Abstract
Ovarian cancer (OC) is the most common gynecological malignancy worldwide, and chemoresistance occurs in most patients, resulting in treatment failure. A better understanding of the molecular processes underlying drug resistance is crucial for development of efficient therapies to improve OC patient outcomes. Circular RNAs (circRNAs) and ferroptosis play crucial roles in tumorigenesis and resistance to chemotherapy. However, little is known about the role(s) of circRNAs in regulating ferroptosis in OC. To gain insights into cisplatin resistance in OC, we studied the ferroptosis-associated circRNA circSnx12. We evaluated circSnx12 expression in OC cell lines and tissues that were susceptible or resistant to cisplatin using quantitative real-time PCR VSports注册入口. We also conducted in vitro and in vivo assays examining the function and mechanism of lnc-LBCSs. Knockdown of circSnx12 rendered cisplatin-resistant OC cells more sensitive to cisplatin in vitro and in vivo by activating ferroptosis, which was at least partially abolished by downregulation of miR-194-5p. Molecular mechanics studies indicate that circSnx12 can be a molecular sponge of miR-194-5p, which targets SLC7A11. According to our findings, circSnx12 ameliorates cisplatin resistance by blocking ferroptosis via a miR-194-5p/SLC7A11 pathway. CircARNT2 may thus serve as an effective therapeutic target for overcoming cisplatin resistance in OC.
Keywords: Chemoresistance, circSnx12, Ferroptosis, miR-194-5p, Ovarian cancer, SLC7A11
INTRODUCTION
Acquired chemoresistance to cisplatin (DDP) is a major therapeutic challenge facing ovarian cancer (OC) treatment (1). Thus, it is crucial to identify new diagnostic and prognostic metrics to aid in initiating and improving personalized treatment, ultimately improving patient survival. Circular RNA (circRNA), a type of single-stranded closed-loop RNA, is increasingly appreciated to play important roles in gene transcription and translation (2) largely by adsorbing miRNAs. Differentially expressed circRNAs have been identified in OC VSports在线直播. circRNAs play multiple critical roles in OC biological behavior, including tumor invasion, migration, metastasis, angiogenesis, and resistance to cisplatin chemotherapy (3, 4).
Ferroptosis is induced by abnormalities in iron, amino acid, and lipid metabolism (5). Recent evidence suggests that ferroptosis may play a role in chemoresistance in several cancers, and homeostasis of intracellular cysteine is key to protecting cells from ferroptosis (6). Solute Carrier Family 7 member 11 (SLC7A11), a key component of the cystine/glutamate antiporter system, is vital for glutathione (GSH) synthesis and resistance to ferroptosis (7) V体育2025版. It has also been suggested that inducing ferroptosis in OC may overcome cisplatin resistance (8). Characterization of circRNA signaling pathways and regulatory mechanisms will enable us to enhance our understanding of how circRNAs can impact chemoresistance.
Downregulation of circSnx12, which negatively regulates ferroptosis by adsorbing miR-224-5p, has been implicated in the molecular mechanism of heart failure in an aortal-ligation mouse model (9), suggesting a number of novel targets for overcoming chemoresistance in OC VSports. In this study, we sought to understand the biological role of circSnx12 in DDP-resistant OC cells and tissues. Our study investigated the roles of circSnx12 and its associated targets, and the molecular mechanisms underlying DDP resistance in OC.
RESULTS
Ferroptosis resistance contributes to DDP-resistance in OC cells, and CircSnx12 is elevated in OC tissues and cells resistant to cisplatin
As shown in Fig. 1A, the intracellular iron concentration increased after treatment with DDP. While ovarian cancer cell viability was markedly decreased by DDP treatment, the ferroptosis inducer-erastin acted synergistically with DDP treatment to increase cytotoxicity toward SKOV3 and A2780 cells, while the iron chelator-desferrioxamine (DFO) or the ferroptosis specific inhibitor ferrostatin-1 (Fer-1) alleviated the effects of DDP on SKOV3 and A2780 cell viability 24 h after DDP administration (Fig. 1B). Under the same conditions, the intensity of Fe staining and ferrous ion concentration in SKOV3/DDP and A2780/DDP cells decreased consistently (Fig. 1C, D). Expression of the ferroptosis inhibitors SLC7A11 and GPX4 increased markedly, and the level of the ferroptosis product 4-HNE decreased markedly in SKOV3/DDP and A2780/DDP cells (Fig. 1E). RT-qPCR revealed that circSnx12 expression was substantially elevated in OC tissues resistant to cisplatin relative to cisplatin-sensitive OC tissues (Fig. 1F). This result was confirmed by FISH immunofluorescence (Fig. 1G). We also noted increased circSnx12 expression in A2780/DDP and SKOV3/DDP cells resistant to cisplatin, relative to parent cells (Fig VSports app下载. 1H).
Fig. 1.
Assessment of the role of ferroptosis and CircSnx12 expression during DDP-induced chemoresistance in ovarian cancer. (A, B) Cell viability was detected in SKOV3 and A2780 cells treated with Erastin, DFO, or Fer-1 after treatment with DDP. Fe2+ was detected by staining with FerroOrange probe (C) and measured using an ELISA kit (D) in DDP-treated SKOV3, A2780, SKOV3/DDP, and A2780/DDP cells. Scale bars, 50 μm. (E) Ferroptosis protein biomarkers SLC7A11, GPX4, and 4-HNE were examined by Western blotting. (F) Quantitative real-time PCR (qRT-PCR) quantification of circSnx12 expression in OC tissues susceptible or resistant to DDP. (G) Fluorescence in situ hybridization (FISH) results examining circSnx12 distribution in OC tissues sensitive or resistant to DDP V体育官网. Scale bars, 200 μm. (H) CircSnx12 expression was elevated in DDP-resistant A2780/DDP and SKOV3/DDP cells relative to parental cells. Significance: ***P < 0. 001.
CircSnx12 protects DDP-resistant ovarian cancer cells from DDP by regulating ferroptosis
Two shRNAs targeting the circSnx12 back-spliced junction were also investigated. Because only lentivirus containing circSnx12-directed shRNA 2 significantly reduced circSnx12 in SKOV3/DDP and A2780/DDP cells (Fig. 2A), shRNA2-circSnx12 was selected for subsequent experiments. A CCK8 assay demonstrated that circSnx12-knockdown significantly reduced viability of DDP exposed cells compared to that of control cells (Fig. 2B). EdU assays showed that circSnx12-knockdown substantially decreased the number of EdU-positive proliferating A2780/DDP and SKOV3/DDP cells following DDP treatment (Fig. 2C). We evaluated apoptosis rates in SKOV3/DDP and A2780/DDP cells using flow cytometry, and found that DDP + circSnx12-knockdown significantly increased apoptosis (Fig. 2D). Glutathione (GSH) depletion, lipid peroxidation, and iron accumulation are key events in ferroptosis. In agreement with our conjecture, circSnx12-knockdown significantly increased GSH depletion (Fig. 2E), lipid peroxidation (Fig. 2F), and cellular Fe2+ (Fig. 2G, H) levels compared to A2780/DDP and SKOV3/DDP cells transfected with shRNA-Control. Altered expression of the ferroptosis-associated genes SLC7A11, GPX4, and GPX4 detected by western blot agreed well with this theoretical framework (Fig. 2I). We next explored the role of circSnx12 knockdown in the in vivo sensitivity of OC cells to DPP. Knockdown of circSnx12 significantly increased the DDP sensitivity of SKOV3/DDP cells (Fig. 2J). Subsequent IHC assays showed that Ki67 proliferative markers decreased more significantly in mice treated with DDP + circSnx12 knockdown than in mice treated with DDP or circSnx12 knockdown alone (Fig. 2K). Furthermore, DDP + circSnx12 knockdown significantly upregulated the ferroptosis product 4-HNE (Fig. 2K). These data illustrate that circSnx12 suppression lowers cisplatin resistance in OC in vivo.
Fig. 2.
Knockdown of circSnx12 increased DDP and ferroptosis sensitivity in resistant ovarian cancer. (A) The influence of shRNA targeting circSnx12 was evaluated by quantitative real-time PCR (qRT-PCR) in A2780/DDP and SKOV3/DDP cells. (B) DDP sensitivity was examined using a CCK-8 assay. (C) The percentage of EdU-stained cells was substantially reduced by circSnx12 knockdown in A2780/DDP and SKOV3/DDP cells. Scale bars, 100 μm. (D) Flow cytometric analysis and quantification of cell apoptosis following DDP administration in A2780/DDP and SKOV3/DDP cells transfected with shRNA-circSnx12 or shRNA-control. (E) A GSH Assay kit was used to examine intracellular levels of the antioxidant thiol GSH following DDP treatment in A2780/DDP and SKOV3/DDP cells transfected with shRNA-circSnx12 or shRNA-control. (F) Lipid peroxidation was detected using flow cytometry in A2780/DDP and SKOV3/DDP cells following DDP treatment. Fe2+ was detected with FerroOrange probe staining (G) and measured using an ELISA kit (H) in A2780/DDP and SKOV3/DDP cells following DDP treatment. Scale bar, 50 μm. (I) Ferroptosis protein biomarkers SLC7A11, GPX4, and 4-HNE were examined using western blotting. (J) A mouse xenograft tumor model was used to examine whether circSnx12 knockdown contributed to the antitumor effects of DDP. (K) Immunohistochemical image demonstrating expression of Ki-67 and ferroptosis product 4-HNE in xenograft tumors. Scale bar, 50 μm. Significance: *** P < 0.001.
Down-regulation of miR-194-5p reverses the impact of circSnx12 knockdown, restoring DDP and ferroptosis resistance in resistant ovarian cancer cells
It has been established that circRNA and miRNA can interact via miRNA recognition elements. We aimed to determine whether circSnx12 interacts with miRNAs in OC to clarify its mechanism of action. According to combinatorial evaluation of several databases (RegRNA, TargetScan, and Starbase), by contrast with other target miRNAs discovered, miR-194-5p was identified in common as a putative target of circSnx12 (Fig. 3A). The relative miR-194-5p expression level was considerably lower in DDP-resistant OC tissues according to RT-qPCR (Fig. 3B). In ovarian cancer tissues, Pearson’s correlation analysis indicated a substantial negative association between circSnx12 and miR-194-5p (Fig. 3C). Furthermore, circSnx12 and miR-194-5p were mostly located in the cytoplasm in SKOV3/DDP cells, with approximately the same spatial distribution (Fig. 3D). To validate the interaction between circSnx12 and miR-194-5p, a miR-194-5p-inhibitor, miR-NC, miR-194-5p, miR-194-5p-mimic, and dual-luciferase reporter were co-transfected into SKOV3/DDP cells. Dual-Luciferase results revealed that transfection of miR-194-5p-mimics considerably attenuate luciferase activity in cells transfected with circSnx12-WT, but not circSnx12-Mut reporter. The opposite outcome was obtained following miR-194-5p-inhibitor transfection (Fig. 3E). Furthermore, in SKOV3/DDP cells, transfection with lentivirus-overexpressing circSnx12 dramatically reduced miR-194-5p expression levels, whereas transfection with shRNA-circSnx12 significantly increased miR-194-5p expression (Fig. 3F). To examine if the circSnx12 knockdown-elicited increases in DDP and ferroptosis sensitivity were mediated by effects on miR-194-5p, we transfected A2780/DDP and SKOV3/DDP cells with shRNA-Control, shRNA-circSnx12, shRNA-circSnx12 + miR-NC or miR-194-5p-inhibitor, then exposed them to cisplatin. As illustrated in Fig. 3G, miR-194-5p expression was remarkably elevated bycircSnx12 knockdown in A2780/DDP and SKOV3/DDP cells, but was restored by transfection with the miR-194-5p-inhibitor. Additionally, downregulation of miR-194-5p attenuated circSnx12 knockdown-mediated elevation of DDP sensitivity, manifested by elevated EdU-positive cells and decreased apoptotic rates in cisplatin-challenged A2780/DDP and SKOV3/DDP cells (Fig. 3H, I). Restoration of miR-194-5p also relieved the impact of circSnx12 knockdown on lipid peroxidation, ferrous ion content, and ferroptosis-associated gene expression in A2780/DDP and SKOV3/DDP cells (Fig. 3J-L). These results indicate that circSnx12 knockdown might enhance susceptibility to DDP and ferroptosis in resistant OC cells by regulating miR-194-5p.
Fig. 3.
CircSnx12 functions as a sponge toward miR-194-5p to mediate DDP and ferroptosis sensitivity in DDP-treated resistant ovarian cancer. (A) The predicted binding domains between circSnx12 and miR-195-5p are presented. (B) miR-194-5p expression in OC tissues sensitive or resistant to DDP was quantified by qRT-PCR. (C) Correlation analysis of circSnx12 and miR-195-5p expression in OC is shown. (D) circSnx12 and miR-195-5p localization as detected by FISH assay in SKOV3/DDP cells. (E) CircSnx12 is shown to be a direct target of miR-195-5p utilizing a dual-luciferase reporter assay. (F) qRT-PCR analysis of miR-195-5p expression in SKOV3/DDP cells in different groups. (G) miR-194-5p mRNA levels were determined utilizing qRT-PCR in DDP-treated A2780/DDP and SKOV3/DDP cells transfected with shRNA-circSnx12, miR-194-5p-inhibitor or respective controls. (H) Cell proliferation was monitored through EdU assay. (I) A2780/DDP and SKOV3/DDP cells were transfected with shRNA-circSnx12, miR-194-5p-inhibitor, or respective controls, and the apoptosis rate, and the proportion of cell apoptosis caused by DDP administration, were measured by flow cytometry analysis. (J) Lipid peroxidation was detected with flow cytometry in A2780/DDP and SKOV3/DDP cells transfected with shRNA-circSnx12, miR-194-5p-inhibitor, or respective controls after treatment with DDP. (K) Fe2+ was detected using an ELISA kit. (L) Ferroptosis protein biomarkers SLC7A11, GPX4, and 4-HNE were evaluated by Western blotting. Significance: *P < 0.05, **P < 0.01, ***P < 0.001.
SLC7A11 mRNA was confirmed as a functional target of miR-194-5p
Potential miR-194-5p targets in ovarian cancer cells were predicted using TargetScan/miRanda database analysis. SLC7A11 was identified as a possible target meriting further study (Fig. 4A). Luciferase Reporter analysis confirmed that the 3-UTR of SLC7A11 was a downstream target of miR-194-5p in A2780/DDP and SKOV3/DDP cells (Fig. 4A). SLC7A11 expression was assessed in DDP-resistant OC tissues and cells to examine the possible role of SLC7A11 in DDP resistance in OC. SLC7A11 expression was elevated in chemoresistant OC tissues and DDP-resistant A2780/DDP and SKOV3/DDP OC cells relative to chemosensitive tissues and parental A2780 and SKOV3 cells (Fig. 4B, C). Western blotting and RT-qPCR were used to study the association between miR-194-5p and SLC7A11. MiR-194-5p-mimic considerably down-regulated SLC7A11 expression and the miR-194-5p-inhibitor exerted the opposite effect, whereas lentivirus overexpressing SLC7A11 increased SLC7A11 expression at both mRNA and protein levels (Fig. 4D, E). EdU analysis illustrated that miR-194-5p up-regulation lowered the number of EdU-positive cells, and SLC7A11 overexpression boosted EdU-positive cells under DDP administration (Fig. 4F). In agreement with our previous results, miR-194-5p overexpression promoted cell apoptosis, whereas SLC7A11 overexpression inhibited ovarian cancer cell apoptosis following DDP administration (Fig. 4G).
Fig. 4.
SLC7A11 is a direct target of miR-194-5p in ovarian cancer. (A) Targetscan was employed to predict binding domains between miR-194-5p and SLC7A11. The interplay between miR-194-5p and SLC7A11 in A2780/DDP and SKOV3/DDP cells was verified by luciferase reporter assay. (B) IHC analysis of SLC7A11 expression level in DDP-resistant/sensitive ovarian tumor tissues. Scale bar, 200 μm. (C) SLC7A11 protein was monitored by immunofluorescence in OC cells and parental cells that are DDP-resistant. Scale bar, 20 μm. (D, E) The impacts of miR-194-5p on SLC7A11 expression in A2780/DDP and SKOV3/DDP cells were examined by qPCR and western blot. (F) The percentage of EdU-stained cells was significantly rescued by SLC7A11 overexpression in A2780/DDP and SKOV3/DDP cells. (G) Flow cytometric analysis and quantification of cell apoptosis after DDP administration in A2780/DDP and SKOV3/DDP cells correspondingly transfected. Significance: **P < 0.01, ***P < 0.001.
DISCUSSION
When treating OC patients with chemotherapy, DDP is usually the first choice to suppress tumor cell vitality and destroy tumor cells (10). CircRNAs play critical roles in regulating chemosensitivity in various cancers (11). In view of the emerging role of ferroptosis in cancer treatment, we here explored whether the ferroptosis-regulating circSnx12 mediated the underlying mechanism of OC resistance. CircSnx12 expression is substantially enhanced in OC tissues and DDP-resistant cells. CircSnx12 knockdown reduced cell viability and enhanced ferroptosis, restoring DDP-sensitivity to DDP-resistant OC cells. Furthermore, circSnx12 knockdown in OC cells using viral shRNA transfer enhanced DDP antitumor efficacy in vivo. Consequently, chemoresistance in OC was prevented in vitro and in vivo by downregulating CircSnx12.
Classic circRNA mechanisms include adsorbing miRNA targets to inhibit their function. Consequently, we screened for potential circSnx12 target miRNAs using bioinformatic analysis, and confirmed that miR-194-5p is a circSnx12 target. Our data indicate that circSnx12 upregulates SLC7A11 expression in OC by sponging miR-194-5p. The exact function of miR-194-5p in OC DDP resistance remains a mystery. In this study, miR-194-5p expression was repressed in DDP-resistant OC tissues, and cicrRNA-miRNA interactions and mRNA silencing are the mechanisms by which this miRNA exerts its function in regulating OC cell resistance to DDP.
miRNA-194-5p has reportedly been implicated in the chemotherapy resistance mechanisms of many cancers. Taxol resistance is enhanced by circ _0006168 mediated miR-194-5p/JMJD1C regulation in esophageal squamous cell carcinoma (12). In colorectal cancer, H19, a long noncoding RNA, increases 5-Fu resistance through autophagy mediation by miR-194-5p (13). Similarly, CCND2 is suppressed by EZH2-related knockdown of miR-194-5p by the long noncoding RNA TUG1 to promote cell growth and chemoresistance in bladder cancer (14). By targeting hypoxia-inducible factor-1, MiR-194-5p may improve the sensitivity of non-small cell lung cancer to the chemotherapeutic drug doxorubicin (15). Our results support those of previous OC-related studies showing that paclitaxel resistance in OC cells is modulated by miR-194-5p through modulation of ZEB1 expression (16), and miR-194-5p modulates OC cell resistance to paclitaxel by regulating MDM2 expression (17). Moreover, circSnx12 can physically interact with miR-194-5p to negatively affect its function. Hence, circSnx12 may facilitate OC chemoresistance by sequestering miR-194-5p.
Ferroptosis can be triggered by SLC7A11 inhibition, which can alleviate tumor drug resistance (18). Erastin can induce ferroptosis in ovarian cancer, reversing ABCB1-mediated resistance to docetaxel (8). Erastin is the most powerful known inhibitor of SLC7A11, and thereby disrupts chemotherapeutic resistance. Our results obtained from co-administration of erastin and DDP corroborate this conclusion, and suggest that SLC7A11 might be a viable therapeutic target. At present, the molecular processes underlying this modulation in OC are not completely understood. We have here demonstrated for the first time that ferroptosis can be induced in OC cells by administration of DDP, and ferroptosis resistance contributes to drug resistance in cancer cells. We also showed that circSnx12 inhibition impacts SLC7A11 and ferroptosis regulation. Mechanistically, circSnx12 inhibition allowed miR-194-5p to suppress SLC7A11 expression, whereas loss of miR-194-5p prevented SLC7A11 downregulation upon circSnx12 inhibition. Taken together, our data link circSnx12 with ferroptosis and chemoresistance via the miR-194-5p-SLC7A11 pathway.
Our in vitro experiments shed light on the molecular mechanisms underlying the contribution of CircSnx12 to chemoresistance. We also evaluated CircSnx12’s function in vivo. A reduction in chemoresistance was observed in OC cell lines when circSnx12 expression was knocked out, and tumorigenicity was also reduced in nude mice. CircSnx12 is a possible target for OC treatment and chemoresistance to DDP.
CONCLUSION
This study provides a novel experimental and theoretical basis for understanding OC chemoresistance to DDP-based chemotherapy. We have shown that circSnx12 interacts with miR-194-5p/SLC7A11 to enhance DDP sensitivity of ferroptosis in OC cells. This finding contributes to understanding the therapeutic role of circRNAs in OC and provides critical insights into the beneficial manipulation of circSnx12/miR-194-5p/SLC7A11 in combating drug resistance during OC treatment.
MATERIALS AND METHODS
Cell culture and transfection
The Cell Bank of the Chinese Academy of Sciences (Shanghai, China) supplied SKOV3 and A2780 cell lines. These cells were cultured at 37°C in a humidified chamber containing 5% CO2 in DMEM supplemented with 10% fetal bovine serum (FBS) (Gibco, Carlsbad, CA, USA), 1% antibiotics (Gibco), 100 μg/ml streptomycin, and 100 U/ml penicillin (Sigma-Aldrich, St. Louis, MO, USA). Subsequently, DDP-resistant cell lines A2780/DDP and SKOV3/DDP were established by culturing for 3 months in increasing concentrations of DDP (Sigma-Aldrich, USA) (from 0.5 ug/ml to 1.0 ug/ml). DDP treatment was performed using 1.0 ug/ml DDP. Lentiviral vectors encoding a short hairpin RNA (shRNA) targeting circSnx12 and a negative control (shRNA-circSnx12, shRNA-Control), miR-194-5p mimic, inhibitor, and control (miR-194-5p-inhibitor, miR-194-5p-mimic, and miR-NC) were acquired from GenePharma (Shanghai, China). The miRNA sequences were as follows: miR-194-5p mimic, 5’-AA GGCAGGGCCCCCGCUCCCC-3’; miR-194-5p-inhibitor, 5’-GG AG CGGGGGCCCUGCCUUUU-3; scrambled miRNA control, 5’-CAGUACUUUUGUGUAGUACAA-3. SLC7A11 overexpression was achieved by constructing pcDNA-SLC7A11 using 100 molecular clones and ligating the SLC7A11 sequence into the pcDNA vector (Invitrogen, Carlsbad, CA, USA). Vectors or RNAs were transfected into OC cells in accordance with the guidelines of the LipofectamineTM 3000 Kit (Invitrogen) for 48 h based on the reagent instructions with a final concentration of 20 nM. Transfected cells were used for experiments after 48 h of transfection. Transfection efficiency was examined using Realtime Quantitative Polymerase Chain reaction (qRT-PCR) and western blotting. Primer sequences for SLC7A11 were F:5’-ATACGCTGAGTGTGGTTTGC-3’ and R:5’-CTTCATCCACTTCC ACAGCG-3’. Primer sequences for miR-194-5p were F:5’-GC GGCGGTGTAACAGCAACTCC-3’; R:5’-ATCCAGTGCAGGGT CCGAGG-3’. Primer sequences for circSnx12 were F:5’-ATCG CTCCCTCGATGTGTC-3’ and R:5’-TCCGGGGGAGAAGGTTC-3’.
Cell viability
A CCK-8 assay was carried out to assess cell viability. Cells (1 × 105 cells/ml) were plated in 96-well plates and incubated for 24 h at 37°C with 5% CO2. Next, 10 μl CCK8 solution was added to each well, and cells were incubated for 4 h. Absorbance at 450 nm was measured using a microplate reader.
AVAILABILITY OF DATA AND MATERIALS
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Funding Statement
ACKNOWLEDGEMENTS This study was supported by the Key Project of the Natural Science Foundation of Hebei Province (Grant No. H2020206223).
V体育官网入口 - Footnotes
CONFLICTS OF INTEREST
The authors have no conflicting interests.
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Associated Data
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Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.