Immunohistochemical and In Situ Hybridization Analyses of Midkine Expression in Thyroid Papillary Carcinoma

Abstract

Midkine (MK) is a novel heparin-binding growth factor whose gene has been identified in embryonal carcinoma cells in early stages of retinoic acidinduced differentiation. We immunohistochemically examined 90 thyroid papillary carcinomas (85 invasive type and five encapsulated type), using a rat IgG2a monoclonal antibody against the carboxyl terminal region of human MK in archival paraffin sections. The thyroid tumors exhibited an intense reaction in the cytoplasm. Most of the papillary carcinomas (77/90), had tumor cells that expressed MK. These were classified into the following two types: invasive type (76/85) and encapsulated type (1/5). Notably, the intensity of MK was stronger at the invading border area of the tumors than in the center. In tissues adjacent to the cancer tissues, normal follicular epithelial cells expressed MK very faintly or not at all. The in situ hybridization analysis revealed that the signals of MK transcripts were found in the cytoplasm of the cancer cells. In the noncancerous follicular epithelial cells adjacent to neoplasm the signals of MK transcripts were detected very weakly or not at all. The distribution and localization of the MK-transcript signals determined by in situ hybridization analysis were similar to those obtained by immunohistochemical analysis. We conclude that thyroid papillary carcinoma strongly expresses MK protein and messenger RNA, and that this overexpression may relate to the development and invasion of these carcinomas.

New molecular mediators in tumor angiogenesis

“…Furthermore, overexpression of MK predicted a poor outcome in patients with invasive bladder cancer [53]. In thyroid papillary carcinomas the expression of MK has been shown to relate to the invasion of these carcinomas [54]. Two other studies have demonstrated an overexpression of MK in hepatocellular carcinomas and Sternberg Reed cells of Hodgkin's disease [55,56].…”

Clinical significance of midkine expression in pancreatic head carcinoma

“…Furthermore, overexpression of MK mRNA is positively correlated with advanced tumours and poor prognosis, especially in the case of patients with neuroblastoma and bladder carcinoma (Nakagawara et al, 1995;O'Brien et al, 1996). Immunohistochemical studies revealed MK protein expression in other carcinomas, including oral carcinoma (Ruan et al, 2007), oesophageal carcinoma (Ren and Zhang, 2006), gastrointestinal stromal tumours (Kaifi et al, 2007), liver carcinoma (Kato et al, 2000b), lung carcinoma (Sakitani et al, 1999), thyroid carcinoma (Kato et al, 2000a), and prostate carcinoma .…”

Midkine expression is correlated with an adverse prognosis and is down-regulated by p53 in oral squamous cell carcinoma

“…Midkine (MK) is a novel heparin-binding growth factor found as a product of a retinoic acid-responsive gene (8). MK has been reported to be intensely expressed in various human tumors including lung (9), breast (10), gastric (11), colorectal (12), esophageal (13), liver (14), thyroid (15), prostate (16) and pancreatic (17). In addition, MK expression has been correlated with poor prognosis in patients with neuroblastomas (18), astrocytomas (19), pancreatic cancers (17) and gastrointestinal stromal tumors (20).…”