Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Oncogene. 2010 Jan 7;29(1):34-44. doi: 10.1038/onc.2009.305. Epub 2009 Oct 5.
Tyrosine kinase receptors represent targets of great interest for cancer therapy. Here we show, for the first time, the importance of the orphan tyrosine kinase receptor, ROR2, in melanoma progression. Using melanoma tissue microarrays, we show that ROR2 is expressed predominantly in metastatic melanoma. As ROR2 has been shown to specifically interact with the non-canonical Wnt ligand, Wnt5A, this corroborates our earlier data implicating Wnt5A as a mediator of melanoma metastasis. We show here that increases in Wnt5A cause increases in ROR2 expression, as well as the PKC-dependent, clathrin-mediated internalization of ROR2. WNT5A knockdown by siRNA decreases ROR2 expression, but silencing of ROR2 has no effect on WNT5A levels. ROR2 knockdown does, however, result in a decrease in signaling downstream of Wnt5A. Using in vitro and in vivo metastasis assays, we show that ROR2 is necessary for the Wnt5A-mediated metastasis of melanoma cells. These data imply that ROR2 may represent a novel target for melanoma therapy.
酪氨酸激酶受体是癌症治疗的重要靶点。在这里，我们首次展示了孤儿酪氨酸激酶受体 ROR2 在黑色素瘤进展中的重要性。我们使用黑色素瘤组织微阵列表明 ROR2 主要在转移性黑色素瘤中表达。由于 ROR2 已被证明与非典型 Wnt 配体 Wnt5A 特异性相互作用，这证实了我们之前的数据表明 Wnt5A 是黑色素瘤转移的介质。我们在这里表明，Wnt5A 的增加导致 ROR2 表达的增加，以及 ROR2 的 PKC 依赖性、网格蛋白介导的内化。用 siRNA 敲低 WNT5A 可降低 ROR2 表达，但沉默 ROR2 对 WNT5A 水平没有影响。然而，ROR2 的敲低确实导致 Wnt5A 下游信号的减少。使用体外和体内转移测定，我们表明 ROR2 是 Wnt5A 介导的黑色素瘤细胞转移所必需的。这些数据表明 ROR2 可能代表一种新的黑色素瘤治疗靶点。
