DataSheet_1_Long Noncoding RNA MIR210HG Promotes the Warburg Effect and Tumor Growth by Enhancing HIF-1α Translation in Triple-Negative Breast Cancer.pdf

BackgroundHypoxia is an important environmental factor and has been correlated with tumor progression, treatment resistance and poor prognosis in many solid tumors, including triple-negative breast cancer (TNBC). Emerging evidence suggests that long noncoding RNA (lncRNA) functions as a critical regulator in tumor biology. However, little is known about the link between hypoxia and lncRNAs in TNBC.
MethodsTNBC molecular profiles from The Cancer Genome Atlas (TCGA) were leveraged to identify hypoxia-related molecular alterations. Loss-of-function studies were performed to determine the regulatory role of MIR210HG in tumor glycolysis. The potential functions and mechanisms of hypoxia-MIR210HG axis were explored using qPCR, Western blotting, luciferase reporter assay, and polysome profiling.
ResultsWe found that MIR210HG is a hypoxia-induced lncRNA in TNBC. Loss-of-function studies revealed that MIR210HG promoted the Warburg effect as demonstrated by glucose uptake, lactate production and expression of glycolytic components. Mechanistically, MIR210HG potentiated the metabolic transcription factor hypoxia-inducible factor 1α (HIF-1α) translation via directly binding to the 5’-UTR of HIF-1α mRNA, leading to increased HIF-1a protein level, thereby upregulating expression of glycolytic enzymes. MIR210HG knockdown in TNBC cells reduced their glycolytic metabolism and abolished their tumorigenic potential, indicating the glycolysis-dependent oncogenic activity of MIR210HG in TNBC. Moreover, MIR210HG was highly expressed in breast cancer and predicted poor clinical outcome.
ConclusionOur results decipher a positive feedback loop between hypoxia and MIR210HG that drive the Warburg effect and suggest that MIR210HG may be a good prognostic marker and therapeutic target for TNBC patients.

背景 缺氧是重要的环境应激因子，已在包括三阴性乳腺癌（triple-negative breast cancer, TNBC）在内的多种实体瘤中被证实与肿瘤进展、治疗耐药及不良预后密切相关。越来越多的研究表明，长链非编码RNA（long noncoding RNA, lncRNA）是肿瘤生物学过程中的关键调控因子，但目前对于三阴性乳腺癌中缺氧与长链非编码RNA之间的关联仍知之甚少。
方法 本研究借助癌症基因组图谱（The Cancer Genome Atlas, TCGA）中的三阴性乳腺癌分子谱数据，筛选缺氧相关的分子改变。通过功能丧失实验，明确MIR210HG在肿瘤糖酵解中的调控作用。采用实时荧光定量PCR（qPCR）、蛋白质印迹（Western blotting）、双荧光素酶报告基因实验及多聚核糖体谱分析，探究缺氧-MIR210HG轴的潜在功能与作用机制。
结果 本研究发现，MIR210HG是三阴性乳腺癌中缺氧诱导的长链非编码RNA。功能丧失实验证实，MIR210HG可通过葡萄糖摄取、乳酸生成及糖酵解相关组分的表达变化，促进瓦博格效应（Warburg effect）。机制层面，MIR210HG可直接结合缺氧诱导因子1α（hypoxia-inducible factor 1α, HIF-1α）mRNA的5'-非翻译区（5'-UTR），增强该代谢相关转录因子的翻译过程，提升HIF-1α蛋白表达水平，进而上调糖酵解酶的表达。在三阴性乳腺癌细胞中敲低MIR210HG可抑制其糖酵解代谢活性，并消除其成瘤能力，表明MIR210HG在三阴性乳腺癌中依赖糖酵解发挥致癌活性。此外，MIR210HG在乳腺癌组织中呈高表达状态，且与不良临床预后显著相关。
结论 本研究揭示了缺氧与MIR210HG之间的正反馈环路，该环路可驱动瓦博格效应，提示MIR210HG有望成为三阴性乳腺癌患者的优质预后标志物与潜在治疗靶点。