation index, but negatively correlated with survival rate in breast cancer patients. HDGF over-expression was associated with lymph node metastasis and represented an independent prognostic factor for tumour recurrence. Gene transfer studies were performed to elucidate the influence of cellular HDGF level on the malignant behaviour and epithelial-mesenchymal transition (EMT) of breast cancer cells. Adenovirus-mediated HDGF over-expression stimulated the invasiveness and colony formation of MCF-7 cells. Moreover, HDGF over-expression promoted breast cancer cell EMT by E-cadherin down-regulation and vimentin up-regulation. Conversely, HDGF knockdown by RNA interference in MDA-MB-231 cells attenuated the malignant behaviour and elicited EMT reversal by enhancing E-cadherin expression while depleting vimentin expression. Because HDGF is a secreted protein, we evaluated the cellular function of recombinant HDGF and found that exogenously supplied HDGF enhanced the invasiveness of breast cancer cells by down-regulating E-cadherin and up-regulating vimentin at transcriptional and translational levels. In contrast, blockade of HDGF secretion with an HDGF antibody inhibited the malignant behaviours and EMT. Finally, exogenous HDGF partially reversed benzyl isothiocyanate (BITC)-induced EMT suppression. HDGF over-expression may exert a prognostic role for tumour metastasis and recurrence in breast cancer by modulating EMT. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Prognostic Role of Hepatoma-derived Growth Factor in Solid Tumors of Eastern Asia: a Systematic Review and Meta-Analysis

“…Down-regulation of HDGF participates in miRNAs-induced suppression of migration and invasion on several cancer cells Guo et al, 2014a), and induces relapse of various cancer cells . Moreover, previous studies had shown that HDGF overexpression promoted epithelial-mesenchymal transition (Chen et al, 2012a;Tsai et al, 2013) and affected cell metastasis processes via mitogen-activated protein kinase signaling pathways (Mao et al, 2008) or a novel HDGF-disintegrin and metalloproteinase-9 pathway , thereby promoting the invasion and metastasis in several cancer cells. In addition, combining the anti-HDGF antibody with anti-VEGF antibody might enhance their antiangiogenic activities (Ren et al, 2009).…”

“…The following articles were also excluded: three duplicated publications (Zhou et al, 2007b;Zhou et al, 2010a;Yang et al, 2014); three without data for HR and 95%CI calculations and adequate contact with the investigators could not be established (Natrajan et al, 2006;Mao et al, 2008;Hanada et al, 2013); two with a sample size<50 (Hsu et al, 2012;Tao et al, 2014); two in which HDGF expression was not detected by IHC methods (Savola et al, 2009;Zhang et al, 2010); three uncorrelated. Finally, 26 cohort studies were found eligible for the meta-analysis (Hu et al, 2003;Ren et al, 2004;Iwasaki et al, 2005;Uyama et al, 2006;Yamamoto et al, 2006;Yoshida et al, 2006;Chang et al, 2007;Yamamoto et al, 2007;Zhou et al, 2007a;Hu et al, 2009;Zhou et al, 2010b;Liu et al, 2011;Wang et al, 2011;Zhang et al, 2011;Chen et al, 2012a;Chen et al, 2012b;Lin et al, 2012;Han et al, 2013;Li et al, 2013a;Li et al, 2013b;Li et al, 2013c;Yang et al, 2013;Guo et al, 2014b;Song et al, 2014;Wang et al, 2014;Zhang et al, 2014), containing 32 datasets (29 datasets for OS; 17 datasets for DFS) were qualified to the standard of the meta-analysis. The main characteristics of the selected studies were summari...…”

“…In recent years, elevated levels of hepatoma-derived growth factor (HDGF) have been observed in a variety of malignancies and high levels of HDGF appears to be associated with increased malignancy across cancers, as witnessed by the correlation with adverse characteristics such as poor patient survival (Hu et al, 2003;Ren et al, 2004;Iwasaki et al, 2005;Uyama et al, 2006;Yamamoto et al, 2006;Yoshida et al, 2006;Chang et al, 2007;Yamamoto et al, 2007;Zhou et al, 2007a;Hu et al, 2009;Savola et al, 2009;Zhang et al, 2010;Zhou et al, 2010b;Liu et al, 2011;Wang et al, 2011;Ye et al, 2011;Zhang et al, 2011;Chen et al, 2012a;Chen et al, 2012b;Hsu et al, 2012;Lin et al, 2012;Han et al, 2013;Hanada et al, 2013;Li et al, 2013a;Li et al, 2013b;Li et al, 2013c;Yang et al, 2013;Guo et al, 2014b;Song et al, 2014;Wang et al, 2014;Yang et al, 2014;Zhang et al, 2014). As a multifunctional protein Bao et al, 2014) widely expressed by many types of human cells, HDGF is involved in the regulations of a myriad of cancer cell activities during cancer transformation (Yang et al, 2013), apoptosis , angiogenesis (Ren et al, 2009), and metastasis (Chen et al, 2012a).…”

“…As a multifunctional protein Bao et al, 2014) widely expressed by many types of human cells, HDGF is involved in the regulations of a myriad of cancer cell activities during cancer transformation (Yang et al, 2013), apoptosis , angiogenesis (Ren et al, 2009), and metastasis (Chen et al, 2012a). Therefore, HDGF not only promote cancer progression but also may be an indicator of the prognosis of various tumors.…”

Downregulation of Hepatoma-Derived Growth Factor Contributes to Retarded Lung Metastasis via Inhibition of Epithelial–Mesenchymal Transition by Systemic POMC Gene Delivery in Melanoma

“…HDGF has also been recognized as an important prognostic marker that HDGF overexpression was correlated with advanced stages and poor survival outcome in several types of cancers including liver cancer (13) and esophageal carcinoma (14). Furthermore, we have recently shown that HDGF overexpression promoted epithelial-to-mesenchymal transition (EMT) by E-cadherin downregulation and vimentin upregulation, thereby promoting the invasion and metastasis in breast cancer cell (15). However, the upstream molecules or signaling mechanisms that modulate HDGF expression and therefore affect cancer progression remain largely unknown.…”