Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 329-345 http://medscipublisher.com/index.php/cge 338 7.1 Mechanism of gene silencing: how ncRNAs regulate gene expression post-transcriptionally Non-coding RNAs (ncRNAs) play a pivotal role in the regulation of gene expression at the post-transcriptional level. This regulation is primarily achieved through mechanisms such as RNA interference (RNAi), where small ncRNAs like microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) bind to target messenger RNAs (mRNAs) to inhibit their translation or promote their degradation. miRNAs, for instance, typically bind to the 3' untranslated region (3' UTR) of target mRNAs, leading to either translational repression or mRNA degradation (Hussen et al., 2021; Khan et al., 2021). This binding is facilitated by the RNA-induced silencing complex (RISC), which guides the miRNA to its complementary mRNA target (Syeda et al., 2020). LncRNAs, on the other hand, can act as competing endogenous RNAs (ceRNAs) by sponging miRNAs, thereby preventing them from binding to their target mRNAs. This sponging action effectively de-represses the miRNA target genes, allowing their expression (Liu et al., 2020; Zhu et al., 2021). Additionally, lncRNAs can directly interact with mRNAs or proteins to modulate gene expression through various mechanisms, including chromatin remodeling and transcriptional regulation (Braga et al., 2020). 7.2 Examples of Silencing ncRNAs: miR-139-5p and its role in cancer progression One notable example of a silencing ncRNA in ovarian cancer is miR-139-5p. This miRNA has been shown to play a significant role in the progression of ovarian cancer by targeting and downregulating specific oncogenes. For instance, miR-139-5p targets Rho-associated coiled-coil containing protein kinase 2 (ROCK2), a gene involved in cell proliferation, migration, and invasion. The lncRNA TTN-AS1 has been found to promote ovarian cancer progression by sponging miR-139-5p, thereby preventing it from inhibiting ROCK2 expression. This interaction highlights the ceRNA mechanism where TTN-AS1 indirectly upregulates ROCK2 by sequestering miR-139-5p (Liu et al., 2020). Another example is the lncRNA LINC01132, which acts as a ceRNA for miR-431-5p in epithelial ovarian cancer (EOC). By sponging miR-431-5p, LINC01132 prevents it from downregulating the oncogene SOX9, thereby promoting cancer cell proliferation, migration, and invasion (Zhu et al., 2021). These examples underscore the complex regulatory networks involving ncRNAs and their significant impact on gene expression and cancer progression. 7.3 Clinical implications: how silencing mechanisms affect therapy resistance and outcomes The mechanisms of ncRNA-mediated gene silencing have profound clinical implications, particularly in the context of therapy resistance and patient outcomes in ovarian cancer. The dysregulation of ncRNAs can lead to altered expression of genes involved in drug resistance, metastasis, and overall cancer aggressiveness. For instance, the overexpression of lncRNAs that act as ceRNAs can sequester tumor-suppressive miRNAs, leading to the upregulation of oncogenes and contributing to chemoresistance (Braga et al., 2020). In ovarian cancer, the lncRNA GAS5 has been shown to suppress tumor progression by targeting miR-196a-5p and thereby regulating the expression of HOXA5, a gene involved in cell proliferation and apoptosis. Lower levels of GAS5 and higher levels of miR-196a-5p are associated with larger tumor sizes and advanced disease stages, indicating that the GAS5/miR-196a-5p/HOXA5 axis plays a critical role in ovarian cancer progression and could be a potential therapeutic target (Zhao et al., 2018). Moreover, the epigenetic silencing of tumor-suppressive miRNAs through DNA methylation and histone modifications can also contribute to poor prognosis and therapy resistance. For example, the hypermethylation of miR-124a in acute lymphoblastic leukemia (ALL) leads to its downregulation, resulting in the upregulation of its target gene CDK6 and promoting cancer cell proliferation. Similar epigenetic mechanisms may be at play in ovarian cancer, affecting the expression of key miRNAs and their target genes (Agirre et al., 2009). Understanding these ncRNA-mediated silencing mechanisms provides valuable insights into the molecular underpinnings of ovarian cancer and highlights potential avenues for developing targeted therapies. By modulating the expression of specific ncRNAs or their target genes, it may be possible to overcome therapy
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