PAUF/ZG16B promotes colorectal cancer progression through alterations of the mitotic functions and the Wnt/β-catenin pathway
PAUF/ZG16B promotes colorectal cancer progression through alterations of the mitotic functions and the Wnt/β-catenin pathway
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DOI：
10.1093/carcin/bgz093
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发表时间：
2020-02-01
期刊：
影响因子：
4.7
通讯作者：
Ignacio Casal, J.
中科院分区：
文献类型：
--
作者：
Escudero-Paniagua, Beatriz;Bartolome, Ruben A.;Ignacio Casal, J.
胰腺癌上调因子（PAUF），也称为ZG16B，之前在转移性结直肠癌细胞的分泌组中发现。在这里，我们证明了 PAUF 在细胞内水平的存在及其对癌症进展的多重影响。在结直肠癌的早期阶段观察到 PAUF 表达最初下降，随后在转移部位增加。 PAUF 位于不同的细胞区室：膜相关囊泡、内体、微管相关囊泡、细胞生长锥和细胞核。两种结直肠癌细胞系中 PAUF 缺失导致细胞表型和细胞周期发生严重改变，包括四倍体、广泛的基因组改变、微核和细胞凋亡增加。使用不同蛋白质组学方法对 PAUF 相互作用组进行详尽分析，揭示了细胞周期、有丝分裂检查点、Wnt 通路和细胞内转运的多个组成部分的存在。在相互作用的蛋白质中，我们发现了 ZW10，一种兼职蛋白质，具有膜运输和有丝分裂的双重功能。此外，PAUF 沉默与 APC 丢失和 β-连环蛋白核表达增加有关。总而言之，我们的结果表明，PAUF 耗尽会增加结直肠癌细胞中的非整倍性、促进细胞凋亡并激活 Wnt/β-连环蛋白途径，从而促进癌症进展。总之，PAUF 是一种多功能蛋白，根据细胞外或细胞内的表达在癌症进展中发挥不同的作用，这表明 PAUF 对结直肠癌具有治疗价值。
Pancreatic adenocarcinoma upregulated factor (PAUF), also known as ZG16B, was previously found in the secretome of metastatic colorectal cancer cells. Here, we demonstrated the presence of PAUF at the intracellular level and its multiple effects on cancer progression. An initial decline of PAUF expression was observed at early stages of colorectal cancer followed by an increase at the metastatic site. PAUF was located at different cellular compartments: membrane-associated vesicles, endosomes, microtubule-associated vesicles, cell growth cones and the cell nucleus. PAUF loss in two colorectal cancer cell lines caused severe alterations in the cell phenotype and cell cycle, including tetraploidy, extensive genomic alterations, micronuclei and increased apoptosis. An exhaustive analysis of the PAUF interactome using different proteomic approaches revealed the presence of multiple components of the cell cycle, mitotic checkpoint, Wnt pathway and intracellular transport. Among the interacting proteins we found ZW10, a moonlighting protein with a dual function in membrane trafficking and mitosis. In addition, PAUF silencing was associated to APC loss and increased beta-catenin nuclear expression. Altogether, our results suggest that PAUF depletion increases aneuploidy, promotes apoptosis and activates the Wnt/beta-catenin pathway in colorectal cancer cells facilitating cancer progression. In summary, PAUF behaves as a multifunctional protein, with different roles in cancer progression according to the extra- or intracellular expression, suggesting a therapeutic value for colorectal cancer.