Localization of heparanase in esophageal cancer cells: respective roles in prognosis and differentiation.
In this study, we examined the distribution of heparanase protein in 75 esophageal squamous cell carcinomas by immunohistochemistry and analyzed the relationship between heparanase expression and clinicopathological characteristics. In situ hybridization showed that the mRNA expression pattern of heparanase was similar to that of the protein, suggesting that increased expression of the heparanase protein at the invasive front was caused by an increase of heparanase mRNA in tumor cells. Heparanase expression correlated significantly with depth of tumor invasion, lymph node metastasis, tumor node metastasis (TNM) stage and lymphatic invasion. Overexpression of heparanase in esophageal cancers was also associated with poor survival. In addition to its localization in the cytoplasm and cell membrane, heparanase was also identified in the nuclei of normal epithelial and tumor cells by immunohistochemistry. Furthermore, nuclear heparanase was detected in nuclear extract of cancer cell lines by Western blot and immunohistochemistry. Examination of the role of nuclear heparanase in cell proliferation and differentiation by double immunostaining for proliferating cell nuclear antigen (PCNA) and cytokeratin 10 (CK10) showed significant relationship between nuclear heparanase expression and differentiation (heparanase vs CK10), but not for proliferative state of esophageal cancer cells (heparanase vs PCNA). Our results suggest that cytoplasmic heparanase appears to be a useful prognostic marker in patients with esophageal cancer and that nuclear heparanase protein may play a role in differentiation. Inhibition of heparanase activity may be effective in the control of esophageal tumor invasion and metastasis.
Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan.
Takaomi
T
Ohkawa
Yoshio
Y
Naomoto
Munenori
M
Takaoka
Tetsuji
T
Nobuhisa
Kazuhiro
K
Noma
Takayuki
T
Motoki
Toshihiro
T
Murata
Hirokazu
H
Uetsuka
Masahiko
M
Kobayashi
Yasuhiro
Y
Shirakawa
Tomoki
T
Yamatsuji
Nagahide
N
Matsubara
Junji
J
Matsuoka
Minoru
M
Haisa
Mehmet
M
Gunduz
Hidetsugu
H
Tsujigiwa
Hitoshi
H
Nagatsuka
Masao
M
Hosokawa
Motowo
M
Nakajima
Noriaki
N
Tanaka
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D002454:Cell Differentiation; D002455:Cell Division; D045744:Cell Line, Tumor / Q000201:enzymology / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007633:Keratins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D000099175:Heparanase
D014408:Biomarkers, Tumor; D005966:Glucuronidase; D007633:Keratins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D000099175:Heparanase