WNT5A augments cell invasiveness by inducing CXCL8 in HER2-positive breast cancer cells
WNT5A augments cell invasiveness by inducing CXCL8 in HER2-positive breast cancer cells
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DOI：
10.1016/j.cyto.2020.155213
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发表时间：
2020-11-01
期刊：
影响因子：
3.8
通讯作者：
Lee, Jeong Eon
中科院分区：
文献类型：
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作者：
Kim, Sangmin;You, Daeun;Lee, Jeong Eon
WNT5A在包括乳腺癌在内的多种癌症中异常升高，对预后有不良影响。然而，WNT5A在HER2阳性（HER2+）乳腺癌中的生物学功能尚不完全清楚。利用公开的临床数据，我们分析了无病生存期（DFS）和无远处转移生存期（DMFS）。本研究发现，异常WNT5A诱导与HER2+乳腺癌预后不良相关。泛her抑制剂neratinib也能降低WNT5A的表达，但曲妥珠单抗不能。此外，WNT5A增强了HER2+乳腺癌细胞的侵袭性。为了寻找wnt5a诱导的元静态相关因子，我们做了人细胞因子阵列。WNT5A使GM-CSF和CXCL8水平显著升高。CXCL8也加速了HCC1954乳腺癌细胞的细胞侵袭。MEK抑制剂比尼米替尼显著降低WNT5A诱导的CXCL8表达。最后，我们研究了CXCR2拮抗剂SB225002的作用，以验证CXCL8在wnt5a诱导的细胞侵袭中的相关性。正如预期的那样，我们发现SB225002完全抑制了wnt5a诱导的细胞侵袭。综上所述，我们已经证明WNT5A通过诱导CXCL8直接介导细胞侵袭，并最终影响HER2+乳腺癌的生存率。
WNT5A is abnormally increased in a variety of cancers including breast cancer and has an adverse effect on the prognosis. However, the biological function of WNT5A is not fully known in HER2-positive (HER2+) breast cancer. Using public clinical data, we analyzed disease-free survival (DFS) and distant metastasis-free survival (DMFS). Here, we found that abnormal WNT5A induction is a correlation with the poor prognosis of HER2+ breast cancer. WNT5A expression was also decreased by pan-HER inhibitor neratinib but not by trastuzumab. In addition, WNT5A augmented cell invasiveness of HER2+ breast-cancer cells. To find WNT5A-induced meta- static-related factors, we did a human cytokine array. The levels of GM-CSF and CXCL8 were significantly in- creased by WNT5A. CXCL8 also accelerated cell invasiveness in HCC1954 breast-cancer cells. The expression of CXCL8 induced by WNT5A has been significantly reduced by MEK inhibitor, binimetinib. Finally, we studied the effect of CXCR2 antagonist, SB225002, to verify the relevance of CXCL8 in WNT5A-induced cell invasion. As expected, we found that WNT5A-induced cell invasion is completely inhibited by SB225002. Taken together, we have demonstrated that WNT5A directly mediates cell invasion through the induction of CXCL8 and ultimately affects the survival rate of HER2+ breast cancer.