Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 294-305 http://medscipublisher.com/index.php/cge 297 Additionally, the modulation of microRNA expression has been studied, with miRNAs like miR-18a and miR-654-5p showing tumor-suppressive effects in ovarian cancer by inhibiting cell proliferation and invasion, thus presenting potential therapeutic avenues (Quiñones-Díaz et al., 2020). These findings have shed light on the genetic mechanisms underlying tumor growth and metastasis, offering new targets for cancer treatment. 3.3 Genetic modifications in ovarian cancer cell lines Ovarian cancer cell lines have been genetically modified using CRISPR-Cas9, TALENs, and RNA interference to study cancer progression and resistance to chemotherapy. These modifications allow researchers to simulate specific genetic changes and study their impacts on cancer behavior. For instance, high-throughput CRISPR screens in high-grade serous ovarian cancer (HGSOC) cell lines have identified novel genes that could be targeted to overcome chemoresistance. One study, which involved knocking out 188 drug-target genes, revealed that only a small subset of these genes were highly expressed in platinum-resistant ovarian cancer cells, indicating their potential as therapeutic targets (Dai et al., 2018). Additionally, modifications in Cyclin A1 expression in ovarian cancer cell lines have been linked to increased resistance to paclitaxel, doxorubicin, and other chemotherapeutic agents, providing insights into the role of this gene in drug resistance (Huang et al., 2016). These genetic modifications are crucial for developing new drug resistance models and identifying genes involved in cancer cell survival and proliferation. 3.4 Genome-wide screens for drug resistance genes Genome-wide CRISPR and shRNA screens have become essential tools for identifying genes responsible for drug resistance in ovarian cancer. By systematically knocking out genes across the genome, researchers can identify those that confer resistance to chemotherapy. For instance, in one study, a pooled shRNA library screen identified 34 potential tumor suppressor genes involved in peritoneal metastasis and resistance to platinum-based chemotherapy. Key genes like RAD51C and TXN were found to suppress metastasis by regulating cell adhesion and invasion, while knockdown of KPNB1 sensitized ovarian cancer cells to platinum-based chemotherapy (Kodama et al., 2016). Another study explored the role of DNA methylation in drug resistance, identifying epigenetic modifications that alter the expression of genes involved in chemoresistance. The study revealed that targeting methylation pathways could restore chemosensitivity in resistant ovarian cancer cells (Romero ‐Garcia et al., 2020). These genome-wide approaches provide a comprehensive view of the genetic alterations contributing to drug resistance, paving the way for new therapeutic strategies to overcome chemoresistance in ovarian cancer. 4 Gene Editing in Ovarian Cancer Therapy Development 4.1 Targeting BRCA1/BRCA2 mutations in ovarian cancer Gene editing technologies, notably CRISPR-Cas9, have transformed the development of therapeutic approaches in ovarian cancer. These advancements allow targeted modification of cancer-related genes, such as BRCA1/BRCA2, providing insights into personalized treatments. Furthermore, gene editing enhances immunotherapies and corrects tumor suppressor gene functions, offering promising strategies to combat the disease. Mutations in BRCA1 and BRCA2 are commonly found in ovarian cancer and lead to defects in DNA repair through homologous recombination (HR), increasing vulnerability to DNA-damaging agents like PARP inhibitors and platinum-based chemotherapy. CRISPR-Cas9 has been effectively used to knock out or repair BRCA1 and BRCA2 in ovarian cancer models to study their function and potential therapeutic responses. For example, in a CRISPR study, ovarian cancer models with BRCA2 knockout showed increased sensitivity to the PARP inhibitor rucaparib, highlighting the potential for synthetic lethality in treating BRCA-mutated cancers (Walton et al., 2016). Additionally, alternative splicing variants of BRCA1, such as BRCA1-Δ11q, have been identified as mechanisms for drug resistance. By using CRISPR to target and correct splicing errors, researchers can potentially overcome therapeutic resistance, restoring sensitivity to treatments like PARP inhibitors (Wang et al., 2016).
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