SMAD4-independent activation of TGF-β signaling by MUC1 in a human pancreatic cancer cell line.
SMAD4-independent activation of TGF-β signaling by MUC1 in a human pancreatic cancer cell line.
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DOI：
10.18632/oncotarget.23966
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发表时间：
2018-01-23
期刊：
影响因子：
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通讯作者：
Mukherjee P
中科院分区：
文献类型：
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作者：
Grover P;Nath S;Nye MD;Zhou R;Ahmad M;Mukherjee P
胰腺导管腺癌（PDA）的死亡率几乎与其发病率相当。转化生长因子β（TGF-β）是一种在肿瘤发展中具有双重作用的细胞因子，从肿瘤抑制因子转变为肿瘤促进因子。关于TGF-β功能在肿瘤发生过程中如何转换的知识有限。粘蛋白1（MUC 1）是一种异常糖基化的膜结合糖蛋白，在>80%的PDA病例中过表达，并与不良预后相关。在PDA中，MUC 1通过其胞质尾区（MUC 1-CT）的信号传导以及与其他致癌信号分子的相互作用促进肿瘤进展和转移。我们推测PDA中高水平的MUC 1可能是肿瘤发生过程中TGF-β功能转换的部分原因。我们报道了MUC 1在BxPC 3人PDA细胞（BxPC3.MUC1）中的过表达增强了上皮细胞向间充质细胞转化的诱导，导致对外源性TGF-β1的响应增加了侵袭性。同时，这些细胞通过下调切割的半胱天冬酶的水平来抵抗TGF-β诱导的细胞凋亡。我们发现，将MUC 1-CT中的酪氨酸突变为苯丙氨酸逆转了TGF-β诱导的侵袭性。这表明MUC 1-CT中的酪氨酸残基是TGF-β诱导的侵袭所需的。这些酪氨酸中的一些被酪氨酸激酶c-Src磷酸化。因此，用c-Src抑制剂（PP 2）处理BxPC3.MUC1细胞显著降低TGF-β诱导的侵袭性。在中国仓鼠卵巢（CHO）细胞系中证实了类似的观察结果。数据强烈表明MUC 1可以调节PDA细胞中的TGF-β功能，因此在临床试验中使用TGF-β抑制剂具有潜在的临床相关性。
Pancreatic Ductal Adenocarcinoma (PDA) has a mortality rate that nearly matches its incidence rate. Transforming Growth Factor Beta (TGF-β) is a cytokine with a dual role in tumor development switching from a tumor suppressor to a tumor promoter. There is limited knowledge of how TGF-β function switches during tumorigenesis. Mucin 1 (MUC1) is an aberrantly glycosylated, membrane-bound, glycoprotein that is overexpressed in >80% of PDA cases and is associated with poor prognosis. In PDA, MUC1 promotes tumor progression and metastasis via signaling through its cytoplasmic tail (MUC1-CT) and interacting with other oncogenic signaling molecules. We hypothesize that high levels of MUC1 in PDA may be partly responsible for the TGF-β functional switch during oncogenesis. We report that overexpression of MUC1 in BxPC3 human PDA cells (BxPC3.MUC1) enhances the induction of epithelial to mesenchymal transition leading to increased invasiveness in response to exogenous TGF-β1. Simultaneously, these cells resist TGF-β induced apoptosis by downregulating levels of cleaved caspases. We show that mutating the tyrosines in MUC1-CT to phenylalanine reverses the TGF-β induced invasiveness. This suggests that the tyrosine residues in MUC1-CT are required for TGF-β induced invasion. Some of these tyrosines are phosphorylated by the tyrosine kinase c-Src. Thus, treatment of BxPC3.MUC1 cells with a c-Src inhibitor (PP2) significantly reduces TGF-β induced invasiveness. Similar observations were confirmed in the Chinese hamster ovarian (CHO) cell line. Data strongly suggests that MUC1 may regulate TGF-β function in PDA cells and thus have potential clinical relevance in the use of TGF-β inhibitors in clinical trials.