Shuo Li

Application in Gene Editing in Ovarian Cancer Therapy

The onset and progression of ovarian cancer (OC) are closely related to dysregulated gene expression. Current treatments for OC are mainly limited to surgery and chemotherapy. However, due to low drug sensitivity, the prognosis OC is exceptionally poor and the recurrence rate remains high. Hence, it is vital to develop new treatment strategies. Gene editing for site-specific genomic modification is a powerful novel tool for the treatment of OC. In this article, current gene editing research for the treatment of OC is reviewed to provide a reference for the clinical application of new approaches to improve treatment outcomes and prognosis.

FUS-stabilized USP7 facilitates the bevacizumab resistance of ovarian cancer through deubiquitinating PTK2

The emergence of drug resistance brings new challenges to the clinical management of ovarian cancer (OC) patients. This study aimed to explore the role and mechanism of ubiquitin-specific peptidase 7 (USP7) on the bevacizumab resistance of OC. The mRNA levels of USP7 and protein tyrosine kinase 2 (PTK2) were measured using quantitative real-time polymerase chain reaction. Western blot analysis was used for detecting the protein levels of USP7, PTK2 and fused in sarcoma (FUS). Cell resistance, proliferation, apoptosis, invasion and angiogenesis were determined by cell counting kit 8 assay, colony formation assay, flow cytometry, transwell assay and tube formation assay. Glucose consumption, lactate production, and ATP/ADP ratio were used to evaluate glycolysis. The interactions between USP7 and PTK2/FUS were detected by co-immunoprecipitation assay. Mice xenograft model was also constructed to explore USP7 roles in vivo. USP7 was upregulated in OC tissues and bevacizumab-resistant cells. USP7 knockdown or its inhibitor P22077 inhibited the bevacizumab resistance of OC cells via suppressing cell growth, metastasis, angiogenesis and glycolysis. USP7 stabilized PTK2 protein expression via deubiquitinating. PTK2 overexpression reversed the effect of USP7 knockdown on the bevacizumab resistance of OC cells. Besides, FUS stabilized USP7 mRNA to regulate its protein level, and it could affect PTK2 expression by mediating USP7. USP7 knockdown enhanced the sensitivity of OC tumors to bevacizumab in vivo. FUS-stabilized USP7 enhanced the bevacizumab resistance of OC by deubiquitinating PTK2, providing a new idea for overcoming bevacizumab resistance in OC.

Resensitizing Paclitaxel-Resistant Ovarian Cancer via Targeting Lipid Metabolism Key Enzymes CPT1A, SCD and FASN

Epithelial ovarian cancer (EOC) is a lethal gynecological cancer, of which paclitaxel resistance is the major factor limiting treatment outcomes, and identification of paclitaxel resistance-related genes is arduous. We obtained transcriptomic data from seven paclitaxel-resistant ovarian cancer cell lines and corresponding sensitive cell lines. Define genes significantly up-regulated in at least three resistant cell lines, meanwhile they did not down-regulate in the other resistant cell lines as candidate genes. Candidate genes were then ranked according to the frequencies of significant up-regulation in resistant cell lines, defining genes with the highest rankings as paclitaxel resistance-related genes (PRGs). Patients were grouped based on the median expression of PRGs. The lipid metabolism-related gene set and the oncological gene set were established and took intersections with genes co-upregulated with PRGs, obtaining 229 co-upregulated genes associated with lipid metabolism and tumorigenesis. The PPI network obtained 19 highly confidential synergistic targets (interaction score > 0.7) that directly associated with CPT1A. Finally, FASN and SCD were up-stream substrate provider and competitor of CPT1A, respectively. Western blot and qRT-PCR results confirmed the over-expression of CPT1A, SCD and FASN in the A2780/PTX cell line. The inhibition of CPT1A, SCD and FASN down-regulated cell viability and migration, pharmacological blockade of CPT1A and SCD increased apoptosis rate and paclitaxel sensitivity of A2780/PTX. In summary, our novel bioinformatic methods can overcome difficulties in drug resistance evaluation, providing promising therapeutical strategies for paclitaxel-resistant EOC via taregting lipid metabolism-related enzymes.