Abstract
To clarify the role of hepatoma-derived growth factor (HDGF) and β-catenin in carcinogenesis of colorectal cancer (CRC), our results showed that high HDGF expression was found in CRC cells and tissues and significantly related to histological differentiation (p = 0.035) and lymph node metastasis (p = 0.000). Significant positive correlation between HDGF expression and β-catenin abnormal expression was found in CRC tissues. High HDGF and lymph node metastasis were the strong independent prognostic indicators for reduced overall survival in CRC patients. HDGF knockdown dramatically inhibited cellular proliferation, migration, invasion, and tumorigenesis, both in vitro and in vivo, but induced G1 phase arrest and apoptosis in CRC cells. HDGF knock-down dramatically suppressed β-catenin and its down-stream genes expression in CRC cells. Intriguingly, β-catenin knock-down dramatically suppressed HDGF expression in CRC cells. Human recombinant Wnt3a and DKK1 treatment increased and decreased HDGF, β-catenin, c-Myc, cyclin D1, MMP9, and phos-GSK-3β (Ser9) protein expression in nuclear and cytoplasmic fraction of CRC cells upon β-catenin knock-down, respectively. Three HDGF-binding elements in β-catenin promoter were found and specific for transcriptional activation of β-catenin in CRC cells. In conclusion, our results first suggest that HDGF and β-catenin interacts as a positive feedback loop, which plays an important role in carcinogenesis and progression of CRC.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies worldwide
Hepatoma-derived growth factor (HDGF) and β-catenin protein expressions were higher in CRC cell lines including HT29, SW116, HCT116, and LOVO compared with non-tumor colorectal mucosa (ANM) by Western blot analysis, respectively
Our data showed that HDGF expression was significantly related to histological differentiation and lymph node metastasis in CRC
Summary
Hepatoma-derived growth factor (HDGF) is a heparin-binding protein that was originally purified from the conditioned media of human hepatocellular carcinoma cell line HuH-7, which proliferate autonomously in serum-free chemically defined medium [1]. HDGF is a prognostic marker in several types of cancer including hepatocellular carcinoma, esophageal squamous cell carcinoma, gastric cancer, intrahepatic cholangiocarcinoma, early-stage cervical adenocarcinoma, gallbladder cancer, and non small cell lung cancer [2,3,4,5,6,7]. Our recent study shows that HDGF exhibits oncogenic properties and may be a novel prognostic factor in. HDGF expression is overexpressed in CRC and gradually increased in the colorectal carcinogenesis process [9, 10]. Blocking HDGF exhibits potent pro-apoptotic properties in CRC cells [10]. The molecular mechanism of HDGF involving in carcinogenesis of CRC remains unknown
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