Cancer cells often co-opt post-transcriptional regulatory mechanisms to achieve pathologic expression of gene networks that drive metastasis. Translational control is a major regulatory hub in oncogenesis; however, its effects on cancer progression remain poorly understood. Here, to address this, we used ribosome profiling to compare genome-wide translation efficiencies of poorly and highly metastatic breast cancer cells and patient-derived xenografts. We developed dedicated regression-based methods to analyse ribosome profiling and alternative polyadenylation data, and identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a translational controller of a specific mRNA regulon. We found that HNRNPC is downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3′ untranslated region lengthening and, subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. In addition, the reduced expression of HNRNPC and its regulon is associated with the worse prognosis in breast cancer patient cohorts.

癌细胞经常选择转录后调节机制来实现驱动转移的基因网络的病理表达。翻译控制是肿瘤发生的主要调控中心；然而，它对癌症进展的影响仍知之甚少。为了解决这个问题，我们使用核糖体分析来比较低转移性和高转移性乳腺癌细胞以及患者来源的异种移植物的全基因组翻译效率。我们开发了专用的基于回归的方法来分析核糖体分析和替代多聚腺苷酸化数据，并确定异质核核糖核蛋白 C (HNRNPC) 作为特定 mRNA 调节子的翻译控制器。我们发现 HNRNPC 在高度转移的细胞中下调，这导致 HNRNPC 结合的 mRNA 经历 3' 非翻译区延长，随后发生翻译抑制。我们发现调节 HNRNPC 表达会影响异种移植小鼠模型中乳腺癌细胞的转移能力。此外，HNRNPC 及其调节子表达的降低与乳腺癌患者队列中较差的预后相关。