ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation.
ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation.
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DOI：
10.1186/s12929-021-00776-w
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发表时间：
2021-11-13
影响因子：
11
通讯作者：
Lopez-Bergami P
中科院分区：
文献类型：
--
作者：
Castro MV;Barbero GA;Villanueva MB;Grumolato L;Nsengimana J;Newton-Bishop J;Illescas E;Quezada MJ;Lopez-Bergami P
受体酪氨酸激酶样孤儿受体2（ROR 2）是在癌症中异常表达的Wnt 5a受体，其显示在不同肿瘤类型中抑制或促进致癌作用。我们的目标是研究ROR 2在黑色素瘤中的作用。采用功能获得和功能丧失策略研究ROR 2在黑色素瘤中的生物学功能。使用增殖测定、流式细胞术和蛋白质印迹法来评价细胞增殖以及细胞周期和增殖标记物的表达水平的变化。在异种移植实验中评估ROR 2在肿瘤生长中的作用，随后进行肿瘤的免疫组织化学分析。通过分析来自利兹黑色素瘤队列的临床数据来评估ROR 2在黑色素瘤患者中的作用。与先前的研究结果描述ROR 2作为黑色素瘤中的致癌基因不同，我们描述ROR 2通过抑制细胞周期进展和黑色素瘤细胞增殖来防止肿瘤生长。ROR 2的作用是通过抑制Akt磷酸化和活性介导的，Akt磷酸化和活性反过来调节主要细胞周期调节因子的表达、磷酸化和定位，包括细胞周期蛋白（A、B、D和E）、CDK 1、CDK 4、RB、p21和p27。异种移植实验表明，ROR 2还减少体内增殖，导致肿瘤生长的抑制。与这些发现一致，较高的ROR 2水平有利于薄的和非溃疡的原发性黑色素瘤，具有降低的有丝分裂率和更好的预后。我们的结论是ROR 2的表达减缓了原发性肿瘤的生长，并有助于延长黑色素瘤的生存期。我们的研究结果表明，ROR 2具有比最初描述的复杂得多的作用。在线版本包含补充材料，可通过10.1186/s12929-021-00776-w获得。
Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described. The online version contains supplementary material available at 10.1186/s12929-021-00776-w.
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影响因子：
5.8
作者：
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