Department of Molecular Biology Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Department of Rehabilitation Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Mol Cell Biochem. 2021 Sep;476(9):3383-3391. doi: 10.1007/s11010-021-04165-7. Epub 2021 May 5.
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.
尽管腔上皮乳腺癌细胞通常是高度有凝聚力的上皮细胞，侵袭能力较低，但许多细胞最终会发展为转移。到目前为止，其潜在的机制仍不清楚。在这项工作中，我们表明透明质酸合酶 2（HAS2）的水平与乳腺癌细胞的恶性表型呈正相关。值得注意的是，HAS2 的表达增加促进了腔上皮乳腺癌细胞在体外的侵袭和迁移能力，随后 E-钙粘蛋白、β-连环蛋白和 ZO-1 的表达降低，而 N-钙粘蛋白和波形蛋白的表达升高。此外，HAS2 的过表达促进了侵袭小窝的形成，而 HAS2 的敲低则阻碍了侵袭小窝的形成，这随后增加或减少了 cortactin、Tks5 和基质金属蛋白酶（MMPs）的激活。HAS2 的抑制或 HA 的破坏阻止了这些侵袭小窝相关蛋白的激活，从而减弱了迁移和侵袭能力的增加。此外，体内研究表明，HAS2 通过驱动腔上皮乳腺癌细胞在 SCID 小鼠中向侵袭性细胞表型的转变，从而增加肿瘤生长和肺转移的速度。总之，我们的结果表明，HAS2 通过诱导侵袭表型的转变和增强腔上皮乳腺癌细胞中的侵袭小窝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。
