Abstract：
BACKGROUND: One of the confounding factors in pancreatic cancer (PC) pathogenesis is hyperglycemia. The molecular mechanism by which high glucose (HG) influences PC severity is poorly understood. Our investigation delved into the impact of lncRNA highly upregulated in liver cancer (HULC) and its interaction with yes-associated protein (YAP) in regulating the fate of pancreatic ductal adenocarcinoma cells (PDAC) under HG-induced conditions. PDAC cells were cultured under normal or HG conditions. We thereafter measured the effect of HG on the viability of PDAC cells, their migration potential and drug resistance properties. The lncRNAs putatively dysregulated in PC and diabetes were shortlisted by bioinformatics analysis followed by wet lab validation of function.
RESULTS: HG led to enhanced proliferation and drug refractoriness in PDAC cells. HULC was identified as one of the major deregulated lncRNAs following bioinformatics analysis. HULC was found to regulate the expression of the potent transcriptional regulator - YAP through selective histone modifications at the YAP promoter. siRNA-mediated ablation of HULC resulted in a concurrent decrease in YAP transcriptional activity. Importantly, HULC and YAP were found to co-operatively regulate the cellular homeostatic process autophagy, thus inculcating drug resistance and proliferative potential in PDAC cells. Moreover, inhibition of autophagy or YAP led to a decrease in HULC levels, suggesting the existence of an inter-regulatory feedback loop.
CONCLUSIONS: We observed that HG triggers aggressive properties in PDAC cells. Mechanistically, up-regulation of lncRNA HULC resulted in activation of YAP and differential regulation of autophagy coupled to increased proliferation of PDAC cells.
CONCLUSIONS: Inhibition of HULC and YAP may represent a novel therapeutic strategy for PDAC. Furthermore, this study portrays the intricate molecular interplay between HULC, YAP and autophagy in PDAC pathogenesis.
RESULTS: HG led to enhanced proliferation and drug refractoriness in PDAC cells. HULC was identified as one of the major deregulated lncRNAs following bioinformatics analysis. HULC was found to regulate the expression of the potent transcriptional regulator - YAP through selective histone modifications at the YAP promoter. siRNA-mediated ablation of HULC resulted in a concurrent decrease in YAP transcriptional activity. Importantly, HULC and YAP were found to co-operatively regulate the cellular homeostatic process autophagy, thus inculcating drug resistance and proliferative potential in PDAC cells. Moreover, inhibition of autophagy or YAP led to a decrease in HULC levels, suggesting the existence of an inter-regulatory feedback loop.
CONCLUSIONS: We observed that HG triggers aggressive properties in PDAC cells. Mechanistically, up-regulation of lncRNA HULC resulted in activation of YAP and differential regulation of autophagy coupled to increased proliferation of PDAC cells.
CONCLUSIONS: Inhibition of HULC and YAP may represent a novel therapeutic strategy for PDAC. Furthermore, this study portrays the intricate molecular interplay between HULC, YAP and autophagy in PDAC pathogenesis.
摘要：
背景：胰腺癌（PC）发病机制中的混杂因素之一是高血糖。尚不清楚高葡萄糖（HG）影响PC严重程度的分子机制。我们的研究探讨了lncRNA在肝癌（HULC）中高度上调的影响及其与yes相关蛋白（YAP）在调节HG诱导条件下胰腺导管腺癌细胞（PDAC）命运中的相互作用。PDAC细胞在正常或HG条件下培养。之后，我们测量了HG对PDAC细胞活力的影响，它们的迁移潜力和耐药特性。在PC和糖尿病中推定失调的lncRNAs通过生物信息学分析入围，然后进行湿实验室功能验证。
结果：HG导致PDAC细胞增殖和药物难治性增强。在生物信息学分析后，HULC被鉴定为主要的去调节的lncRNA之一。发现HULC通过在YAP启动子处的选择性组蛋白修饰来调节有效的转录调节因子-YAP的表达。siRNA介导的HULC消融导致YAP转录活性的同时降低。重要的是,发现HULC和YAP协同调节细胞稳态过程自噬，从而在PDAC细胞中灌输耐药性和增殖潜力。此外，抑制自噬或YAP导致HULC水平降低，这表明存在一个相互调节的反馈回路。
结论：我们观察到HG在PDAC细胞中触发侵袭性。机械上,lncRNAHULC的上调导致YAP的激活和自噬的差异调节与PDAC细胞的增殖增加有关。
结论：抑制HULC和YAP可能代表PDAC的新治疗策略。此外，这项研究描绘了HULC之间复杂的分子相互作用，YAP和自噬在PDAC发病机制中的作用.
结果：HG导致PDAC细胞增殖和药物难治性增强。在生物信息学分析后，HULC被鉴定为主要的去调节的lncRNA之一。发现HULC通过在YAP启动子处的选择性组蛋白修饰来调节有效的转录调节因子-YAP的表达。siRNA介导的HULC消融导致YAP转录活性的同时降低。重要的是,发现HULC和YAP协同调节细胞稳态过程自噬，从而在PDAC细胞中灌输耐药性和增殖潜力。此外，抑制自噬或YAP导致HULC水平降低，这表明存在一个相互调节的反馈回路。
结论：我们观察到HG在PDAC细胞中触发侵袭性。机械上,lncRNAHULC的上调导致YAP的激活和自噬的差异调节与PDAC细胞的增殖增加有关。
结论：抑制HULC和YAP可能代表PDAC的新治疗策略。此外，这项研究描绘了HULC之间复杂的分子相互作用，YAP和自噬在PDAC发病机制中的作用.
