PCBP2 Posttranscriptional Modifications Induce Breast Cancer Progression via Upregulation of UFD1 and NT5E
PCBP2 Posttranscriptional Modifications Induce Breast Cancer Progression via Upregulation of UFD1 and NT5E
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DOI：
10.1158/1541-7786.mcr-20-0390
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发表时间：
2021-01-01
影响因子：
5.2
通讯作者：
Wu, Zhengsheng
中科院分区：
文献类型：
--
作者：
Wang, Xiaonan;Guo, Qianying;Wu, Zhengsheng
通常认为，细胞蛋白质水平主要由mRNA水平决定。然而，蛋白质和mRNA表达之间的不一致性已经涉及许多病理条件，包括肿瘤发生。这种不一致的机制是复杂的，远未被理解。在这项研究中，观察到聚（C）结合蛋白2（PCBP 2）mRNA和蛋白的表达水平在乳腺正常和癌细胞系，石蜡包埋和新鲜组织标本中是完全不同的，与癌症基因组图谱和临床蛋白质组肿瘤分析联盟的数据一致。此外，PCBP 2蛋白表达与乳腺癌患者的疾病进展和不良结局显著相关。PCBP 2蛋白的耗尽抑制细胞增殖、集落形成、迁移、侵袭以及体内肿瘤生长和转移。PCBP 2的强制表达表现出相反的效果。从机制上讲，已证明PCBP 2 30非翻译区（3 'UTR）在乳腺癌组织和细胞系中经历选择性剪接和多聚腺苷酸化（阿帕）。非全长3 'UTR PCBP 2转录物比全长3' UTR转录物产生更多的蛋白质，并增强人乳腺癌细胞的致癌和转移能力。此外，UFD 1和NT 5E被鉴定为PCBP 2的下游基因。PCBP 2促进乳腺癌细胞的致癌性，通过上调UFD 1和NT 5E的表达，通过直接结合到他们的3 'UTR-B portions.Implications：研究结果表明，阿帕的PCBP 2 3' UTR有助于其表达增加，随后促进乳腺癌的进展，通过调节UFD 1和NT 5E。
It is commonly accepted that cellular protein levels are primarily determined by mRNA levels. However, discordance between protein and mRNA expression has been implicated in many pathologic conditions including oncogenesis. The mechanisms involved in this discordance are complicated and far from understood. In this study, it was observed that the expression levels of poly(C) binding protein 2 (PCBP2) mRNA and protein were diametric in breast normal and cancer cell lines, paraffin-embedded and fresh tissue specimens, consistent with data from The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium. Moreover, PCBP2 protein expression was significantly associated with disease progression and poor outcome in patients with breast cancer. Depletion of PCBP2 protein inhibited cell proliferation, colony formation, migration, invasion, and in vivo tumor growth and metastasis. Forced expression of PCBP2 exhibited the opposite effect. Mechanistically, it was demonstrated that PCBP2 30 untranslated region (3'UTR) was subject to alternative splicing and polyadenylation (APA) in breast cancer tissues and cell lines. Non-full-length 3'UTR PCBP2 transcripts yielded more protein than the full-length 3'UTR transcripts and enhanced the oncogenic and metastatic capacities of human breast cancer cells. Furthermore, UFD1 and NT5E were identified as genes downstream of PCBP2. PCBP2 promoted oncogenicity of breast cancer cells via upregulation of the expression of UFD1 and NT5E by direct binding to their 3'UTR-B portions.Implications: Findings demonstrate that APA of PCBP2 3'UTR contributes to its increased expression with subsequent promotion of breast cancer progression by regulating UFD1 and NT5E.