Midkine Expression in Reed-Sternberg Cells of Hodgkin's Disease

Abstract

Midkine (MK) was originally cloned as a product of a retinoic acid-responsive gene. The rationale for studying MK expression is based on previous reports showing that it transforms 3T3 cells, and that it acts as an autocrine growth factor in Wilm's tumors, and that its overexpression has been associated with worse outcome in bladder carcinoma. Besides bladder carcinoma, its expression was reported in various solid tumors. We investigated the expression of MK protein and/or MK gene in biopsied specimens from 40 patients with primary malignant lymphoma, 21 with Hodgkin's disease (HD) and 19 with non-Hodgkin's lymphoma (NHL). Reed-Sternberg (R-S) cells were stained positive in 10 of 16 HD cases evaluated by immunohistochemical method, whereas 18 of 19 NHL cases did not stain, and one B-cell NHL stained weakly positive. Immunostaining analysis was extended to established cell lines and to normal lymphocytes with or without lectin stimulation or with EB virus transformation. Among hematopoietic cells examined, erythro- or megakaryoblastic leukemia cell lines (K562, MEG-01 and UT7) were positive, while normal lymphocytes (except the EB virus-transformed one) and most myeloid and lymphoid cell lines (except Raji cells) were negative. On the contrary, solid tumor cell lines showed high and strongly positive staining including cell lines derived from of lung gastric, colon, and a pancreatic cancer. Using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), which is suitable for the detection of weakly expressed mRNA, the relative ratio of MK mRNA to beta-actin mRNA of samples was measured and compared in cases where RNA was available. The mean values of relative ratio (MK/beta-actin) of HD were almost twice as those of NHL samples, peripheral blood T cells, and spleen B cells. Our findings showed that MK is expressed in Reed-Sternberg cells of HD, and that MK might play a role in the pathogenesis of HD.

Comparative Genome-Scale Analysis of Gene Expression Profiles in T Cell Lymphoma Cells during Malignant Progression Using a Complementary DNA Microarray

“…Many of these genes have been found to be strongly expressed in a variety of carcinomas and lymphomas. [22][23][24][25] Two genes that may play a role in drug resistance showed increased expression in the 2A cells (Group B). Ferrando et al 26 showed that one of these genes, encoding bleomycin hydrolase (Figure 1), was expressed at an elevated level in head and neck carcinomas when compared to an adjacent normal mucosa.…”

Midkine as a regulator of B cell survival in health and disease

“…MK gene expression is universally detected in lymphomas (of both HD and NHL types). However, analysis of protein expression using immunostaining revealed that R-S cells of HD express MK, while MK protein was detected in only about 5% of NHL (B cell type) (Kato et al, 2000).…”

“…MK expression has been detected in Hodgkin's lymphoma (HD) (Kato et al, 2000), B cell chronic lymphocytic leukaemia (CLL) (Cohen et al, 2012) and B-precursor acute lymphoblastic leukaemia (ALL) (Hidaka et al, 2007;Wang et al, 2008;Hu et al, 2010). Among the known MK receptors, ALK and PTPRZ1 were found to be expressed in a subtype of large B cell lymphoma and in CLL cells respectively (Wan et al, 2006;Cohen et al, 2012).…”

The Cytokine Midkine and Its Receptor RPTPζ Regulate B Cell Survival in a Pathway Induced by CD74

“…This dimerization appears to be required for MK activity (27). MK is expressed in adult peripheral lymphocytes (28) and specifically, in normal splenic B cells (29). …”