Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149 Münster, Germany.
Int J Mol Sci. 2021 Jul 8;22(14):7359. doi: 10.3390/ijms22147359.
microRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Let-7d is a microRNA of the conserved let-7 family that is dysregulated in female malignancies including breast cancer, ovarian cancer, endometrial cancer, and cervical cancer. Moreover, a dysregulation is observed in endometriosis and pregnancy-associated diseases such as preeclampsia and fetal growth restriction. Let-7d expression is regulated by cytokines and steroids, involving transcriptional regulation by OCT4, MYC and p53, as well as posttranscriptional regulation via LIN28 and ADAR. By downregulating a wide range of relevant mRNA targets, let-7d affects cellular processes that drive disease progression such as cell proliferation, apoptosis (resistance), angiogenesis and immune cell function. In an oncological context, let-7d has a tumor-suppressive function, although some of its functions are context-dependent. Notably, its expression is associated with improved therapeutic responses to chemotherapy in breast and ovarian cancer. Studies in mouse models have furthermore revealed important roles in uterine development and function, with implications for obstetric diseases. Apart from a possible utility as a diagnostic blood-based biomarker, pharmacological modulation of let-7d emerges as a promising therapeutic concept in a variety of female disease conditions.
微小 RNA 是一种小的非编码 RNA，可在后转录水平调节基因表达。Let-7d 是保守的 let-7 家族中的微小 RNA，在女性恶性肿瘤中失调，包括乳腺癌、卵巢癌、子宫内膜癌和宫颈癌。此外，在子宫内膜异位症和与妊娠相关的疾病中也观察到失调，如子痫前期和胎儿生长受限。Let-7d 的表达受细胞因子和类固醇调节，涉及 OCT4、MYC 和 p53 的转录调节，以及通过 LIN28 和 ADAR 的转录后调节。通过下调广泛的相关 mRNA 靶标，Let-7d 影响驱动疾病进展的细胞过程，如细胞增殖、凋亡（抵抗）、血管生成和免疫细胞功能。在肿瘤学背景下，Let-7d 具有肿瘤抑制功能，尽管其某些功能取决于具体情况。值得注意的是，它的表达与乳腺癌和卵巢癌对化疗的治疗反应改善有关。在小鼠模型中的研究进一步揭示了其在子宫发育和功能中的重要作用，对产科疾病有影响。除了作为诊断性血液生物标志物的潜在用途外，Let-7d 的药理学调节在各种女性疾病中作为一种有前途的治疗概念出现。
