Emergence of nuclear heparanase induces differentiation of human mammary cancer cells q Tetsuji Nobuhisa a , Yoshio Naomoto a, * , Munenori Takaoka a , Yoko Tabuchi a , Keizou Ookawa b , Dai Kitamoto c , Esra Gunduz d , Mehmet Gunduz d , Hitoshi Nagatsuka d , Minoru Haisa d , Junji Matsuoka a , Motowo Nakajima e , Noriaki Tanaka a a Department of Gastroenterological Surgery Transplant and Surgical Oncology, Graduate School of Medicine and Dentistry, Okayama University, Okayama 700-8558, Japan b Second Department of Biochemistry, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan c Research Institute of Green Technology, National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8565, Japan d Oral Pathology and Medicine, Graduate School of Medicine and Dentistry, Okayama University, Okayama 700-8558, Japan e Tsukuba Research Institute, Novartis Pharma KK, Tsukuba 300-2611, Japan Received 16 March 2005 Available online 30 March 2005 Abstract The study of epithelial differentiation touches upon many modern aspects of biology. The epithelium is in constant dialo the underlying mesenchyme to control stem cell activity,proliferation in transit-amplifying compartments, lineage commitment, terminaldifferentiation and, ultimately, celldeath.There are spatially distinct compartments dedicated to each of these events. Recently we reported that heparanase is expressed in nucleus as well as in the cytoplasm and that nuclear heparanase seems to be related to cell differentiation. In this study, we investigated the role of nuclear heparanase in differentiation by transdu mammary epithelial cancer cells with heparanase which was delivered specifically into nucleus. We observed that expression of nuclear heparanase allowed the cells to differentiate with the appearance of lipid droplets. This finding supports the idea that heparanase plays a novel role in epithelial cell differentiation apart from its known enzymatic function. 2005 Elsevier Inc. All rights reserved. Keywords:Heparanase; Nucleus; Differentiation; Epithelial cancer; MCF-7 Heparanase is an endo-b-glucuronidase that specifi- cally cleavescarbohydratechainsof heparan sulfate proteoglycans (HSPG), which are importantcompo- nents of extracellular matrix (ECM) [1–5].Most previ- ous studiesreported thatheparanase is involved in invasion and metastasis of many types ofcancers by mediating the degradation of HSPG in the basement membrane (BM) and ECM [1–3,6,7]. In addition, hepa- ranase expression has been associated with an aggressive malignantphenotype and adverse prognosis in cancer patients. Increased heparanase expression was demon- strated in several human primary cancers, including co- lon [8], stomach [9,17], esophagus [10],bladder[11], pancreas [12], liver [13], prostate [14], malignant mela- noma [15], and breast [16]. On the other hand, recentstudiesclaimed that heparanase is also expressed in the nucleus [17–19] and that nuclear heparanaseis statisticallycorrelated with the expression of a differentiation marker in the esophagus [19]. 0006-291X/$ - see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2005.03.129 q Abbreviations: BM, basementmembrane;ECM, extracellular matrix; HSPG, heparan sulfate proteoglycans. * Corresponding author: Fax: +81 86 221 8775. E-mail address: ynaomoto@md.okayama-u.ac.jp (Y. Naomoto). www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 331 (2005) 175–180 BBRC