Research ArticleExperimental Studies
Open Access

Adenosine Deaminase Family Acting on RNA 1 (ADAR1) May Be a De Novo Target for Endometriosis Treatment

THUY HA VU, KEIICHIRO NAKAMURA, KUNITOSHI SHIGEYASU, KOTARO KUBO, CHIAKI KASHINO and HISASHI MASUYAMA
In Vivo March 2024, 38 (2) 683-690; DOI: https://doi.org/10.21873/invivo.13489

Abstract

Background/Aim: Adenosine deaminase family acting on RNA 1 (ADAR1) expression was examined to determine its correlation with endometriosis. The biological functions and inhibitory effects of ADAR1 knockdown were investigated in a human endometriotic cell line. Materials and Methods: ADAR1 was examined in patients with and without endometriosis using reverse transcription polymerase chain reaction (RT-PCR), and the apoptotic expression of ADAR1 small interfering RNA (siRNA) was confirmed using flow cytometry. The biological functions and inhibitory effects of ADAR1 knockdown were investigated using RT-PCR in a 12Z immortalized human endometriotic cell line. Results: ADAR1 expression was significantly higher in patients with endometriosis than in those without (p<0.001). ADAR1 siRNA increased early and late apoptosis, compared to the mock (24.83%) and control (19.96%) cells. ADAR1 knockdown led to apoptosis through MDA5, RIG-I, IRF3, IRF7, caspase 3, caspase 7, and caspase 8 expression in the cell lines. Conclusion: ADAR1 is a potential novel therapeutic target in endometriosis.

Key Words:

Endometriosis is a chronic inflammatory disease associated with debilitating chronic pelvic pain, which affects 6%-10% of women of reproductive age (1). The main hypotheses regarding the etiopathogenesis of endometriosis include retrograde menstruation, coelomic metaplasia, and an embryonic origin. Mechanisms involved in this complex and multifactorial disease include estrogen dependence, aberrant inflammatory response, abnormal angiogenesis, and genetic and epigenetic alterations (2).

The aim of the study was to discover new therapeutic targets for endometriosis, focusing on epigenetic factors. One type of epigenetic mechanism is RNA editing, which regulates the posttranscriptional activity of essential genes by altering their amino acid sequences, leading to changes in gene expression (3). One such RNA editing process, wherein the conversion of adenosine (A) to inosine (I) in primary RNA transcripts (A-to-I editing) is mediated by adenosine deaminase family acting on RNA (ADAR), leads to transcriptome diversification in human cells (4). This family includes three enzymes: ADAR1, ADAR2, and ADAR3. ADAR1 and ADAR2 are ubiquitously expressed and exhibit catalytic activity (5-9). ADAR1 suppresses interferon (IFN) expression and IFN-mediated activity, and it is the most abundant gene in humans (10). Li et al. reported that high ADAR1 expression is significantly associated with endometriosis (11). However, the role of ADAR1 in endometriosis has not yet been investigated in detail. Therefore, this study aimed to explore the role of ADAR1 in endometriosis and demonstrate the potential of ADAR1 as a new therapeutic target for endometriosis.

Materials and Methods

Patient and tissue specimens. The study was approved by the Institutional Ethics Committee of the Okayama University (approval number: K2212-042). Informed consent was obtained from all the participants. All procedures were performed in accordance with relevant ethical standards and institutional ethics committee regulations. The endometriosis group was collected from retroperitoneal adipose tissue from the peritoneum of the ovarian fossa, and the non-endometriosis group was collected from peritoneal adipose tissue excised during hysterectomy. Endometriotic lesions were confirmed by histopathology using the ASRM classification of endometriosis. Twenty female patients of reproductive age who underwent surgical treatment at the Okayama University Hospital between April 2014 and October 2022 were recruited into the study after providing informed consent. Subjects were classified into the endometriosis group (n=15) or the control group (n=5). Numbers represent the data from triplicate experiments.

RNA isolation and real-time quantitative PCR analyses. The degree of RNA editing of ADAR1, interferon regulatory factor (IRF) response gene, such as melanoma differentiation-associated gene 5 (MDA5), retinoic acid inducible gene-I (RIG-I), protein kinase R (PKR), IRF3, IRF7, apoptosis pathway of Caspase 3, Caspase 7, and Caspase 8 were analyzed using real-time quantitative PCR as previously reported (12). We added the cytokines IL-1β, IL-6, and IL-8 and performed real-time quantitative PCR. The real-time PCR used the primers: 5′-CCCTTCAGCCACATCCTTC-3′ (ADAR1-F), 5′-GCCATCTGCTTTGCCACTT-3′ (ADAR1-R); 5′-TCACGGACT TGCCCTCTCCA-3′ (MDA5-F), 5′GCAGCAATCCGGTTTCTG TCT-3′ (MDA5-R); 5′-GCAGAGCACAAGCCTGTCTTCC-3′ [interleukin (IL)-1β-F], 5′-ACCTGTCTTGGCCGAGGACTAAG - 3′ (IL-1β-R); 5′- TGAATTGGATGGTCTTGGTCC-3′ (IL-6-F), 5′-CCCAATTTCCAATGCTCTCCT-3′ (IL-6-R); 5′-CTATTTGACCT CTGCGCATT-3′ [retinoic acid-inducible gene-I (RIG-I)-F], 5′-CCATACCACACGTTGCTACA-3′ (RIG-I-R); 5′-GCAGCAGTGGTTGGAAAAGA-3′ [protein kinase R (PKR)-F], 5′-TGTT GCAAGGCCAAAGTCTC-3′ (PKR-R); 5′-TCGAGGTGACAGC CTTCTAC-3′ [interferon regulatory factor (IRF)3-F], 5′-GCCT CACGTAGCTCATCACT-3′ (IRF3-R); 5′-TACCATCTACCTGGGCTTCG-3′ (IRF7-F), 5′-GCTCCATAAGGAAGCACTCG-3′ (IRF7-R); 5′-TGTATGCTTACTCTACCGCACCCG-3′ (Caspase 3-F), 5′-GCGCAAAGTGACTGGATGAACC-3′ (Caspase 3-R); 5′-TTCGACGGAAGACGGAGTTG-3′ (Caspase 7-F), 5′-CCGG ACATCCATACCTGTCG-3′ (Caspase 7-R); 5′-CAACTACAGC AGCCTATGCCACCTAGT-3′ (Caspase 8-F), and 5′-CCAGTCCGCCAAAGTTTAC-3′ (Caspase 8-R), 5′- CTGCACCACCAACTGCTTAG-3′ (GAPDH-F), and 5′-GTCTTCTGGGTGGCAG TGAT-3′ (GAPDH-R).

All procedures were performed according to the manufacturer’s instructions. The real-time quantitative PCR was performed for gene expression analysis using the The iTaq Universal SYBR Green OneStep Kit and the MiniOpticon Real-Time PCR System (Bio-Rad, Hercules, CA, USA), as reported in our previous study (12). GAPDH was used as a normalization control. The relative expression of each mRNA was determined using the ΔΔCt method. Numbers represent the data from triplicate experiments.

Reagents. 12Z immortalized human endometriotic cell line was purchased from Applied Biological Materials (Vancouver, Canada). The effect of estrogen was obtained from Fujifilm (Fujifilm, Osaka, Japan). ADAR1 siRNA (siADAR1, sc-37657), control siRNA (siControl, sc-37007), and siRNA transfection reagent (sc-29528) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA).

Cell culture and small-interfering RNA (siRNA) transfection. 12Z immortalized human endometriotic cell line was maintained in Dulbecco’s modified eagle’s medium (DMEM)/F12 phenol red-free (Life Technologies, Carlsbad, CA, USA), supplemented with 10% fetal bovine serum (FBS) in a humidified incubator containing 5% CO2 at 37°C. All experiments were performed using cells that did not exceed 15-20 passages. These Cell lines were transfected with an annealed ADAR1 siRNA, control siRNA, or an empty vector (mock) for gene silencing using an siRNA transfection reagent.

3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. The effect of estrogen and ADAR1 siRNA on the cell proliferation of 12Z immortalized human endometriotic cell line was evaluated using the MTS assay (Promega, Madison, WI, USA). After the cells were cultured overnight in phenol red-free DMEM/F12 medium supplemented with 10% FBS, they were deprived of 10% FBS, and incubated with the control or assigned concentration of estrogen. For small-interfering RNA (siRNA) transfection, cells were transiently transfected with the control siRNA and ADAR1 siRNA for 48 h. After incubation with MTS for 1 h, the absorbances were measured at a wavelength of 490 nm using an ELISA plate reader (Bio-Rad). Numbers represent the data from triplicate experiments.

Apoptosis assay. The apoptosis of endometrial cells was evaluated by staining with fluorescein isothiocyanate (FITC)-conjugated annexin V using a MEBCYTO Apoptosis kit (MBL International Corp., Woburn, MA, USA). Furthermore, the apoptosis was analyzed with the FACS cytometer as previously described (12).

Cell growth in monolayers. For evaluation of cell growth in monolayers, cells were plated at a density of 2×104 cells/well in 6-well plates containing DMEM/F12 supplemented with 10% FBS. The cell numbers were counted in triplicate after 2, 4, and 6 days using a hemocytometer to assess cell proliferation. Numbers represent the data from triplicate experiments.

Statistical analysis. The StatView version 26.0 software (Abacus Concepts, Berkeley, CA, USA) was used to perform statistical analyses. Between-group differences were assessed using the Mann–Whitney U-test and χ2 test, as appropriate. Two-sided p-values<0.05 were considered statistically significant.

Results

ADAR1 expression is positively correlated with endometriosis. ADAR1, IL-1β, IL-6, and IL-8 expressions were examined in endometriosis patients and non-endometriosis patients by RT-PCR. ADAR1, IL-1β, IL-6, and IL-8 expressions were significantly higher in endometriosis patients than in non-endometriosis patients (p<0.001, p<0.001, p<0.001, and p=0.002) (Figure 1A). Furthermore, we examined the relationship between ADAR1 expression and IL-1β, IL-6, and IL-8. We found that ADAR1 expression was significantly correlated to IL-1β (R=0.594, R2=0.53, p=0.019), IL-6 (R=0.706, R2=0.498, p=0.003), and IL-8 (R=0.606, R2=0.367, p=0.017), as shown in Figure 1B.

Figure 1.
Figure 1.

Adenosine deaminase family acting on RNA 1 (ADAR1) interleukin (IL)-1β, IL-6, and IL-8 of non-endometriosis and endometriosis patients were analyzed by RT-PCR. (A) Tissue analysis of ADAR1 IL-1β, IL-6, and IL-8 with 5 non-endometriosis and 15 endometriosis patients. (B) Regression analysis for the ADAR1 and IL-1β, ADAR1 and IL-6, and ADAR1 and IL-8 into 15 endometriosis patients.

Estrogen strengthened ADAR1 expression in immortalized human endometriotic cell line. Estrogen at each concentration induced activation in the 12Z immortalized human endometriotic cell line, as shown in MTS assays (Figure 2A). Therefore, 12Z cells showed potent estrogenic effects. Furthermore, we investigated the changes in ADAR1 and cytokines, such as IL-1β, IL-6, and IL-8, induced by estrogen. The efficiency of ADAR1, IL-1β, IL-6, and IL-8 expressions were confirmed by PCR. As shown in Figure 2B, ADAR1 expression was significantly increased by 10−8 mol/l estrogen into the 12Z cell line (p=0.002). IL-1β and IL-6 expressions were significantly increased by estrogen in the 12Z cell line (p=0.008 and p=0.003). Moreover, IL-8 expression was significantly increased by estrogen in the 12Z cell line (p=0.001, Figure 2C).

Figure 2.
Figure 2.

Adenosine deaminase family acting on RNA 1 (ADAR1) interleukin (IL)-1β, IL-6, and IL-8 expressions of immortalized human endometriotic cell line by estrogen. (A) 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays of 12Z immortalized human endometriotic cell line for each concentration of estrogen (10−5-10−10 mol/l) for 48 h (h). (B) Real-time PCR analysis of the ADAR1 expression levels by 10−8 mol/l E2 into a 12Z immortalized human endometriotic cell line for 48 h. (C) Real-time PCR analysis of the IL-1β, IL-6, and IL-8 expression levels by 10−8 mol/l E2 into a 12Z immortalized human endometriotic cell line for 48 h.

Knockdown of ADAR1 attenuated ADAR1 expression in the immortalized human endometriotic cell line. We decided to perform ADAR1 knockdown in the 12Z cell line to examine expression changes. The knockdown efficiency of ADAR1 was confirmed by performing PCR. ADAR1 expression was significantly decreased by transfection of the ADAR1 siRNA into the 12Z cells (Mock: p=0.001 and Control: p=0.003), as shown in Figure 3A.

Figure 3.
Figure 3.

Adenosine deaminase family acting on RNA 1 (ADAR1) expression, cell proliferation, and apoptosis investigated by knockdown ADAR1 in immortalized human endometriosis cell lines. (A) Real-time PCR analysis of the ADAR1 expression levels after transient transfection of the mock, control siRNA (siCon), or ADAR1 siRNA (siADAR1) into a 12Z immortalized human endometriotic cell line for 48 h. (B) 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays of a 12Z immortalized human endometriotic cell line after transient transfection of mock, siCon, or siADAR1 siRNA for 48 h. (C) Representative flow cytometric data for apoptosis of a 12Z immortalized human endometriotic cell line after transient transfection of mock, siCon, or siADAR1 siRNA for 48 h.

Knockdown of ADAR1 suppressed cell proliferation and increased apoptosis in the immortalized human endometriotic cell line. We determined the effects of ADAR1 on cell proliferation in the immortalized human endometriotic cell line. We performed an MTS assay after transient transfection of the ADAR1 siRNA into the 12Z cell line. The number of viable cells decreased to 40.9% (Mock) and 33.7% (Control) of that of the control cell viability at 48 hours after transient transfection of the ADAR1 siRNA into 12Z cells (p<0.001, Figure 3B). Therefore, the knockdown of ADAR1 suppressed the cell proliferation in the immortalized human endometriotic cell line.

The following apoptosis profiles were obtained from transient transfection of the ADAR1 into 12Z cells. ADAR1 siRNA increased early and late apoptosis, compared with the mock and control of 24.83% and 19.96% for the 12Z cells. Therefore, we concluded that ADAR1 siRNA was likely to regulate the early and late apoptosis in the immortalized human endometriotic cell line (Figure 3C).

Knockdown of ADAR1 activated the apoptosis-related pathway in immortalized human endometriotic cell line. Based on previous findings, we hypothesized that ADAR1 might suppress apoptosis in 12Z cells by suppressing the dsRNA-sensing signaling pathway. ADAR1 was shown to suppress innate immunity primarily through the RIG-I-like receptor (RLR)-initiated cytosolic dsRNA-sensing signaling pathway, including MDA5 and RIG-I (13, 14). Moreover, RIG-I, MDA5, and PKR have been reported to induce apoptosis (15-17). To trace the steps in the apoptosis, we evaluated the activation of Caspase 3, Caspase 7, and Caspase 8. We first examined the effects of ADAR1 knockdown on the expression of MDA5, RIG-I, PKR, IRF3, IRF7, Caspase 3, Caspase 7, and Caspase 8 in the 12Z cell line. The MDA5 expression significantly increased after transfection of ADAR1 siRNA into 12Z cells (Mock, p<0.001; Control siRNA, p<0.001). The RIG-I expression significantly increased after the transfection of ADAR1 siRNA into 12-Z cells (Mock, p<0.001; Control siRNA, p<0.001). However, no association was observed between ADAR1 and PKR in 12Z cells. The expression of one of the IFN-stimulated genes (IRF3 and IRF7) which is downstream of MDA5, and that of RIG-I also increased after transfection of the ADAR1 into 12Z cells (IRF3: Mock, p<0.001; Control siRNA, p<0.001; IRF7: Mock, p=0.002; Control siRNA, p=0.002). To trace the steps in the apoptosis, Caspase 3, Caspase 7, and Caspase 8 expressions significantly increased after transfection of ADAR1 siRNA into the 12Z cell line (Caspase 3: Mock, p<0.001; Control siRNA, p<0.001; Caspase 7: Mock, p<0.001; Control siRNA, p<0.001; Caspase 8: Mock, p<0.001; Control siRNA, p<0.001) as shown in Figure 4A. These results suggest that suppression of ADAR1 activates the dsRNA-sensing signaling pathway, which in turn increases the expression of apoptosis factors of MDA5, RIG-I, Caspase 3, Caspase 7, and Caspase 8.

Figure 4.
Figure 4.

The mechanism and cell growth in monolayers were investigated by knockdown adenosine deaminase family acting on RNA 1 (ADAR1) in an immortalized human endometriosis cell line. (A) Real-time PCR of the 12Z immortalized human endometriotic cell line after transient transfection of the mock, control (siCon), or ADAR1 siRNA (siADAR1) for 48 h. Real-time PCR of MDA5, RIG-I, PKR, IRF3, IRF7, Caspase 3, Caspase 7, and Caspase 8 expression after transfection of the mock, iCon, and siADAR1 into a 12Z immortalized human endometriotic cell line for 48 h. (B) The cell growth in monolayers after transient transfection of the mock, siCon, or siADAR1 into a 12Z immortalized human endometriotic cell line in DMEM/ham’s F12 medium supplemented with 10% FBS for 2, 4, and 6 days. Numbers represent the data from triplicate experiments.

Knockdown of ADAR1 inhibited cell growth. The effects of ADAR1 expression on monolayer growth were analyzed using transfection of ADAR1 siRNA into the 12Z cell line. Knockdown of ADAR1 significantly inhibited monolayer growth in 12Z cells when compared with mock and control siRNA (Day 6 Mock: p=0.007, siControl: p=0.007), as shown in Figure 4B.

Discussion

The aim of the study was to discover new therapeutic targets for endometriosis by employing epigenetic methods. We focused on RNA editing, a recently identified epigenetic mechanism that modulates the post-transcriptional activity of essential genes by changing their amino acid sequences (3). ADAR, a type of RNA editing, is also involved in immune recognition, mainly through IFN responses (18, 19). However, there are no reports on the mechanism of action of ADAR1 in endometriosis. Therefore, we investigated the biological function of ADAR1 in endometriosis.

Li et al. reported that high ADAR1 expression was significantly associated with endometriosis (11). In the present study, ADAR1 expression was significantly higher in cells from patients with endometriosis than in those from non-patients. ADAR1 expression was significantly correlated with cytokine dependence in IL-1β, IL-6, and IL-8 with endometriosis. Endometriosis is estrogen-dependent, so we investigated the relationship between estrogen and ADAR1. Therefore, estrogen induced overexpression of ADAR1, and ADAR1 expression was strongly associated with estrogen dependence.

ADAR1 is also involved in immune recognition, which is primarily explained by the interferon (IFN) response in various cancer types (20, 21). ADAR1 activates the type-I IFN pathway via dsRNA sensors (MDA5 and RIG-I). RIG-I and MDA5 were previously reported to promote pro-apoptotic signaling, known as type-I IFN–dependent apoptosis (22). Herein, ADAR1 knockdown increased MDA5, RIG-1, PKR, IRF3, IRF7, Caspase 3, Caspase 7, and Caspase 8 expression in an immortalized human endometriotic cell line, leading to apoptosis. Our results indicate that ADAR1 shows potential as a new therapeutic target for endometriosis.

This retrospective study had several limitations. First, it was performed at a single center. Large-scale prospective studies are required to further ascertain the role and clinical significance of ADAR1 in endometriosis, and we hope to report such results soon.

In summary, our study provides novel evidence for a critical role of ADAR1 in endometriosis. Our study highlights the finding that ADAR1 increases the potential of endometriosis and hence could be a potential therapeutic target in endometriosis.

Conclusion

In this study, we investigated the biological function of ADAR1 in endometriosis and found that ADAR1 expression was significantly higher in endometriosis patients. ADAR1 expression was significantly correlated to IL-1b, IL-6, and IL-8. Knockdown of ADAR1 led to apoptosis through MDA5, RIG-I, PKR, IRF3, IRF7, Caspase 3, Caspase 7, and Caspase 8 expression into an immortalized human endometriotic cell line. Our results show that ADAR1 could be a valuable therapeutic target in endometriosis.

Acknowledgements

This study was supported by Grants-in-Aid for Scientific Research (22K09619, 23K15815).

Footnotes

  • Authors’ Contributions

    KN contributed to the study design, laboratory work, data collection, data management, statistical analysis, data interpretation, and manuscript writing. THV, KS, KK, CK, and HM participated in the design and coordination of the study and helped draft the manuscript. All Authors read and approved the final version of the manuscript.

  • Conflicts of Interest

    None of the Authors have any conflicts of interest to declare in relation to this study.

  • Received November 14, 2023.
  • Revision received December 20, 2023.
  • Accepted January 5, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Adenosine Deaminase Family Acting on RNA 1 (ADAR1) May Be a De Novo Target for Endometriosis Treatment
THUY HA VU, KEIICHIRO NAKAMURA, KUNITOSHI SHIGEYASU, KOTARO KUBO, CHIAKI KASHINO, HISASHI MASUYAMA
In Vivo Mar 2024, 38 (2) 683-690; DOI: 10.21873/invivo.13489
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