Chen Yanyan, Rao Xianping, Huang Kangmao, Jiang Xiaoxia, Wang Haohao, Teng Lisong
Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Department of Cell Biology and Program in Molecular Cell Biology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
J Cancer. 2017 Sep 12;8(16):3142-3153. doi: 10.7150/jca.19273. eCollection 2017.
Aberrant Wnt/β-catenin pathway activation is frequently observed in human colorectal cancer (CRC) and has become a promising target for CRC treatment. Our study aimed to evaluate the effect of FH535, a small molecule inhibitor of Wnt/β-catenin pathway, on two colon cancer cell lines, HT29 and SW480. We found FH535 significantly inhibited colon cancer cell proliferation and induced cell cycle arrest. Moreover, FH535 inhibited colon cancer xenograft growth . Wound-healing assay and Transwell assay revealed that FH535 notably suppressed migration and invasion of SW480 cells. FH535 also repressed expression of cancer stem cell markers, CD24, CD44 and CD133 in HT29 cells. Real time-quantitative PCR and Western blotting revealed that targeting Wnt/β-catenin pathway using FH535 effectively downregulated target genes including cyclin D1 and survivin at mRNA and protein level, which contributed to the FH535-induced inhibitory effect on colon cancer cell proliferation. As mechanisms for suppressing cancer cell motility, FH535 downregulated expression of matrix metalloproteinase-7 and -9, Snail and vimentin. RNA sequencing revealed that FH535 prominently altered multiple biological pathways associated with DNA replication, cell cycle and metabolism. Our study highlights the anti-cancer effect of FH535 on colon cancer and presents its potential in colon cancer treatment.
异常的Wnt/β-连环蛋白信号通路激活在人类结直肠癌（CRC）中经常被观察到，并且已成为CRC治疗的一个有前景的靶点。我们的研究旨在评估Wnt/β-连环蛋白信号通路的小分子抑制剂FH535对两种结肠癌细胞系HT29和SW480的作用。我们发现FH535显著抑制结肠癌细胞增殖并诱导细胞周期停滞。此外，FH535抑制结肠癌异种移植瘤的生长。伤口愈合试验和Transwell试验表明，FH535显著抑制SW480细胞的迁移和侵袭。FH535还抑制HT29细胞中癌症干细胞标志物CD24、CD44和CD133的表达。实时定量PCR和蛋白质印迹显示，使用FH535靶向Wnt/β-连环蛋白信号通路可在mRNA和蛋白质水平有效下调包括细胞周期蛋白D1和生存素在内的靶基因，这有助于FH535对结肠癌细胞增殖的抑制作用。作为抑制癌细胞运动的机制，FH535下调基质金属蛋白酶-7和-9、Snail和波形蛋白的表达。RNA测序显示，FH535显著改变了与DNA复制、细胞周期和代谢相关的多种生物学途径。我们的研究突出了FH535对结肠癌的抗癌作用，并展示了其在结肠癌治疗中的潜力。
