WNT5A-ROR2 is induced by inflammatory mediators and is involved in the migration of human ovarian cancer cell line SKOV-3.
WNT5A-ROR2 is induced by inflammatory mediators and is involved in the migration of human ovarian cancer cell line SKOV-3.
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DOI：
10.1186/s11658-016-0003-3
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发表时间：
2016
影响因子：
8.3
通讯作者：
Zarnani AH
中科院分区：
文献类型：
--
作者：
Arabzadeh S;Hossein G;Salehi-Dulabi Z;Zarnani AH
Wnt5A是非转化Wnt蛋白家族的一员，与炎症过程有关。它在卵巢癌细胞中也高度表达。ROR2是受体酪氨酸激酶ror家族的成员，作为Wnt5A的受体或共受体。Wnt5A-ROR2信号通路在多种类型肿瘤细胞的迁移和侵袭中发挥重要作用，并影响其细胞极性。我们研究了炎症介质对Wnt5A-ROR2的调节及其在人卵巢癌细胞系SKOV-3迁移中的作用。将LPS（脂多糖）、LTA（脂质胆酸）和重组人IL-6单独或联合STAT3抑制剂（S1155S31-201）或NF-kB抑制剂（BAY11-7082）处理SKOV-3细胞4、8、12、24和48 h，在基因和蛋白水平上检测Wnt5A和ROR2的表达水平。在没有或存在人抗ror2抗体的情况下，用针对Wnt5A的特异性siRNA转染细胞，并使用transwells评估细胞迁移。在STAT3或NF-kB抑制剂的存在下，Wnt5A的表达明显下调。LTA或IL-6刺激细胞8小时后，Wnt5A水平显著升高（分别升高5倍和3倍）。LPS、LTA或IL-6处理显著增加ROR2表达（48 h后2倍）。在STAT3抑制剂存在的情况下，LPS或lta诱导的Wnt5A或ROR2表达被消除（p < 0.001）。STAT3和NF-kB抑制剂均可抑制il -6诱导的Wnt5A表达（p < 0.001）。虽然不显著，但当使用STAT3抑制剂时，il -6诱导的ROR2表达略有下降。此外，siRNA wnt5a转染的细胞在存在抗人ROR2抗体的情况下，细胞迁移减少了80% （p < 0.001）。本研究首次揭示炎症介质通过NF-kB和STAT3转录因子调控Wnt5A和ROR2，并可能在卵巢癌细胞迁移中发挥作用。本文描述的结果为Wnt5A-ROR2复合物在卵巢癌炎症进展中的作用提供了新的见解。
Wnt5A, which is a member of the non-transforming Wnt protein family, is implicated in inflammatory processes. It is also highly expressed by ovarian cancer cells. ROR2, which is a member of the Ror-family of receptor tyrosine kinases, acts as a receptor or co-receptor for Wnt5A. The Wnt5A–ROR2 signaling pathway plays essential roles in the migration and invasion of several types of tumor cell and influences their cell polarity. We investigated the modulation of Wnt5A–ROR2 by inflammatory mediators and its involvement in the migration of the human ovarian cancer cell line SKOV-3. SKOV-3 cells were treated with LPS (lipopolysaccharide), LTA (lipoteichoic acid) and recombinant human IL-6 alone or in combination with STAT3 inhibitor (S1155S31-201) or NF-kB inhibitor (BAY11-7082) for 4, 8, 12, 24 and 48 h. The Wnt5A and ROR2 expression levels were determined at the gene and protein levels. Cells were transfected with specific siRNA against Wnt5A in the absence or presence of human anti-ROR2 antibody and cell migration was assessed using transwells. There was a strong downregulation of Wnt5A expression in the presence of STAT3 or NF-kB inhibitors. Cell stimulation with LTA or IL-6 for 8 h led to significantly increased levels of Wnt5A (5- and 3-fold higher, respectively). LPS, LTA or IL-6 treatment significantly increased ROR2 expression (2-fold after 48 h). LPS- or LTA-induced Wnt5A or ROR2 expression was abrogated in the presence of STAT3 inhibitor (p < 0.001). IL-6-induced Wnt5A expression was abrogated by both STAT3 and NF-kB inhibitors (p < 0.001). Although not significant, IL-6-induced ROR2 expression showed a modest decrease when STAT3 inhibitor was used. Moreover, cell migration was decreased by 80 % in siRNA Wnt5A-transfected cells in the presence of anti-human ROR2 antibody (p < 0.001). This study revealed for the first time that inflammatory mediators modulate Wnt5A and ROR2 through NF-kB and STAT3 transcription factors and this may play a role in ovarian cancer cell migration. The results described here provide new insight into the role of the Wnt5A–ROR2 complex in ovarian cancer progression in relation to inflammation.