Ling Hu1, Dongxu Wang2, Hongbin Zhu2, Longteng Ma3, Shiping Hu2, Xiangyang Zhao4, Shuyao Ren4, Sujuan Zhan2, Yuzhuo He2, Jiana Li2
1Department of Respiratory Medicine, the 983rd Hospital of Joint Logistic Support Force of PLA, Tianjin, China, 300142
2 Department of Gastroenterology and Hepatology, the 983rd Hospital of Joint Logistic Support Force of PLA, Tianjin, China, 300142
3 Department of Neurology, the 983rd Hospital of Joint Logistic Support Force of PLA, Tianjin, China, 300142
4 Department of General Surgery, the 983rd Hospital of Joint Logistic Support Force of PLA, Tianjin, China, 300142.
Background/Aims: Dachshund homologue 1 (DACH1) has been shown to act as a tumor suppressor by inhibiting stemness of hepatocellular carcinoma (HCC) cells involving suppression of Wnt/beta-catenin signaling. However, little is known about the correlation between DACH1 and the prognosis and the mechanisms underlying inhibition of Wnt/beta-catenin signaling by DACH1.
Methods: Data from the The Cancer Genome Atlas (TCGA) and public microarray were used to demonstrate clinical significance. The stable DACH1-knockdown QGY-7703 cells and DACH1-overexpressing Hep3B cells were constructed using a lentiviral vector containing DACH1 shRNA and DACH1 expression vector, respectively. Flow cytometry was used to detect the role of DACH1 in HCC sorafenib sensitivity. The effect of DACH1 on FOXM1 signaling was investigated by Western blot.
Results: Data from the TCGA database LIHC cohort indicated that HCC patients with higher DACH1 expression had a longer recurrence-free survival time than those with lower DACH1 expression (p = 0.033). Analysis based on the study published by Pinyol et al. indicated that DACH1 expression in sorafenib responding HCC patients was were significantly higher than those in sorafenib non-responding HCC patients (p = 0.0189). Furthermore, the recurrence rate in the low DACH1 expression group was significantly higher than in the high DACH1 expression group (48.4% vs 27.2%, p = 0.029). Overexpression of DACH1 was shown to increase the proportion of apoptotic cells after sorafenib treatment (p = 0.0032), while silencing DACH1 decreased sorafenib-induced apoptosis (p = 0.0089). DACH1 was also found to decrease ERK phosphorylation by inhibiting EGFR expression, and nuclear accumulations of FOXM1 and beta-catenin were reduced accordingly. Furthermore, stemness genes Myc and Nanog were downregulated correspondingly.
Conclusion: DACH1 was associated with good prognosis and sorafenib sensitivity in HCC, and inhibited Wnt/beta-catenin by down-regulating EGFR/ERK/FOXM1 axis. Our data will contribute to a better understanding of the molecular mechanisms underlying HCC relapse and drug resistance.
Keywords: hepatocellular carcinoma,DACH1,Wnt/?-catenin signaling,FOXM1,sorafenib sensitivity