Discoidin Domain Receptor Tyrosine Kinase 1 (DDR1): A Novel Predictor for Recurrence of Hepatocellular Carcinoma After Curative Resection

Abstract

BACKGROUND Previous studies showed that the discoidin domain receptor tyrosine kinase 1 (DDR1) is significantly elevated in a variety of cancers, and it is closely related to the occurrence and development of tumors. However, its clinical significance in hepatocellular carcinoma (HCC) is not fully elucidated. So, in this study, we aimed to systemically evaluate the prognostic value of DDR1 in HCC. MATERIAL AND METHODS A total of 200 individuals were enrolled in this study (including 120 HCC patients, 40 chronic hepatitis patients, and 40 health individuals). The contents of DDR1 in serum was measured by enzyme-linked immunosorbent assay (ELISA), while the expression level of DDR1 in para-tumor and tumor tissue was detected by immunohistochemistry staining. Kaplan-Meier, Cox regression analyses, and log-rank test were used to assess the prognostic value. RESULTS The contents of DDR1 in serum of HCC patients was significantly higher compared with chronic hepatitis patients (P<0.01) and health individuals (P<0.001). The expression level of DDR1 in tumors was higher than that in normal liver tissue, and it had relatively strong correlation with DDR1 in serum. We next demonstrated that high DDR1 has utility as a prognostic risk factor for tumor recurrence and metastasis, and it still retains its discrimination ability in low-risk groups (BCLC 0+A). Moreover, DDR1 is as an independent predictor of prognosis in HCC patients with microvascular invasion (MVI), and is strongly associated with epithelial-mesenchymal transition (EMT)-related protein. CONCLUSIONS DDR1 is a novel predictor for HCC recurrence. Integration of serum and tumor DDR1 detection into clinical management would provide convenience and enhanced accuracy in clinical practice.

Figure 1

The expression of DDR1 was increased in serum and tumor in HCC patients. (A) Distributions of serum DDR1 in HCC patients (n=120), CHB patients (n=40), and healthy donors (n=40) and its expression level after HCC patients receiving curative resection. (B) The expression of DDR1 in tumor and para-tumor tissues in HCC patients. (C) Strong correlation between DDR1 in serum and in tumors. Scar bar: 100 nm.

Figure 2

Increased DDR1 in serum and in tumors was associated with poor outcome of HCC patients. (A) HCC patients with high expression of DDR1 trended to have high possibility of recurrence and metastasis. (B) ROC analysis of different variables for predicting recurrence (B1) and AUC (B2).

Figure 3

DDR1 was a promising marker of prognosis for HCC patients in the low-risk HCC group. (A) Kaplan-Meier analysis of TTR evaluated with DDR1 expression in serum and tumors. (B) Kaplan-Meier analyses of TTR according to DDR1 in the low AFP (≤400 ng/ml) group, the single-tumor group, the tumor size ≤5 cm group, and the BCLC 0-A group.

Figure 4

The correlation between DDR1 and EMT-related protein. (A) Representative images of E-cadherin, N-cadherin, vimentin, and DDR1 immunohistochemistry in tissue microarray slides are shown. (B) Patients with high DDR1 tended to have higher N-cadherin and vimentin and lower E-cadherin. Scar bar: 100 nm.