Down-regulation of SLC35C1 induces colon cancer through over-activating Wnt pathway
Down-regulation of SLC35C1 induces colon cancer through over-activating Wnt pathway
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DOI：
10.1111/jcmm.14969
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发表时间：
2020-01-21
影响因子：
5.3
通讯作者：
Liu, Heli
中科院分区：
文献类型：
--
作者：
Deng, Minzi;Chen, Zhihong;Liu, Heli
经典Wnt信号通路是参与细胞增殖的关键通路。众所周知，它在结直肠癌的发生和发展过程中发挥着核心作用。然而，规范 Wnt 通路如何微调的确切分子机制仍然难以捉摸。我们发现 SLC35C1（一种 GDP-岩藻糖转运蛋白）对 Wnt 信号通路产生负调节。我们通过免疫组织化学图像和 TCGA 数据表明，所有结肠癌中的 SLC35C1 均减少，而 β-连环蛋白则增加。通过实时 PCR，在 3 期和 4 期结直肠癌组织中也检测到 SLC35C1 的下调。此外，通过cBioPortal分析TCGA数据库发现SLC35C1 mRNA水平与β-catenin表达呈负相关。减少的SLC35C1显着促进HEK293细胞的细胞增殖和集落形成。同时，在 HEK293 细胞中，沉默 SLC35C1 会激活经典 Wnt 通路，而过表达 SLC35C1 会抑制它。一致地，HEK293细胞中SLC35C1的减少也提高了Wnt靶基因C-myc、Axin2和Cyclin D1的mRNA水平，以及Wnt3a的分泌。总之，我们确定 SLC35C1 是结肠癌 Wnt 信号通路的负调节因子。 SLC35C1 减少可能导致结直肠癌中 Wnt 信号过度激活。
The canonical Wnt signalling pathway is a critical pathway involved in the proliferation of cells. It has been well-established that it plays the central role during colorectal carcinogenesis and development. Yet the exact molecular mechanism of how the canonical Wnt pathway is fine-tuned remains elusive. We found that SLC35C1, a GDP-fucose transporter, negatively regulates the Wnt signalling pathway. We show here that SLC35C1 is reduced in all colon cancer by both immunohistochemistry images and TCGA data, whereas beta-catenin is increased. Down-regulation of SLC35C1 is also detected by real-time PCR in stage 3 and stage 4 colorectal cancer tissues. Moreover, analysing the TCGA database with cBioPortal reveals the negative correlation of SLC35C1 mRNA level to the expression of beta-catenin. Reduced SLC35C1 significantly promotes cell proliferation and colony formation of HEK293 cells. Meanwhile, in HEK293 cells silencing SLC35C1 activates canonical Wnt pathway, whereas overexpressing SLC35C1 inhibits it. Consistently, the reduction of SLC35C1 in HEK293 cells also elevated the mRNA level of Wnt target genes C-myc, Axin2 and Cyclin D1, as well as the secretion of Wnt3a. In conclusion, we identified SLC35C1 as a negative regulator of the Wnt signalling pathway in colon cancer. Decreased SLC35C1 may cause over-activation of Wnt signalling in colorectal cancer.