Preliminary mechanism on the methylation modification of Dkk-1 and Dkk-3 in hepatocellular carcinoma
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Wnt/β-catenin signaling pathway, having a crucial role in regulating diverse cellular processes, can be a new therapeutic target in cancer. To investigate the role of Dkk-1 (Dickkopf-1) and Dkk-3 in tumors and cirrhoses of the liver tissue in hepatocellular carcinoma (HCC), tissues from 38 patients with HCC resections including 5 patients who underwent hemangioma surgery of adjacent tumor tissues at the same time were obtained. Tissues were divided into three groups (nonfibrosis, cirrhosis, and carcinoma) through hematoxylin-eosin (HE) staining. Methylation-specific polymerase chain reaction (PCR) (MSP) measured the methylation status, and reverse transcription-PCR tested the messenger RNA (mRNA) levels, and immunohistochemical analysis provided levels of protein expression. The methylation detection rate of Dkk-1 and Dkk-3 was the highest (P < 0.05) and the mRNA levels of Dkk-1 and Dkk-3 were the lowest (P < 0.05) in the carcinoma tissues. The mRNA levels of β-catenin were significantly higher in the carcinoma tissue than the other tissues (P < 0.05). The expression of Dkk-1 and Dkk-3 was significantly higher in the carcinoma tissues than the other tissues (P < 0.05); but the β-catenin expression was the highest (P < 0.05). Compared with the control, the mRNA levels of β-catenin in the Dkk-1 and Dkk-3 silencing cells increased 5.34 (P < 0.05) and 3.5 times (P > 0.05). After the interference of 5-aza-2′-deoxycytidine, the mRNA levels of Dkk-1 and Dkk-3 significantly increased 58.9 and 59.3 times (P < 0.0001), and the mRNA levels of β-catenin decreased 6.02 times (P < 0.05). In the process of HCC, the abnormal activity of Wnt/β-catenin signaling may be associated with the methylation of Dkk-1 and Dkk-3.
KeywordsHepatocellular carcinoma Dkk-1 Dkk-3 Methylation
We thank Ying Binwu for the excellent technical support. This study was supported by West China College of Stomatology Sichuan University and the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University in Chengdu. This study was also supported by the Nature Science Foundation of China (#81100303) and the Science and Technology Department of Sichuan Province (#2014SZ0170).
Liang Libo and He He contributed equally to this work. Liang Libo, He He, and Lv Ruixue designed the study. Liang Libo and Tan Chunlu were involved in the acquisition of data. He He, Zhang Mei, and Huang Hengjian were involved in the interpretation of data. Liang Libo, He He and Li Shuangqing were involved in the manuscript preparation. An Zhenmei provided essential tools.
Conflict of interest
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