Metformin may antagonize Lin28 and/or Lin28B activity, thereby boosting let-7 levels and antagonizing cancer progression
Metformin may antagonize Lin28 and/or Lin28B activity, thereby boosting let-7 levels and antagonizing cancer progression
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DOI：
10.1016/j.mehy.2011.10.041
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发表时间：
2012-02-01
影响因子：
4.7
通讯作者：
McCarty, Mark F.
中科院分区：
文献类型：
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作者：
McCarty, Mark F.
大多数肿瘤都含有具有干细胞特征的癌细胞，其特征是上皮间质转化（EMT）（促进侵袭性生长和转移）、化疗耐药性以及重建新肿瘤的能力。因此，控制或破坏癌症干细胞应该是癌症治疗的主要目标。 let-7 家族的 microRNA 具有癌症抑制活性，最近的证据表明，let-7 水平的显着降低不仅是癌症干细胞的典型特征，而且可能在很大程度上导致癌症的严重性。因此，特别令人感兴趣的是，二甲双胍这种被认为具有预防和治疗癌症潜力的糖尿病药物，最近被发现可以对抗癌细胞的严厉性，显着增强小鼠异种移植模型中癌症的化疗控制，并显着提高癌症干细胞中的let-7a水平。有人提出，二甲双胍的后一种作用可能反映了 AMPK 介导的对 Lin28/Lin28A 表达或活性的抑制，Lin28/Lin28A 蛋白在转录后发挥作用，降低所有 let-7 家族成员的水平。 Lin28B 的转录由 NF-kappaB 和 Myc 促进；因此，拮抗 NF-kappaB 或 Myc 活性的实际措施可能会补充二甲双胍增强 let-7 表达和控制癌症严重程度的效用；水杨酸、抗氧化剂、酪氨酸激酶和 cox-2 抑制剂、利巴韦林、维生素 D、γ-分泌酶抑制剂（如果有）和肠胃外姜黄素在这方面可能有一定作用。尽管组蛋白脱乙酰酶抑制剂对 let-7 表达的影响尚未评估，但有理由怀疑这些药物可能会补充 let-7 对化疗耐药、EMT 和 Sternness 的影响。以二甲双胍为中心的多焦点策略可能具有逆转癌症严重程度并使晚期癌症更容易受到长期控制的巨大潜力。 (C) 2011 Elsevier Ltd. 保留所有权利。
Cancer cells with stem cell characteristics are harbored by most tumors, and are characterized by epithelial-mesenchymal transition (EMT) - which promotes invasive growth and metastasis - chemoresistance, and the capacity to reconstitute new tumors. Hence, the control or destruction of cancer stem cells should be a major goal of cancer management. The let-7 family of microRNAs has cancer suppressor activity, and recent evidence suggests that markedly reduced levels of let-7 are not only a typical feature of cancer stem cells, but may be largely responsible for cancer sternness. It is therefore particularly intriguing that metformin, a diabetes drug thought to have potential in the prevention and treatment of cancer, has recently been found to oppose cancer cell sternness, to markedly potentiate chemotherapeutic control of cancer in mouse xenograft models, and to notably boost let-7a levels in cancer stem cells. It is proposed that this latter effect of metformin may reflect AMPK-mediated inhibition of the expression or activity of Lin28/Lin28A, proteins which act post-transcriptionally to decrease the levels of all let-7 family members. The transcription of Lin28B is promoted by NF-kappaB and by Myc; hence, practical measures which antagonize NF-kappaB or Myc activity may complement the utility of metformin for boosting let-7 expression and controlling cancer sternness; salsalate, antioxidants, tyrosine kinase and cox-2 inhibitors, ribavirin, vitamin D, gamma-secretase inhibitors (when available), and parenteral curcumin may have some utility in this regard. Although the impact of histone deacetylase inhibitors on let-7 expression has not been assessed, there is reason to suspect that these drugs might complement let-7's impact on chemoresistance, EMT, and sternness. Multifocal strategies centering on metformin may have considerable potential for reversing cancer sternness and rendering advanced cancers more susceptible to long term control. (C) 2011 Elsevier Ltd. All rights reserved.