miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer.,British Journal of Cancer

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miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer.
British Journal of Cancer ( IF 6.4 ) Pub Date : 2020-03-05 , DOI: 10.1038/s41416-020-0773-2
Giovannina Barisciano ₁ , Tommaso Colangelo ₂ , Valeria Rosato ₁ , Livio Muccillo ₁ , Maria Letizia Taddei ₃ , Luigi Ippolito ₃ , Paola Chiarugi ₃ , Mario Galgani ₄ , Sara Bruzzaniti ₅ , Giuseppe Matarese _{4,

6} , Matteo Fassan ₇ , Marco Agostini ₈ , Francesca Bergamo ₉ , Salvatore Pucciarelli ₈ , Annalucia Carbone ₁₀ , Gianluigi Mazzoccoli ₁₀ , Vittorio Colantuoni ₁ , Fabrizio Bianchi ₂ , Lina Sabatino ₁

Affiliation

Department of Sciences and Technologies, University of Sannio, Via Francesco de Sanctis, 82100, Benevento, Italy.
Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Biomarkers Unit, Viale Padre Pio, 7, 71013, San Giovanni Rotondo, FG, Italy.
Department of Experimental Biomedical and Clinical Medicine, University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
Department of Molecular Medicine and Medical Biotechnologies "Federico II", University, Naples Via S. Pansini, 5, 80131, Naples, Italy.
Department of Biology, "Federico II" University, 80126, Naples, Italy.
Laboratory of Immunology, Institute of Experimental Endocrinology and Oncology (IEOS-CNR), Via S. Pansini, 5, 80131, Naples, Italy.
Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy.
Department of Surgery, Oncology and Gastroenterology, First Surgical Clinic Section, University of Padua, Via Giustiniani, 2, 35128, Padua, Italy.
Department of Clinical and Experimental Oncology, Unit of Medical Oncology 1, Veneto Institute of Oncology IOV, IRCCS, Via Gattamelata, 64, 35128, Padua, Italy.
Fondazione IRCCS Casa Sollievo della Sofferenza, Division of Internal Medicine and Chronobiology Unit, Viale Padre Pio, 7, 71013, San Giovanni Rotondo, FG, Italy.

BACKGROUND Metabolic reprogramming towards aerobic glycolysis in cancer supports unrestricted cell proliferation, survival and chemoresistance. The molecular bases of these processes are still undefined. Recent reports suggest crucial roles for microRNAs. Here, we provide new evidence of the implication of miR-27a in modulating colorectal cancer (CRC) metabolism and chemoresistance. METHODS A survey of miR-27a expression profile in TCGA-COAD dataset revealed that miR-27a-overexpressing CRCs are enriched in gene signatures of mitochondrial dysfunction, deregulated oxidative phosphorylation, mTOR activation and reduced chemosensitivity. The same pathways were analysed in cell lines in which we modified miR-27a levels. The response to chemotherapy was investigated in an independent cohort and cell lines. RESULTS miR-27a upregulation in vitro associated with impaired oxidative phosphorylation, overall mitochondrial activities and slight influence on glycolysis. miR-27a hampered AMPK, enhanced mTOR signalling and acted in concert with oncogenes and tumour cell metabolic regulators to force an aerobic glycolytic metabolism supporting biomass production, unrestricted growth and chemoresistance. This latter association was confirmed in our cohort of patients and cell lines. CONCLUSIONS We disclose an unprecedented role for miR-27a as a master regulator of cancer metabolism reprogramming that impinges on CRC response to chemotherapy, underscoring its theragnostic properties.

中文翻译：

miR-27a 是结直肠癌代谢重编程和化学抗性的主要调节因子。

背景癌症中朝向有氧糖酵解的代谢重编程支持不受限制的细胞增殖、存活和化学抗性。这些过程的分子基础仍未确定。最近的报告表明 microRNA 的关键作用。在这里，我们提供了 miR-27a 在调节结直肠癌 (CRC) 代谢和化学抗性中的意义的新证据。方法对 TCGA-COAD 数据集中 miR-27a 表达谱的调查显示，过表达 miR-27a 的 CRC 富含线粒体功能障碍、氧化磷酸化失调、mTOR 激活和化学敏感性降低的基因特征。在我们修改 miR-27a 水平的细胞系中分析了相同的途径。在独立的队列和细胞系中研究了对化疗的反应。结果体外 miR-27a 上调与氧化磷酸化受损、整体线粒体活性和对糖酵解的轻微影响有关。miR-27a 阻碍了 AMPK，增强了 mTOR 信号传导，并与癌基因和肿瘤细胞代谢调节剂协同作用，迫使有氧糖酵解代谢支持生物质生产、不受限制的生长和化学抗性。后一种关联在我们的患者和细胞系队列中得到证实。结论我们揭示了 miR-27a 作为癌症代谢重编程的主要调节因子的前所未有的作用，它影响了 CRC 对化疗的反应，强调了其治疗诊断特性。增强 mTOR 信号并与癌基因和肿瘤细胞代谢调节剂协同作用，以强制进行有氧糖酵解代谢，支持生物质生产、不受限制的生长和化学抗性。后一种关联在我们的患者和细胞系队列中得到证实。结论我们揭示了 miR-27a 作为癌症代谢重编程的主要调节因子的前所未有的作用，它影响了 CRC 对化疗的反应，强调了其治疗诊断特性。增强 mTOR 信号并与癌基因和肿瘤细胞代谢调节剂协同作用，以强制进行有氧糖酵解代谢，支持生物质生产、不受限制的生长和化学抗性。后一种关联在我们的患者和细胞系队列中得到证实。结论我们揭示了 miR-27a 作为癌症代谢重编程的主要调节因子的前所未有的作用，它影响了 CRC 对化疗的反应，强调了其治疗诊断特性。

更新日期：2020-03-05

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