Tsinghua-Peking Joint Center for Life Sciences, Beijing, China.
MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing, China.
EMBO J. 2018 Dec 3;37(23). doi: 10.15252/embj.201899017. Epub 2018 Aug 29.
Elevated expression of RNA binding protein HNRNPC has been reported in cancer cells, while the essentialness and functions of HNRNPC in tumors were not clear. We showed that repression of HNRNPC in the breast cancer cells MCF7 and T47D inhibited cell proliferation and tumor growth. Our computational inference of the key pathways and extensive experimental investigations revealed that the cascade of interferon responses mediated by RIG-I was responsible for such tumor-inhibitory effect. Interestingly, repression of HNRNPC resulted in accumulation of endogenous double-stranded RNA (dsRNA), the binding ligand of RIG-I. These up-regulated dsRNA species were highly enriched by Alu sequences and mostly originated from pre-mRNA introns that harbor the known HNRNPC binding sites. Such source of dsRNA is different than the recently well-characterized endogenous retroviruses that encode dsRNA In summary, essentialness of HNRNPC in the breast cancer cells was attributed to its function in controlling the endogenous dsRNA and the down-stream interferon response. This is a novel extension from the previous understandings about HNRNPC in binding with introns and regulating RNA splicing.
RNA 结合蛋白 HNRNPC 的表达水平在癌细胞中升高，但其在肿瘤中的必需性和功能尚不清楚。我们发现，乳腺癌细胞 MCF7 和 T47D 中 HNRNPC 的抑制可抑制细胞增殖和肿瘤生长。我们通过计算推断出关键途径，并进行了广泛的实验研究，结果表明 RIG-I 介导的干扰素反应级联反应是这种肿瘤抑制作用的原因。有趣的是，HNRNPC 的抑制导致内源性双链 RNA（dsRNA）的积累，dsRNA 是 RIG-I 的结合配体。这些上调的 dsRNA 物种富含 Alu 序列，主要来源于含有已知 HNRNPC 结合位点的 pre-mRNA 内含子。这种 dsRNA 的来源不同于最近研究充分的内源性逆转录病毒，后者编码 dsRNA。综上所述，HNRNPC 在乳腺癌细胞中的必需性归因于其控制内源性 dsRNA 和下游干扰素反应的功能。这是对 HNRNPC 与内含子结合和调节 RNA 剪接的先前认识的一个新的扩展。
