1] Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan [2] Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Oncogene. 2013 Oct 10;32(41):4921-31. doi: 10.1038/onc.2012.514. Epub 2013 Jan 14.
Lung cancer is the leading cause of cancer deaths and is the most occurring malignancy worldwide. Unraveling the molecular mechanisms involved in lung tumorigenesis will greatly improve therapy. During early tumorigenesis, rapid proliferating tumor cells require increased activity of endoplasmic reticulum (ER) for protein synthesis, folding and secretion, thereby are subjected to ER stress. Ribosome-binding protein 1 (RRBP1) was originally identified as a ribosome-binding protein located on the rough ER and associated with unfolding protein response (UPR). In this report, we investigated the role of RRBP1 in lung cancer. RRBP1 was highly expressed in lung cancer tissue, as compared with adjacent normal tissues as assessed by immunohistochemistry (IHC) using lung cancer tissue array (n=87). Knockdown of RRBP1 by short-hairpin RNAs caused ER stress and significantly reduced cell viability and tumorigenicity. This effect was associated with a significant reduction in the expression of glucose-regulated protein 78 (GRP78). UPR regulator GRP78, an anti-apoptotic protein that is widely upregulated in cancer, has a critical role in chemotherapy resistance in some cancers. According to our results, cells with a higher level of RRBP1 were more resistant to ER stress. Ectopic expression of RRBP1 alleviated apoptosis that was induced by the ER-stress agent tunicamycin, 2-deoxy-D-glucose (2DG) or doxorubicin via enhancing GRP78 protein expression. A strong correlation was observed between the expression of RRBP1 and GRP78 in tumor biopsies using the database GSE10072. Our results also indicated that RRBP1 may involve in the regulation of mRNA stability of UPR components including ATF6 and GRP78. Taken together, RRBP1 could alleviate ER stress and help cancer cell survive. RRBP1 is critical for tumor cell survival, which may make it a useful target in lung cancer treatment and a candidate for the development of new targeted therapeutics.
肺癌是癌症死亡的主要原因，也是全球最常见的恶性肿瘤。阐明肺癌发生的分子机制将极大地改善治疗方法。在早期肿瘤发生过程中，快速增殖的肿瘤细胞需要内质网（ER）增加活性以进行蛋白质合成、折叠和分泌，从而受到 ER 应激的影响。核糖体结合蛋白 1（RRBP1）最初被鉴定为一种位于粗面内质网上的核糖体结合蛋白，与未折叠蛋白反应（UPR）有关。在本报告中，我们研究了 RRBP1 在肺癌中的作用。使用肺癌组织芯片（n=87）通过免疫组织化学（IHC）评估，RRBP1 在肺癌组织中高表达，与相邻正常组织相比。短发夹 RNA 敲低 RRBP1 导致 ER 应激，并显著降低细胞活力和致瘤性。这种作用与葡萄糖调节蛋白 78（GRP78）的表达显著降低有关。UPR 调节剂 GRP78 是一种广泛在癌症中上调的抗凋亡蛋白，在某些癌症的化疗耐药性中起着关键作用。根据我们的结果，RRBP1 水平较高的细胞对 ER 应激的抵抗力更强。通过增强 GRP78 蛋白表达，RRBP1 的异位表达缓解了内质网应激剂衣霉素、2-脱氧-D-葡萄糖（2DG）或阿霉素诱导的细胞凋亡。使用数据库 GSE10072 在肿瘤活检中观察到 RRBP1 和 GRP78 之间的表达存在很强的相关性。我们的结果还表明，RRBP1 可能参与 UPR 成分包括 ATF6 和 GRP78 的 mRNA 稳定性调节。总之，RRBP1 可以缓解 ER 应激并帮助癌细胞存活。RRBP1 对肿瘤细胞的存活至关重要，这使其成为肺癌治疗的一个有用靶点，并可能成为新的靶向治疗药物的候选药物。
