College of Pharmacy, Dongguk University, Seoul, Korea.
Division of Cancer Biology, National Cancer Center, Goyang, Korea.
J Cell Physiol. 2020 Feb;235(2):1543-1555. doi: 10.1002/jcp.29073. Epub 2019 Jul 17.
Triple-negative breast cancer (TNBC) is associated with a high mortality rate, which is related to the insufficient number of appropriate biomarkers and targets. Therefore, there is an urgent need to discover appropriate biomarkers and targets for TNBC. SARNP (Hcc-1 and CIP29) is highly expressed in several cancers. It binds to UAP56, an RNA helicase component of the TREX complex in messenger RNA (mRNA) splicing and export. However, the role of SARNP in mRNA splicing and export and in the progression of breast cancer, especially of TNBC, remains unknown. Therefore, we examined the role of SARNP in mRNA splicing and export and progression of TNBC. We confirmed that SARNP binds to UAP56 and Aly and that SARNP overexpression enhances mRNA splicing, whereas its knockdown suppressed mRNA export. The SARNP overexpression induced the proliferation of MCF7 cells, whereas its knockdown induced E-cadherin expression and downregulated vimentin and N-cadherin expressions in SK-BR-3 and MDA-MB-231 cells. SARNP downregulates E-cadherin expression by interaction with pinin. Mice injected with MDA-MB-231 cells exhibited a significant reduction in tumor growth and lung metastasis compared with those injected with MDA-MB-231 cells in vivo. These findings suggested that SARNP is involved in mRNA splicing and export. SARNP maintains mesenchymal phenotype by escaping from inhibitory interaction with pinin leading to the downregulation of E-cadherin expression.
三阴性乳腺癌 (TNBC) 死亡率较高，这与适当的生物标志物和靶点数量不足有关。因此，迫切需要发现 TNBC 的合适生物标志物和靶点。SARNP (Hcc-1 和 CIP29) 在几种癌症中高表达。它与 UAP56 结合，后者是信使 RNA (mRNA) 剪接和输出中 TREX 复合物的 RNA 解旋酶成分。然而，SARNP 在 mRNA 剪接和输出以及乳腺癌，尤其是 TNBC 进展中的作用尚不清楚。因此，我们研究了 SARNP 在 TNBC 的 mRNA 剪接和输出以及进展中的作用。我们证实 SARNP 与 UAP56 和 Aly 结合，SARNP 过表达增强了 mRNA 剪接，而其敲低则抑制了 mRNA 输出。SARNP 过表达诱导 MCF7 细胞增殖，而其敲低则诱导 SK-BR-3 和 MDA-MB-231 细胞中 E-钙黏蛋白的表达，并下调波形蛋白和 N-钙黏蛋白的表达。SARNP 通过与 pinin 相互作用下调 E-钙黏蛋白的表达。与体内注射 MDA-MB-231 细胞的小鼠相比，注射 MDA-MB-231 细胞的小鼠的肿瘤生长和肺转移明显减少。这些发现表明 SARNP 参与了 mRNA 的剪接和输出。SARNP 通过逃避与 pinin 的抑制性相互作用来维持间充质表型，从而导致 E-钙黏蛋白表达下调。
