The microRNA Let-7 and its exosomal form: Epigenetic regulators of gynecological cancers

Abstract

Many types of gynecological cancer (GC) are often silent until they reach an advanced stage, and are therefore often diagnosed too late for effective treatment. Hence, there is a real need for more efficient diagnosis and treatment for patients with GC. During recent years, researchers have increasingly studied the impact of microRNAs cancer development, leading to a number of applications in detection and treatment. MicroRNAs are a particular group of tiny RNA molecules that regulate regular gene expression by affecting the translation process. The downregulation of numerous miRNAs has been observed in human malignancies. Let-7 is an example of a miRNA that controls cellular processes as well as signaling cascades to affect post-transcriptional gene expression. Recent research supports the hypothesis that enhancing let-7 expression in those cancers where it is downregulated may be a potential treatment option. Exosomes are tiny vesicles that move through body fluids and can include components like miRNAs (including let-7) that are important for communication between cells. Studies proved that exosomes are able to enhance tumor growth, angiogenesis, chemoresistance, metastasis, and immune evasion, thus suggesting their importance in GC management.

Keywords: Cervical cancer; Endometrial cancer; Gyncological cancer; Let-7; MicroRNA; Ovarian cancer.

Fig. 1

Canonical pathway of miRNA biogenesis. The standard miRNA biogenesis process is depicted in a schematic diagram. The Drosha microprocessor in the nucleus processes an RNA polymerase II-generated main miRNA transcript. An EXP5-Ran-GTP-dependent mechanism is utilized to transport the pre-miRNA to the cytoplasm for further processing by the Dicer microprocessor to produce a mature miRNA. Prior to Dicer-mediated processing, LIN28A and TUTases mono-uridylate pre-let-7 at its 3′ terminus. Translation of the target mRNA is prevented by loading the mature miRNA into the RISC

Fig. 2

MicroRNA biogenesis (miRNAs). A POL II or POL III transcription of miRNA genes starts the canonical miRNA production. DROSHA/DiGeorge syndrome crucial region 8 processes pri-miRNAs (DGCR8). Exportin-5 (XPO-5) is a pre-miRNA transporter that moves them into the cytoplasm. Splicing out miRtrons and debranching the intron lariat by DBR1 creates pre-miRNAs. TRBP, a protein that cleaves exported pre-miRNAs, is part of the DICER/trans-activation-responsive RNA family. C3PO complex degrades the passenger strand. The RISC-loaded guide strand represses translation and degrades transcripts. B DICER-independent miR-451 processing. The passenger strand is cleaved and destroyed by AGO2-mediated cleavage following DROSHA/DGCR8 processing and export to the cytoplasm. C SnoRNAs are processed non-canonically to produce sdRNAs, which are RNAs derived from them. DBR1 debranches gene-spliced snoRNAs. Unknown mechanisms are involved in the export of SnoRNAs to the cytoplasm, where they are converted by DICER into sdRNAs and loaded into RISC. D MiRNAs are produced by non-canonical tRNA processing. XPO-5/XPO-T transfer tRNAs to the cytoplasm after transcription. The 5′ and 3′ loops are cut by DICER, releasing 5′ and 3′ tRNA-derived RNA (tDR) fragments. Angiogenin (ANG), which cleaves the anticodon loop (tiRNAs), is the source of 5′-tRNA stress-induced fragmentation. Every single tDR-fragment is loaded into RISC similarly to conventional miRNAs. (Bourla and Zamarin 2016) Lupus autoantigen (LA) stabilises after transcription, and XPO-T exports tRNAs to the cytoplasm. LA maintains tRNAs stablility for translation by inhibiting DICER processing. TNRC6A: trinucleotide repeat-containing gene 6A, HSP90: heat shock protein 90

Fig. 3

Mirna nuclear localisation. Pre-miRNAs undergo DICER/TRBP nuclear processing by DROSHA/DGCR8 for either (Rema 2019) destruction or (Bourla and Zamarin 2016) RISC loading by either human antigen R (HuR) or heterogeneous nuclear ribonucleoprotein D (HNRPD). This shuttles between the nucleus and the cytoplasm in an unclear manner

Fig. 4

Role of let-7 in ovarian cancer

Fig. 5

The influence of let-7 on cancers and illnesses affecting the female reproductive system is significant. Let-7 expression is disrupted in a range of obstetric and gynecological disorders. This disruption is caused by hormonal and cytokine factors and is controlled both during transcription and after. The importance of let-7 in the progress and management of various medical conditions lies in its ability to target key mRNA molecules involved in regulating cellular growth, apoptosis, angiogenesis, and immune cell function

Fig. 6

The secretion of extracellular vesicles (EVs) involves several distinct mechanisms. One such mechanism is the direct formation of microvesicles (MVs) through the budding of the plasma membrane. A different process includes changing extracellular vesicles (EVs) into intraluminal vesicles (ILVs) while they are inside multivesicular endosomes (MVBs), and subsequently letting them out by merging with the cell's outer layer, eventually creating exosomes. The essential function of these exosomes is to aid in the transmission of messages between tumor cells and other types of cells, including tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). The exosomes contain important molecules, including let-7 and others, which are transferred to various cells through both microvessel transport and direct internalization by TAMs, CAFs, and other cell types