Abstract：
Breast cancer (BRCA) is the most common malignancies worldwide with increasing rate. Dolichol phosphate mannose synthase (DPMS) is a critical mannosyltransferase involved in the posttranslational modification of proteins. At present, there is limited knowledge regarding the function of DPMS in breast cancer. In this study, silica analysis in multiple datasets found that dolichyl-phosphate mannosyltransferase subunit 2 (DPM2) is an unfavorable prognostic marker, suggesting its oncogenic role. Cell counting kit-8 and apoptosis assays show that DPM2-silenced cancer cells exhibit decreased growth potential and enhanced cell death rate. Further, transwell and wound healing assays show reduced invasion and migration capabilities in DPM2 knockdown groups, xenograft nude mice model demonstrated smaller tumor volume in DPM2 silenced BC cells. Then, the underlying downstream mechanism of DPM2 in BC was predicted and analyzed, highlighting classical tumorigenic pathways like JAK/STAT signaling pathway and oxidative phosphorylation activated in the cancer group. Finally, ChIP-seq analysis, expression correlation analysis, inhibitor treatment, and dual luciferase assays show that DPM2 is transcriptionally activated by estrogen receptor1 (ESR1). The results show that high expression of DPM2 mRNA is significantly correlated with shorter overall survival (OS) and disease-free survival (DFS) in breast cancer patients, and in vitro knockdown of DPM2 can significantly inhibit the malignant phenotypes of cells, including proliferation, invasion, migration, and apoptosis. These results suggest that DPM2 may play an important role in breast cancer. Altogether, we first uncovered the tumorigenic and prognostic role of DPM2 in breast cancer, cellular assays, and bioinformatics analysis highlighted DPM2 as oncogene via inhibited cancer-related signaling pathways in breast cancer. Besides, DPM2 is transcriptionally activated by ESR1, the signaling axis of ESR1/DPM2 provides a new strategy for BC-targeted therapy.
摘要：
乳腺癌(BRCA)是全球范围内最常见的恶性肿瘤,发病率逐年上升。Dolichol磷酸甘露糖合酶（DPMS）是参与蛋白质翻译后修饰的关键甘露糖基转移酶。目前,关于DPMS在乳腺癌中的功能的知识有限。在这项研究中,在多个数据集中的二氧化硅分析发现，dolichyl-磷酸甘露糖基转移酶亚基2（DPM2）是一个不利的预后标记，提示其致癌作用。细胞计数试剂盒-8和细胞凋亡测定显示DPM2沉默的癌细胞表现出降低的生长潜力和提高的细胞死亡率。Further,transwell和伤口愈合试验显示DPM2敲低组的侵袭和迁移能力降低，异种移植裸鼠模型在DPM2沉默的BC细胞中显示出较小的肿瘤体积。然后，预测和分析了BC中DPM2的潜在下游机制，强调经典的致瘤途径，如JAK/STAT信号通路和在癌症组中激活的氧化磷酸化。最后,ChIP-seq分析，表达相关性分析，抑制剂治疗,和双荧光素酶测定显示DPM2被雌激素受体1(ESR1)转录激活。结果表明，DPM2mRNA的高表达与乳腺癌患者的总生存期（OS）和无病生存期（DFS）的缩短显着相关。体外敲除DPM2可以显著抑制细胞的恶性表型,包括扩散，入侵,迁移,和凋亡。这些结果表明DPM2可能在乳腺癌中起重要作用。总之,我们首先发现了DPM2在乳腺癌中的致瘤作用和预后作用，细胞测定，和生物信息学分析强调DPM2通过抑制乳腺癌的癌症相关信号通路作为癌基因。此外,DPM2被ESR1转录激活，ESR1/DPM2的信号轴为BC靶向治疗提供了新的策略。
