Laboratory of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang Key Laboratory of Hepatobiliary Diseases, Zhanjiang, Guangdong 524001, P.R. China.
Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China.
Int J Oncol. 2017 Oct;51(4):1135-1145. doi: 10.3892/ijo.2017.4112. Epub 2017 Sep 1.
Invasion and metastasis are the primary causes of mortality from hepatocellular carcinoma (HCC). Effective inhibition against participants in the tumourigenesis and metastasis process is critical for treatment of HCC. Wnt3a is involved in the development and metastasis of many malignant tumours. However, the specific mechanisms of Wnt3a-mediated cell proliferation, invasion and metastasis in HCC remain unclear. In this study, we found that Wnt3a and its target gene c‑Myc showed higher expression in tumour tissues than normal liver tissues in HCC patients; 71.8% of the cases studied had high Wnt3a and c‑Myc expression levels (n=32); Wnt3a expression positively correlated with its target genes MMP‑7 and c‑Myc. Intriguingly, the expression of Wnt3a, MMP‑7 and c‑Myc is significantly correlated with Notch3 and Hes1 expression. In vitro experiments showed that Wnt3a was highly expressed in MHcc97H and SK‑Hep‑1 cells. Therefore, Wnt3a expression was silenced with siRNA, and then, MTT, flow cytometry, wound healing and Transwell assays were performed to analyse cell proliferation, cycle, migration and invasion. The results demonstrated that downregulation of Wnt3a expression inhibited cell viability and induced G0/G1 cell cycle arrest via decreased expression of cyclin D1 and c‑Myc and increased expression of p21 and p27. In addition, deletion of Wnt3a significantly inhibited migration and invasion by downregulating MMP‑2/-7/-9 expression via the MAPK (p38, ERK1/2 and JNK) pathway. In conclusion, our data show that Wnt3a is involved in HCC development. Wnt3a may be an effective target for treatment of HCC.
侵袭和转移是肝细胞癌(HCC)患者死亡的主要原因。有效抑制肿瘤发生和转移过程中的参与者对于 HCC 的治疗至关重要。Wnt3a 参与许多恶性肿瘤的发生和转移。然而,Wnt3a 介导的 HCC 细胞增殖、侵袭和转移的具体机制尚不清楚。在本研究中,我们发现 Wnt3a 及其靶基因 c-Myc 在 HCC 患者的肿瘤组织中表达高于正常肝组织;研究的 71.8%病例具有高 Wnt3a 和 c-Myc 表达水平(n=32);Wnt3a 的表达与它的靶基因 MMP-7 和 c-Myc 呈正相关。有趣的是,Wnt3a、MMP-7 和 c-Myc 的表达与 Notch3 和 Hes1 的表达显著相关。体外实验表明,Wnt3a 在 MHcc97H 和 SK-Hep-1 细胞中高表达。因此,用 siRNA 沉默 Wnt3a 的表达,然后进行 MTT、流式细胞术、划痕愈合和 Transwell 测定,以分析细胞增殖、周期、迁移和侵袭。结果表明,下调 Wnt3a 的表达通过降低 cyclin D1 和 c-Myc 的表达和增加 p21 和 p27 的表达,抑制细胞活力并诱导 G0/G1 细胞周期停滞。此外,通过下调 MMP-2/-7/-9 的表达,Wnt3a 的缺失显著抑制迁移和侵袭,这是通过 MAPK(p38、ERK1/2 和 JNK)通路实现的。总之,我们的数据表明 Wnt3a 参与 HCC 的发生。Wnt3a 可能是治疗 HCC 的有效靶点。