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.
Highlights
Functional evaluation of let-7d-3p in SKOV3 ovarian cancer cells in this study revealed that its inhibition impaired cell proliferation and activated apoptosis, but did not affect cell motility and invasiveness
Posttranscriptional regulation by the LIN28 and ADAR expands the regulatory repertoire of let-7d
Let-7d acts as a tumor suppressor by synchronously targeting mRNAs involved in the regulation of tumor cell proliferation, apoptosis, angiogenesis and inflammation, resulting in improved therapeutic response
Summary
MicroRNAs are a group of endogenous small single-stranded non-coding RNA molecules of 19–24 nucleotides that regulate gene expression at the posttranscriptional level [1,2,3,4]. Most microRNA encoding genes are inserted in intronic regions of proteinencoding genes. They are either transcribed under the control of their own promoters or they share a promoter with mRNA. After transcription by RNA polymerase II in the nucleus, primary micro-RNA (pri-microRNA), comprising about 500–3000 nucleotides, is processed into stem-loop precursor microRNA (pre-microRNA) by RNA III endonuclease Drosha and the dsRNA binding protein DGCR8/Pasha (a complex known as microprocessor) [4]. 30 -untranslated regions (UTR) of complement target mRNAs as part of the RNA-induced silencing complex (RISC) microRNAs promote either their degradation or translational repression, depending on the degree of complementarity between the so-called seed-sequence of the mature microRNA and the corresponding complementary target region in the cognate mRNA [2,3,6]. MicroRNAs are expressed in tissue and cell-type-specific expression profiles and they are implicated in physiologic and pathologic processes, including the cell cycle, apoptosis, proliferation, differentiation, metabolic pathways and cell response to various types of stress [7,8,9,10]
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