Evaluation of Midkine as a Diagnostic Serum Biomarker in Hepatocellular Carcinoma

Abstract

Purpose: To evaluate the value of serum midkine (MDK) as a diagnostic biomarker in hepatocellular carcinoma, particularly for those with negative alpha-fetoprotein (AFP) and at an early stage.Experimental Design: MDK expression in tumors was assessed by immunohistochemistry from 105 patients with hepatocellular carcinomas or liver cirrhosis. Serum MDK levels were detected by ELISA in 933 participants including hepatocellular carcinomas and hospital controls from different medical centers. Sensitivities and specificities of serum MDK in diagnosing hepatocellular carcinoma according to AFP level and Barcelona Clinic Liver Cancer (BCLC) stage were analyzed.Results: MDK levels were significantly elevated in hepatocellular carcinoma tissues as well as serum samples. The sensitivity of serum MDK for hepatocellular carcinoma diagnosis was much higher than that of AFP (86.9% vs. 51.9%) with similar specificities (83.9% vs. 86.3%). Notably, serum MDK had an outstanding performance in distinguishing AFP-negative hepatocellular carcinomas from different controls: In those AFP-negative hepatocellular carcinomas, the sensitivity could reach as high as 89.2%. Moreover, receiver operating characteristic (ROC) curve analysis also showed that serum MDK had a better performance compared with AFP in distinguishing early-stage hepatocellular carcinomas as well as small hepatocellular carcinomas. Even in very early-stage hepatocellular carcinomas, MDK showed an obviously higher sensitivity compared with AFP (80% vs. 40%). Furthermore, serum MDK level was significantly decreased in patients with hepatocellular carcinomas after curative resection and re-elevated when tumor relapse occurred.Conclusions: Serum MDK is significantly elevated in most hepatocellular carcinomas, including those with negative AFP and at an early stage, which may serve as a novel diagnostic marker in early diagnosis and postoperative monitoring of hepatocellular carcinomas.

The clinical and prognostic significance of midkine in breast cancer patients

“…In lung cancer patients, Ma et al showed that midkine mRNA level in peripheral blood mononuclear cells was significantly increased than that in groups of healthy volunteers and positively correlated with clinical stage, differentiated degree, and lymph node metastasis [16]. Zhu et al found that serum midkine levels were significantly elevated in hepatocellular cancer patients and significantly decreased in hepatocellular cancer patients after curative resection and re-increased when tumor recrudesced [29]. In addition, serum midkine had higher sensitivity for hepatocellular cancer diagnosis than AFP and had an outstanding performance in distinguishing AFP-negative hepatocellular cancers, early-stage hepatocellular cancers, and small hepatocellular cancers [29].…”

“…Zhu et al found that serum midkine levels were significantly elevated in hepatocellular cancer patients and significantly decreased in hepatocellular cancer patients after curative resection and re-increased when tumor recrudesced [29]. In addition, serum midkine had higher sensitivity for hepatocellular cancer diagnosis than AFP and had an outstanding performance in distinguishing AFP-negative hepatocellular cancers, early-stage hepatocellular cancers, and small hepatocellular cancers [29]. In breast cancer, although levels of serum midkine were increased in tumor tissues, there is no any association of serum midkine protein levels with clinical stage, tumor size, and lymph nodal status [25].…”

Role of biomarkers in the prediction and diagnosis of hepatocellular carcinoma

“…Therefore, MDK can be used in the diagnosis of AFPnegative HCCs and very earlystages of HCCs. Furthermore, MDK can be used in HCC patients after curative resections to diagnose tumour recurrence [36] .…”

DcR3, TFF3, and Midkine Are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors

“…It was elevated in all cases of metastatic colorectal cancer and strongly outperformed carcinoembryonic antigen in detecting colorectal cancer at all disease stages [38] . Midkine outperformed the currently used blood biomarker test in multiple tumor types: the hepatocellular carcinoma marker α-fetoprotein [39,40] , the esophageal squamous cell carcinoma markers carcinoembryonic antigen and cytokeratin 19 fragment (CYFRA21-1) [41] , and the differentiated thyroid cancer marker thyroglobulin [42] . This study demonstrated that midkine was elevated in serum in SI-NET patients and is, thus, potentially a novel biomarker for diagnosis.…”