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Review
. 2021 Jul 8;22(14):7359.
doi: 10.3390/ijms22147359.

The Role of microRNA Let-7d in Female Malignancies and Diseases of the Female Reproductive Tract

Chiara De Santis  1 , Martin Götte  1
Affiliations
Review

The Role of microRNA Let-7d in Female Malignancies and Diseases of the Female Reproductive Tract

Chiara De Santis et al. Int J Mol Sci. .

Abstract

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.

Keywords: biomarker; breast cancer; endometriosis; fetal growth restriction; let-7; microRNAs; ovarian cancer; preeclampsia; therapeutic resistance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Impact of let-7d on female malignancies and diseases of the female reproductive tract. Let-7d expression is dysregulated in a variety of gynaecological and obstetric disorders. Its expression is regulated in a hormone- and cytokine-dependent manner involving both transcriptional and post-transcriptional mechanisms. Let-7d targets key mRNAs involved in the regulation of cell proliferation, apoptosis, angiogenesis and immune cell function, thereby modulating disease progression and therapeutic response. See text for details. The Let-7d sequence was retrieved from miRbase [24]. This figure was designed using elements of the free web resource Smart Servier Medical Art (https://smart.servier.com/ (accessed on 1 June 2021)).
Figure 2
Figure 2
Let-7d is upregulated in a variety of gynecological malignancies. RNASeq-based let-7d expression data were retrieved from the TNMPlot database [93]. In the box plots, bars show the proportions of tumor samples displaying higher expression of the selected gene compared to normal samples at each of the quantile cutoff values (minimum, 1st quartile, median, 3rd quartile, maximum). p-values below 0.05 indicate significant differences as assessed by Mann–Whitney test. Significant let-7d upregulation between normal and tumor tissues was observed for invasive breast carcinoma (“Breast cancer”, 403 normal/1097 tumor samples), ovarian serous cystadenocarcinoma (“Ovarian cancer”, 133 normal/374 tumor samples), uterine corpus endometrial carcinoma (“Endometrial cancer” 146 normal/547 tumor samples), and uterine carcinosarcoma (111 normal/56 tumor samples). See reference [93] for a description of retrieved gene expression data and patient collectives.
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