ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma.
ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma.
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DOI：
10.1038/s41388-018-0543-2
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Eberhart CG
中科院分区：
文献类型：
--
作者：
Asnaghi L;White DT;Key N;Choi J;Mahale A;Alkatan H;Edward DP;Elkhamary SM;Al-Mesfer S;Maktabi A;Hurtado CG;Lee GY;Carcaboso AM;Mumm JS;Safieh LA;Eberhart CG
视网膜母细胞瘤是儿童最常见的眼内癌。虽然原发肿瘤通常可以通过局部或全身化疗来治疗，但转移性扩散通常对治疗具有耐药性，并且仍然是世界上许多地区儿童癌症死亡的主要原因。为了在侵袭性肿瘤中发现新的治疗靶点，我们对5个侵袭视神经的快速冷冻视网膜母细胞瘤和5个未侵袭视神经的视网膜母细胞瘤的RNA转录物进行了测序。TGF-β家族I型受体ACVR1C/ALK7 mRNA水平在侵袭性视网膜母细胞瘤中升高3倍，而ACVR1C信号的负调节因子DACT2和LEFTY2在大多数侵袭性肿瘤中下调。与体外非侵袭性细胞相比，侵袭性WERI Rb1和Y79细胞中的ACVR1C mRNA也增加了2至3倍。ACVR1C受体及其配体（Nodal、Activin A/B和GDF3）的转录本在6种视网膜母细胞瘤细胞系中表达，并且在所有这些细胞系中都存在下游SMAD2信号传导的证据。使用SB505124药理抑制ACVR1C信号，或使用shRNA基因下调该受体可有效抑制侵袭、生长、存活，并降低间充质标记物ZEB1和Snail的蛋白水平。通过敲除SMAD2，而不是SMAD3，可以重现对侵袭、生长和增殖的抑制作用。最后，在原位斑马鱼视网膜母细胞瘤模型中，与DMSO相比，用3 μM的SB505124处理幼虫，肿瘤扩散减少55% （p=0.0026）。同样，与打乱shRNA对照相比，在注射肿瘤细胞中使用shRNA敲低ACVR1C也导致斑马鱼眼部肿瘤传播减少54% （p=0.0005）。我们的数据支持ACVR1C/SMAD2通路在促进视网膜母细胞瘤的侵袭和生长中的作用。
Retinoblastoma is the most common intraocular cancer in children. While the primary tumor can often be treated by local or systemic chemotherapy, metastatic dissemination is generally resistant to therapy and remains a leading cause of pediatric cancer death in much of the world. In order to identify new therapeutic targets in aggressive tumors, we sequenced RNA transcripts in five snap frozen retinoblastomas which invaded the optic nerve and five which did not. A three-fold increase was noted in mRNA levels of ACVR1C/ALK7, a type I receptor of the TGF-β family, in invasive retinoblastomas, while downregulation of DACT2 and LEFTY2, negative modulators of the ACVR1C signaling, was observed in most invasive tumors. A two- to three-fold increase in ACVR1C mRNA was also found in invasive WERI Rb1 and Y79 cells as compared to non-invasive cells in vitro. Transcripts of ACVR1C receptor and its ligands (Nodal, Activin A/B, and GDF3) were expressed in six retinoblastoma lines, and evidence of downstream SMAD2 signaling was present in all these lines. Pharmacological inhibition of ACVR1C signaling using SB505124, or genetic downregulation of the receptor using shRNA potently suppressed invasion, growth, survival, and reduced the protein levels of the mesenchymal markers ZEB1 and Snail. The inhibitory effects on invasion, growth, and proliferation were recapitulated by knocking down SMAD2, but not SMAD3. Finally, in an orthotopic zebrafish model of retinoblastoma, a 55% decrease in tumor spread was noted (p=0.0026) when larvae were treated with 3 μM of SB505124, as compared to DMSO. Similarly, knockdown of ACVR1C in injected tumor cells using shRNA also resulted in a 54% reduction in tumor dissemination in the zebrafish eye as compared to scrambled shRNA control (p=0.0005). Our data support a role for the ACVR1C/SMAD2 pathway in promoting invasion and growth of retinoblastoma.
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