ABSTRACT
Midkine (MK) expression has been documented to be inversely correlated with the prognosis of patients with various tumors, but the mechanism of this relationship has not been well characterized. Recent studies have also correlated p53 expression with prognosis of patients with oral squamous cell carcinoma (OSCC). We evaluated the relationship between MK expression and clinicopathological features of patients with OSCC to clarify the influence of p53 status on MK expression in OSCC cells. Our results showed that patients with MK over-expression in OSCC cells had a significantly lower 5-year survival rate compared with patients with low MK expression. Immunohistochemical analyses demonstrated overexpression of MK protein in OSCC samples with mutant p53. Cell culture experiments with human lingual squamous cell carcinoma revealed that the MK gene was regulated by the wild-type p53 gene. Thus, MK expression may affect prognosis via the p53 status and mutation of the p53 gene, and MK may be an attractive target for therapeutic intervention in patients with cancer cells with mutant p53.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/metabolism , Cytokines/metabolism , Mouth Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Biomarkers, Tumor/genetics , Blotting, Western , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cytokines/genetics , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Japan , Kaplan-Meier Estimate , Male , Middle Aged , Midkine , Mouth Neoplasms/genetics , Mouth Neoplasms/mortality , Mouth Neoplasms/pathology , Mutation , Neoplasm Staging , Prognosis , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Time Factors , Transfection , Tumor Suppressor Protein p53/geneticsABSTRACT
The aims of this study were to investigate midkine (MK) expression patterns in salivary gland tumors (SGTs) and to evaluate the correlation between MK expression and the degree of malignancy. We performed immunohistochemistry to examine MK expression in specimens of adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC), and pleomorphic adenoma (PA). In addition, we performed immunohistochemistry for CD31 and measured microvessel density (MVD), which is an indicator of angiogenesis. Immunohistochemistry showed that MK protein expression was significantly higher in specimens of malignant SGTs (ACC [P<0.01] and MEC [P<0.001]) than in benign SGT (PA) samples. Furthermore, MVD values tended to be higher in cases that exhibited high expression of MK, which indicated a significant correlation between the degree of MK expression and MVD (P<0.001). These results suggest that MK may play important roles in malignant transformation and tumor angiogenesis in SGTs.
Subject(s)
Carcinoma, Mucoepidermoid/metabolism , Cytokines/physiology , Neoplasm Proteins/physiology , Neovascularization, Pathologic/pathology , Salivary Gland Neoplasms/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Mucoepidermoid/blood supply , Cytokines/analysis , Female , Humans , Immunohistochemistry , Male , Middle Aged , Midkine , Neoplasm Proteins/analysis , Prognosis , Salivary Gland Neoplasms/blood supply , Young AdultABSTRACT
Midkine, a heparin-binding growth factor, is up-regulated in many types of cancer. The aim of this study was to measure plasma midkine levels in patients with breast cancer and to assess its clinical significance. We examined plasma midkine levels in 95 healthy volunteers, 11 patients with ductal carcinoma in situ (DCIS), 111 patients with primary invasive breast cancer without distant metastasis (PIBC), and 25 patients with distant metastatic breast cancer (MBC), using an automatic immunoasssay analyzer (TOSOH AIA system). In PIBC, we studied the correlation between plasma midkine levels and clinicopathological factors. Immunoreactive midkine was detectable in the plasma of healthy volunteers, and a cut-off level of 750 pg/mL was established. In breast cancer patients, plasma midkine levels were increased above normal values. These elevated levels of midkine were seen in one (9.1%) of 11 patients with DCIS, 36 (32.4%) of 111 patients with PIBC, and 16 (64.0%) of 25 patients with MBC. Increased levels of midkine were correlated with menopausal status (P = 0.0497) and nuclear grade (P = 0.0343) in PIBC. Cancer detection rates based on midkine levels were higher than those based on three conventional markers including CA15-3 (P < 0.0001), CEA (P = 0.0077), and NCCST-439 (P < 0.0001). Detection rates of breast cancer using a combination of two conventional tumor markers (CA15-3/CEA, CA15-3/NCCST-439, or CEA/NCCST-439) with midkine is significantly higher than those using combination of three conventional tumor markers. Midkine may be a useful novel tumor marker for detection of breast cancer, superior to conventional tumor markers.
Subject(s)
Biomarkers, Tumor/blood , Breast Neoplasms/blood , Carcinoma, Ductal, Breast/blood , Carcinoma, Ductal, Breast/secondary , Carcinoma, Intraductal, Noninfiltrating/blood , Nerve Growth Factors/blood , Breast/metabolism , Breast/pathology , Breast Neoplasms/pathology , Carcinoembryonic Antigen/blood , Carcinoma, Intraductal, Noninfiltrating/secondary , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Lymphatic Metastasis , Male , Midkine , Mucin-1/blood , Neoplasm Invasiveness , Neoplasm Staging , PrognosisABSTRACT
In transthyretin (TTR)-related amyloidosis, wild-type TTR (WT-TTR), as well as mutated TTRs play important roles in the pathogenesis of senile systemic amyloidosis and familial amyloidotic polyneuropathy. However, WT-TTR usually forms stable tetramers at physiological pH, and the mechanism of such fibril formation under physiological conditions remains to be elucidated. In this study, we demonstrated WT-TTR amyloid fibril formation at physiological pH with ultrasonication. Cross-linked SDS-PAGE and circular dichroism revealed that ultrasonication induced both tetrameric TTR dissociation and monomeric TTR denaturation. These results indicate that extremely low pH is not an essential condition for TTR amyloid fibril formation if TTR is degenerated in such conditions. In addition, this method allows analysis of accelerator factors or inhibitory agents in TTR amyloid fibril formation at neutral pH.
