Hyaluronan synthase 2 (HAS2) regulates cell phenotype and invadopodia formation in luminal-like breast cancer cells
Hyaluronan synthase 2 (HAS2) regulates cell phenotype and invadopodia formation in luminal-like breast cancer cells
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DOI：
10.1007/s11010-021-04165-7
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发表时间：
2021-05
影响因子：
4.3
通讯作者：
Yumeng Sheng;M. Cao;Yi-wen Liu;Yi-qing He;Guoliang Zhang;Yan Du;F. Gao;Cuixia Yang
中科院分区：
文献类型：
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作者：
Yumeng Sheng;M. Cao;Yi-wen Liu;Yi-qing He;Guoliang Zhang;Yan Du;F. Gao;Cuixia Yang
虽然腔乳腺癌细胞通常是高度粘附的上皮细胞，并且具有低侵袭能力，但许多最终发展为转移。到目前为止，潜在的机制仍然不清楚。在这项工作中，我们发现透明质酸合成酶2（HAS 2）的水平与乳腺癌细胞的恶性表型呈正相关。值得注意的是，HAS 2表达的增加促进了管腔型乳腺癌细胞的体外侵袭和迁移能力，随后是E-钙粘蛋白、β-连环蛋白和ZO-1表达的减少，以及N-钙粘蛋白和波形蛋白表达的增加。此外，HAS 2的过表达促进而HAS 2的敲低阻碍了侵袭伪足的形成，其随后增加或减少了皮质素、Tks 5和金属蛋白酶（MMPs）的活化。通过抑制HAS 2或破坏HA来阻止这些侵袭足相关蛋白的激活，这反过来又减弱了运动性和侵袭性的增加。此外，体内研究表明，HAS 2通过驱动原位移植有管腔乳腺癌细胞的SCID小鼠中向侵袭性细胞表型的转变而增加肿瘤生长和肺转移的速率。总的来说，我们的研究结果表明，HAS 2通过诱导转化为侵袭性表型和通过增强管腔乳腺癌细胞中的侵袭伪足形成来促进细胞侵袭，这可能为其在肿瘤转移中的作用提供新的机制见解。
Although luminal breast cancer cells are typically highly cohesive epithelial cells and have low invasive ability, many eventually develop metastasis. Until now, the underlying mechanisms remain obscure. In this work, we showed that the level of hyaluronic acid synthase 2 (HAS2) was positively correlated with the malignant phenotype of breast cancer cells. Notably, the increased expression of HAS2 promoted the invasive and migratory abilities of luminal breast cancer cells in vitro, followed by a reduced expression of E-cadherin, β-catenin, and ZO-1, and an elevated expression of N-cadherin and vimentin. Furthermore, overexpression of HAS2 promoted while knockdown of HAS2 impeded invadopodia formation, which subsequently increased or decreased the activation of cortactin, Tks5, and metalloproteinases (MMPs). Activation of these invadopodia-related proteins was prevented by inhibition of HAS2 or disruption of HA, which in turn attenuated the increased motility and invasiveness. Further, in vivo study showed that, HAS2 increased tumor growth and the rate of lung metastasis via driving transition to an invasive cell phenotype in SCID mice that were orthotopically transplanted with luminal breast cancer cells. Collectively, our results showed that HAS2 promoted cell invasion by inducing transition to an invasive phenotype and by enhancing invadopodia formation in luminal breast cancer cells, which may provide new mechanistic insights into its role in tumor metastasis.