Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.
Ohio State Biochemistry Program.
JCI Insight. 2017 Mar 9;2(5):e90651. doi: 10.1172/jci.insight.90651.
Metastasis suppressors are key regulators of tumor growth, invasion, and metastases. Loss of metastasis suppressors has been associated with aggressive tumor behaviors and metastatic progression. We previously showed that regulator of calcineurin 1, isoform 4 (RCAN1-4) was upregulated by the KiSS1 metastatic suppression pathway and could inhibit cell motility when overexpressed in cancer cells. To test the effects of endogenous RCAN1-4 loss on thyroid cancer in vivo, we developed RCAN1-4 knockdown stable cells. Subcutaneous xenograft models demonstrated that RCAN1-4 knockdown promotes tumor growth. Intravenous metastasis models demonstrated that RCAN1-4 loss promotes tumor metastases to the lungs and their subsequent growth. Finally, stable induction of RCAN1-4 expression reduced thyroid cancer cell growth and invasion. Microarray analysis predicted that nuclear factor, erythroid 2-like 3 (NFE2L3) was a pivotal downstream effector of RCAN1-4. NFE2L3 overexpression was shown to be necessary for RCAN1-4-mediated enhanced growth and invasiveness and NEF2L3 overexpression independently increased cell invasion. In human samples, NFE2L3 was overexpressed in TCGA thyroid cancer samples versus normal tissues and NFE2L3 overexpression was demonstrated in distant metastasis samples from thyroid cancer patients. In conclusion, we provide the first evidence to our knowledge that RCAN1-4 is a growth and metastasis suppressor in vivo and that it functions in part through NFE2L3.
转移抑制因子是肿瘤生长、侵袭和转移的关键调节因子。转移抑制因子的丧失与侵袭性肿瘤行为和转移进展有关。我们之前的研究表明，钙调神经磷酸酶 1 调节因子 1，异构体 4（RCAN1-4）受 KiSS1 转移抑制途径上调，当在癌细胞中过表达时可以抑制细胞迁移。为了在体内测试内源性 RCAN1-4 缺失对甲状腺癌的影响，我们开发了 RCAN1-4 敲低稳定细胞。皮下异种移植模型表明，RCAN1-4 敲低促进肿瘤生长。静脉转移模型表明，RCAN1-4 缺失促进肿瘤转移到肺部及其随后的生长。最后，RCAN1-4 表达的稳定诱导降低了甲状腺癌细胞的生长和侵袭性。微阵列分析预测核因子，红细胞 2 样 3（NFE2L3）是 RCAN1-4 的关键下游效应物。已经表明，NFE2L3 的过表达对于 RCAN1-4 介导的增强生长和侵袭性是必需的，并且 NFE2L3 的过表达独立地增加了细胞侵袭性。在人类样本中，TCGA 甲状腺癌样本与正常组织相比，NFE2L3 过表达，并且在甲状腺癌患者的远处转移样本中证实了 NFE2L3 过表达。总之，我们提供了第一个证据，据我们所知，RCAN1-4 是体内生长和转移的抑制因子，它部分通过 NFE2L3 发挥作用。
