p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis.
p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis.
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p62/SQSTM1与波形蛋白相互作用增强乳腺癌转移
DOI：
10.1093/carcin/bgx099
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发表时间：
2017-10-26
期刊：
影响因子：
4.7
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Li SS;Xu LZ;Zhou W;Yao S;Wang CL;Xia JL;Wang HF;Kamran M;Xue XY;Dong L;Wang J;Ding XD;Bella L;Bugeon L;Xu J;Zheng FM;Dallman MJ;Lam EWF;Liu Q
p62通过其与波形蛋白的相互作用而起到肿瘤转移促进剂的作用。这一发现可能有助于开发新的乳腺癌转移治疗的分子治疗策略。信号转导衔接子p62在许多癌症类型中经常过表达。在这里，我们发现p62表达在转移性乳腺癌中升高，并且其过表达与减少的无转移和无复发生存时间相关。对乳腺癌细胞系中p62表达的分析表明，p62高表达与乳腺癌的侵袭表型相关。事实上，在体外微流控模型中，沉默p62表达减弱了高转移性细胞的侵袭表型，而过表达p62促进了非转移性细胞的侵袭。此外，在三维培养系统中生长的p62缺失的MDA-MB-231细胞表现出侵袭性突起的丧失。同样，基因切除p62抑制乳腺癌转移在斑马鱼胚胎和免疫缺陷小鼠模型，以及降低体内致瘤性。为了探讨p62促进乳腺癌侵袭的分子机制，我们进行了免疫共沉淀-质谱分析，并显示p62与波形蛋白相互作用，波形蛋白介导p62促进乳腺癌侵袭的功能。在乳腺癌细胞中，波形蛋白表达在p62抑制后下调，在p62过表达时上调。临床乳腺癌标本的线性回归分析显示p62和vimentin蛋白表达呈正相关。总之，我们的研究结果提供了强有力的证据表明，p62作为一个肿瘤转移促进剂结合波形蛋白和促进其表达。这一发现可能有助于开发新的乳腺癌转移治疗的分子治疗策略。
p62 functions as a tumour metastasis promoter through its interaction with vimentin. This finding might help to develop novel molecular therapeutic strategies for breast cancer metastasis treatment. The signalling adaptor p62 is frequently overexpressed in numerous cancer types. Here, we found that p62 expression was elevated in metastatic breast cancer and its overexpression correlated with reduced metastasis- and relapse-free survival times. Analysis of p62 expression in breast cancer cell lines demonstrated that high p62 expression was associated with the invasive phenotypes of breast cancer. Indeed, silencing p62 expression attenuated the invasive phenotypes of highly metastatic cells, whereas overexpressing p62 promoted the invasion of non-metastatic cells in in vitro microfluidic model. Moreover, MDA-MB-231 cells with p62 depletion which were grown in a three-dimensional culture system exhibited a loss of invasive protrusions. Consistently, genetic ablation of p62 suppressed breast cancer metastasis in both zebrafish embryo and immunodeficient mouse models, as well as decreased tumourigenicity in vivo. To explore the molecular mechanism by which p62 promotes breast cancer invasion, we performed a co-immunoprecipitation–mass spectrometry analysis and revealed that p62 interacted with vimentin, which mediated the function of p62 in promoting breast cancer invasion. Vimentin protein expression was downregulated upon p62 suppression and upregulated with p62 overexpression in breast cancer cells. Linear regression analysis of clinical breast cancer specimens showed a positive correlation between p62 and vimentin protein expression. Together, our findings provide strong evidence that p62 functions as a tumour metastasis promoter by binding vimentin and promoting its expression. This finding might help to develop novel molecular therapeutic strategies for breast cancer metastasis treatment.
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影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
50.3
作者：
Duran, Angeles;Linares, Juan F.;Moscat, Jorge
通讯作者：
Moscat, Jorge
影响因子：
4.8
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki