TSPAN1 promotes autophagy flux and mediates cooperation between WNT-CTNNB1 signaling and autophagy via the MIR454-FAM83A-TSPAN1 axis in pancreatic cancer
TSPAN1 promotes autophagy flux and mediates cooperation between WNT-CTNNB1 signaling and autophagy via the MIR454-FAM83A-TSPAN1 axis in pancreatic cancer
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TSPAN1 在胰腺癌中通过 MIR454-FAM83A-TSPAN1 轴促进自噬通量并介导 WNT-CTNNB1 信号传导与自噬之间的合作
DOI：
10.1080/15548627.2020.1826689
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发表时间：
2020-10-23
期刊：
影响因子：
13.3
通讯作者：
Tang, Jingfeng
中科院分区：
文献类型：
--
作者：
Zhou, Cefan;Liang, Yanyan;Tang, Jingfeng
胰腺癌是最具侵袭性的肿瘤之一，临床预后差，治疗效果弱。因此，在胰腺癌中发现新的治疗靶点具有很强的动力。在本研究中，我们首先在体外和体内证明了TSPAN1在胰腺癌中表达上调，并且TSPAN1的缺失降低了胰腺癌细胞的增殖。胰腺癌患者总生存率较差与TSPAN1表达相关。此外，我们证明了TSPAN1是巨噬/自噬的一种新的正调节因子，其特征是降低LC3-II和SQSTM1/p62的表达，抑制GFP-LC3的小点形成和自噬空泡。我们还证明了tspan1突变在斑马鱼模型中破坏了自噬。此外，我们发现TSPAN1通过两个保守的LIR基序直接结合LC3促进自噬成熟。TSPAN1的LIR基序突变导致诱导自噬和促进胰腺癌增殖的能力丧失。其次，我们在TSPAN1基因的启动子区域发现了两个保守的TCF/LEF结合元件，并通过荧光素酶活性和ChIP实验进一步验证了这一点。此外，FAM83A通过典型的WNT-CTNNB1信号通路上调TSPAN1。我们进一步证明，TSPAN1和FAM83A都是MIR454 （microRNA 454）的直接靶点。此外，我们在体外和体内揭示了MIR454-FAM83A-TSPAN1在胰腺癌细胞增殖中的作用。我们的研究结果表明，MIR454-FAM83A-TSPAN1轴的组成部分可能是胰腺癌有价值的预后标志物或治疗靶点。
Pancreatic cancer is one of the most aggressive tumors associated with a poor clinical prognosis, weakly effective therapeutic options. Therefore, there is a strong impetus to discover new therapeutic targets in pancreatic cancer. In the present study, we first demonstrated that TSPAN1 is upregulated in pancreatic cancer and that TSPAN1 depletion decreases pancreatic cancer cell proliferation in vitro and in vivo. TSPAN1 expression was correlated with poor overall survival of pancreatic cancer patients. Moreover, we demonstrated that TSPAN1 is a novel positive regulator of macroautophagy/autophagy characterized by decreased LC3-II and SQSTM1/p62 expressions, inhibited puncta formation of GFP-LC3 and autophagic vacuoles. We also demonstrated that tspan1 mutation impaired autophagy in the zebrafish model. Furthermore, we showed that TSPAN1 promoted autophagy maturation via direct binding to LC3 by two conserved LIR motifs. Mutations in the LIR motifs of TSPAN1 resulted in a loss of the ability to induce autophagy and promote pancreatic cancer proliferation. Second, we discovered two conservative TCF/LEF binding elements present in the promoter region of the TSPAN1 gene, which was further verified through luciferase activity and ChIP assays. Furthermore, TSPAN1 was upregulated by FAM83A through the canonical WNT-CTNNB1 signaling pathway. We further demonstrated that both TSPAN1 and FAM83A are both direct targets of MIR454 (microRNA 454). Additionally, we revealed the role of MIR454-FAM83A-TSPAN1 in the proliferation of pancreatic cancer cells in vitro and in vivo. Our findings suggest that components of the MIR454-FAM83A-TSPAN1 axis may be valuable prognosis markers or therapeutic targets for pancreatic cancer.