Glycoprotein α-Subunit of Glucosidase II (GIIα) is a novel prognostic biomarker correlated with unfavorable outcome of urothelial carcinoma.
Glycoprotein α-Subunit of Glucosidase II (GIIα) is a novel prognostic biomarker correlated with unfavorable outcome of urothelial carcinoma.
复制标题
DOI：
10.1186/s12885-022-09884-8
复制
发表时间：
2022-07-25
期刊：
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
--
作者：
尿路上皮癌(UC)是最常见的恶性肿瘤之一。肌肉浸润性膀胱癌(MIBC)具有侵袭性，预后较差，而非肌肉浸润性膀胱癌(NMIBC)预后较好。然而，相当大比例(10%-30%)的NMIBC病例进展为MIBC。目前，寻找有效的生物标志物来预测UC的进程仍然具有挑战性。最近有研究表明，糖基化的翻译后修饰(PTM)是与肿瘤血管生成、侵袭和转移相关的重要过程。在这里，我们报道了一项数据驱动的发现和实验验证，GANAB是糖基化的关键调节因子，作为UC的一个新的预后标志物。在本研究中，我们采用免疫组织化学方法(IHC)对107例UC标本中GANAB蛋白的表达水平与其预后的相关性进行了研究。利用RNAi进行体外实验，研究GANAB在UC细胞中的生物学功能。我们观察到，在我们的队列中，GANAB蛋白的阳性表达与UC的不良预后显著相关，经对数等级检验，p值为0.0017。值得注意的是，在UC中，位于肿瘤边缘侵袭前沿的肿瘤细胞显示出比肿瘤体内其他肿瘤细胞更强的GANAB表达。我们进一步证实，GANAB的高表达水平与高级别肿瘤(p值为1.72 × 10-10)、晚期肿瘤(6.47 × 10-6)显著相关，并且在腔分子亚型中显著升高。此外，在UM-UC-3和T24细胞中用RNAi敲除GANAB抑制了细胞的增殖和迁移。GANAB基因敲除后，细胞周期停滞于G1期。我们证实GANAB在内质网应激信号中介导HIF1a和ATF6转录激活，并调节细胞周期相关转录因子E2F7和FOXM1的基因表达。GANAB的高表达是UC预后较差的新指标。我们的数据表明，GANAB不仅是一种新的、有前途的UC预后生物标志物，而且可能为以PTM为基础的UC治疗方法的发展提供重要线索。网上版载有补充材料，可在10.1186/s12885-022-09884-8查阅。
Urothelial carcinoma (UC) is among the most prevalent malignancies. The muscle-invasive bladder cancer (MIBC) shows an invasive feature and has poor prognosis, while the non-muscle invasive bladder cancer (NMIBC) shows a better prognosis as compared with the MIBC. However, a significant proportion (10%–30%) of NMIBC cases progress to MIBC. Identification of efficient biomarkers for the prediction of the course of UC remains challenging nowadays. Recently, there is an emerging study showed that post-translational modifications (PTMs) by glycosylation is an important process correlated with tumor angiogenesis, invasion and metastasis. Herein, we reported a data-driven discovery and experimental validation of GANAB, a key regulator of glycosylation, as a novel prognostic marker in UC. In the present study, we conducted immunohistochemistry (IHC) assay to evaluate the correlation between the expression levels of GANAB protein and the prognosis of UC in our cohort of 107 samples using whole slide image (WSI) analysis. In vitro experiments using RNAi were also conducted to investigate the biological functions of GANAB in UC cell lines. We observed that positive GANAB protein expression was significantly correlated with poor prognosis of UC in our cohort, with p-value of 0.0017 in Log-rank test. Notably, tumor cells at the invasive front of the tumor margin showed stronger GANAB expression than the tumor cells inside the tumor body in UCs. We further validated that the elevated expression levels of GANAB were significantly correlated with high grade tumors (p-values of 1.72 × 10–10), advanced stages (6.47 × 10–6), and elevated in luminal molecular subtypes. Moreover, knocking-down GANAB using RNAi in UM-UC-3 and T24 cells inhibited cell proliferation and migration in vitro. Knockdown of GANAB resulted in cell cycle arrest at G1 phase. We demonstrated that GANAB mediated HIF1A and ATF6 transcriptional activation in the ER stress signaling, and regulated the gene expression of cell cycle-related transcriptional factors E2F7 and FOXM1. The elevated expression of GANAB is a novel indicator of poorer prognosis of UC. Our data suggests that GANAB is not only a new and promising prognostic biomarker for UC, but also may provide important cues for the development of PTM-based therapeutics for UC treatment. The online version contains supplementary material available at 10.1186/s12885-022-09884-8.
登录
查看更多内容
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
8
作者：
Chiang, W-F;Cheng, T-M;Wu, M-H
通讯作者：
Wu, M-H
影响因子：
29.4
作者：
Drenth, JPH;Martina, JA;Bonifacino, JS
通讯作者：
Bonifacino, JS
影响因子：
5
作者：
Pei, Lu;Zhu, Qingfeng;Zhuang, Xiaoping;Ruan, Honglian;Zhao, Zhiguang;Qin, Haide;Lin, Qiongqiong
通讯作者：
Lin, Qiongqiong
影响因子：
7.3
作者：
Lee J;Rho JH;Roehrl MH;Wang JY
通讯作者：
Wang JY