Wnt9A Induction Linked to Suppression of Human Colorectal Cancer Cell Proliferation.
Wnt9A Induction Linked to Suppression of Human Colorectal Cancer Cell Proliferation.
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DOI：
10.3390/ijms17040495
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发表时间：
2016-04-02
影响因子：
5.6
通讯作者：
Braun DP
中科院分区：
文献类型：
--
作者：
Ali I;Medegan B;Braun DP
大多数恶性组织中 Wnt 信号传导的研究都集中在经典 Wnt 通路 (CWP)，因为它在刺激细胞增殖中发挥作用。非经典 Wnt 通路 (NCWP) 在 Wnt 信号传导失调的组织中的作用尚不完全清楚。了解 NCWP 的作用非常重要，因为这些相反的途径协同作用以维持健康组织的稳态。我们的初步研究表明，LiCl 抑制结直肠癌 (CRC) 来源的原代细胞的增殖。由于 LiCl 刺激正常组织中的细胞增殖，而 NCWP 会抑制细胞增殖，因此本研究旨在研究 NCWP 成分对 LiCl 介导效应的影响。 LiCl 介导的 CRC 细胞增殖抑制 (p < 0.001) 和细胞凋亡增加 (p < 0.01) 与 NCWP 配体 Wnt9A 表达增加 23 倍 (p < 0.025) 一致。 LiCl 还抑制 β-连环蛋白 mRNA (p < 0.03)、总 β-连环蛋白 (p < 0.025) 和 β-连环蛋白的活性形式。 IWP-2 和 Wnt9A 抗体可部分逆转 LiCl 介导的 CRC 细胞增殖抑制。重组 Wnt9A 蛋白通过抑制 β-连环蛋白 (p < 0.001)、抑制增殖 (p < 0.001) 和增加细胞凋亡 (p < 0.03) 来模拟 LiCl 效应。这是第一项研究证明 NCWP 配体 Wnt9A 的诱导是 LiCl 介导的 CRC 细胞增殖抑制机制的一部分。
Most studies of Wnt signaling in malignant tissues have focused on the canonical Wnt pathway (CWP) due to its role in stimulating cellular proliferation. The role of the non-canonical Wnt pathway (NCWP) in tissues with dysregulated Wnt signaling is not fully understood. Understanding NCWP’s role is important since these opposing pathways act in concert to maintain homeostasis in healthy tissues. Our preliminary studies demonstrated that LiCl inhibited proliferation of primary cells derived from colorectal cancer (CRC). Since LiCl stimulates cell proliferation in normal tissues and NCWP suppresses it, the present study was designed to investigate the impact of NCWP components in LiCl-mediated effects. LiCl-mediated inhibition of CRC cell proliferation (p < 0.001) and increased apoptosis (p < 0.01) coincided with 23-fold increase (p < 0.025) in the expression of the NCWP ligand, Wnt9A. LiCl also suppressed β-catenin mRNA (p < 0.03), total β-catenin protein (p < 0.025) and the active form of β-catenin. LiCl-mediated inhibition of CRC cell proliferation was partially reversed by IWP-2, and Wnt9A antibody. Recombinant Wnt9A protein emulated LiCl effects by suppressing β-catenin protein (p < 0.001), inhibiting proliferation (p < 0.001) and increasing apoptosis (p < 0.03). This is the first study to demonstrate induction of a NCWP ligand, Wnt9A as part of a mechanism for LiCl-mediated suppression of CRC cell proliferation.