Assessment of oxidative and endoplasmic reticulum stress markers in women with uterine myomas

The most frequent benign gynecological tumor in women who are fertile, uterine myoma significantly lowers quality of life. Endoplasmic reticulum stress (ERS) and oxidative stress (OS) play a role in the development of numerous disease states, including gynecological disorders. In order to determine the ERS and OS levels activated in women with uterine myoma, we sought to measure Total Oxidant Status (TOS) level, Glucose regulatory protein 78 (GRP78), C/EBP homologous protein (CHOP) expression, and protein levels. A total of 40 women with uterine myomas and 40 healthy women were included in the study. Serum levels of TOS, GRP78, CHOP, and protein levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit. Reverse transcription polymerase chain reaction (RT-PCR) performed the mRNA levels of endoplasmic reticulum stress-associated molecules GRP78 and CHOP. The TOS levels, GRP78 and CHOP protein levels were significantly higher in women with myomas than in the controls, with values of p = 0.009, p = 0.001, and p = 0.0001, respectively. GRP78 and CHOP expression increased in women with myomas and were significantly higher than the control group used (p < 0.05). ROC curve analysis showed that GRP78 and CHOP are promising biomarkers for uterine myomas (area under the curve (AUC): 0.953, AUC: 0.969, p < 0.001, respectively). Oxidative and ERS may play a vital role in the pathophysiology of the disease due to the increased levels of oxidative and ERS markers in women with uterine myomas.

CHOP; ER stress; GRP78; Uterine myoma

[1] Awiwi MO, Badawy M, Shaaban AM, Menias CO, Horowitz JM, Soliman M, et al. Review of uterine fibroids: imaging of typical and atypical features, variants, and mimics with emphasis on workup and FIGO classification. Abdominal Radiology. 2022; 47: 2468–2485.

[2] Soibi-Harry AP, Makwe CC, Oluwole AA, Garba SR, Ajayi AT, Anyanwu R, et al. Serum oxidative stress markers in women with uterine fibroids in Lagos, Nigeria. To be published in MedRχiv. 2021. [Preprint].

[3] Miyashita-Ishiwata M, El Sabeh M, Reschke LD, Afrin S, Borahay MA. Hypoxia induces proliferation via NOX4-Mediated oxidative stress and TGF-β3 signaling in uterine leiomyoma cells. Free Radical Research. 2022; 56: 163–172.

[4] Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010; 140: 900–917.

[5] Sefah N, Ndebele S, Prince L, Korasare E, Agbleke M, Nkansah A, et al. Uterine fibroids—causes, impact, treatment, and lens to the African perspective. Frontiers in Pharmacology. 2023; 13: 1045783.

[6] Sharifi-Rad M, Anil Kumar NV, Zucca P, Varoni EM, Dini L, Panzarini E, et al. Lifestyle, oxidative stress, and antioxidants: back and forth in the pathophysiology of chronic diseases. Frontiers in Pharmacology. 2020; 11: 694.

[7] Murphy MP, Bayir H, Belousov V, Chang CJ, Davies KJA, Davies MJ, et al. Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo. Nature Metabolism. 2022; 4: 651–662.

[8] Ranganath Pai K, Manokaran K, Bhat P, Nayak D, Baskaran R, Paramasivam P, et al. Oxidative stress and female reproductive disorder: a review. Asian Pacific Journal of Reproduction. 2022; 11: 107.

[9] Pejić S, Kasapović J, Todorović A, Stojiljković V, Pajović SB. Lipid peroxidation and antioxidant status in blood of patients with uterine myoma, endometrial polypus, hyperplastic and malignant endometrium. Biological Research. 2006; 39: 619–629.

[10] AlAshqar A, Lulseged B, Mason-Otey A, Liang J, Begum UAM, Afrin S, et al. Oxidative stress and antioxidants in uterine fibroids: pathophysiology and clinical implications. Antioxidants. 2023; 12: 807.

[11] Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduction and Targeted Therapy. 2023; 8(1): 352.

[12] Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nature Reviews Cancer. 2021; 21: 71–88.

[13] Fu X, Cui J, Meng X, Jiang P, Zheng Q, Zhao W, et al. Endoplasmic reticulum stress, cell death and tumor: association between endoplasmic reticulum stress and the apoptosis pathway in tumors (Review). Oncology Reports. 2021; 45: 801–808.

[14] Santulli P, Borghese B, Lemaréchal H, Leconte M, Millischer AE, Batteux F, et al. Increased serum oxidative stress markers in women with uterine leiomyoma. PLOS ONE. 2013; 8: e72069.

[15] Bhattarai KR, Riaz TA, Kim H, Chae H. The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling. Experimental & Molecular Medicine. 2021; 53: 151–167.

[16] Wang L, Liu Y, Zhang X, Ye Y, Xiong X, Zhang S, et al. Endoplasmic reticulum stress and the unfolded protein response in cerebral ischemia/reperfusion injury. Frontiers in Cellular Neuroscience. 2022; 16: 864426.

[17] Wamsteker K, Emanuel MH, De Kruif JH. Transcervical hysteroscopic resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstetrics & Gynecology. 1993; 82: 736–740.

[18] Erel O. A new automated colorimetric method for measuring total oxidant status. Clinical Biochemistry. 2005; 38: 1103–1111.

[19] Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nature Protocols. 2008; 3: 1101–1108.

[20] Maduanusi C, Balachandran S, Sathiyathasan S, Omar K. Painless spontaneous haemoperitoneum secondary to a uterine leiomyoma/fibroid: unusual presentation of a life-threatening differential. BMJ Case Reports. 2021; 14: e243465.

[21] Suo M, Lin Z, Guo D, Zhang A. Hsa_circ_0056686, derived from cancer-associated fibroblasts, promotes cell proliferation and suppresses apoptosis in uterine leiomyoma through inhibiting endoplasmic reticulum stress. PLOS ONE. 2022; 17: e0266374.

[22] Yang Q, Ciebiera M, Bariani MV, Ali M, Elkafas H, Boyer TG, et al. Comprehensive review of uterine fibroids: developmental origin, pathogenesis, and treatment. Endocrine Reviews. 2022; 43: 678–719.

[23] Fletcher NM, Abusamaan MS, Memaj I, Saed MG, Al-Hendy A, Diamond MP, et al. Oxidative stress: a key regulator of leiomyoma cell survival. Fertility and Sterility. 2017; 107: 1387–1394.e1.

[24] Caglayan A, Katlan DC, Tuncer ZS, Yuce K, Sayal HB, Kocer-Gumusel B. Assessment of oxidant-antioxidant status alterations with tumor biomarkers and reproductive system hormones in uterine MYOMAS. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2018; 229: 1–7.

[25] Chong WC, Shastri MD, Eri R. Endoplasmic reticulum stress and oxidative stress: a vicious nexus implicated in bowel disease pathophysiology. International Journal of Molecular Sciences. 2017; 18: 771.

[26] Bhandary B, Marahatta A, Kim HR, Chae HJ. An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases. International Journal of Molecular Sciences. 2012; 14: 434–456.

[27] Pastore S, Korkina L. Redox imbalance in T Cell-Mediated skin diseases. Mediators of Inflammation. 2010; 2010: 1–9.

[28] Pejić S, Todorović A, Stojiljković V, Cvetković D, Lučić N, Radojičić RM, et al. Superoxide dismutase and lipid hydroperoxides in blood and endometrial tissue of patients with benign, hyperplastic and malignant endometrium. Annals of the Brazilian Academy of Sciences 2008; 80: 515–522.

[29] Hoseini H, Sarani A. Evaluation of serum oxidative stress markers in women with leiomyoma. Health Science Monitor. 2023; 2: 174–179.

[30] Nayki C, Nayki U, Gunay M, Kulhan M, Çankaya M, Humeyra Taskın Kafa A, et al. Oxidative and antioxidative status in the endometrium of patients with benign gynecological disorders. Journal of Gynecology Obstetrics and Human Reproduction. 2017; 46: 243–247.

[31] Guzel E, Arlier S, Guzeloglu-Kayisli O, Tabak MS, Ekiz T, Semerci N, et al. Endoplasmic reticulum stress and homeostasis in reproductive physiology and pathology. International Journal of Molecular Sciences. 2017; 18: 792.

[32] Zheng Y, Cao Z, Hu X, Shao Z. The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer. Breast Cancer Research and Treatment. 2014; 145: 349–358.

[33] Vural M, Camuzcuoglu H, Toy H, Camuzcuoglu A, Aksoy N. Oxidative stress and prolidase activity in women with uterine fibroids. Journal of Obstetrics and Gynaecology. 2012; 32: 68–72.

[34] Wallach EE, Vlahos NF. Uterine myomas: an overview of development, clinical features, and management. Obstetrics & Gynecology. 2004; 104: 393–406.

[35] Xie Y, Tao X, Cheng Z, Guan Q, Yang W, Zhu Y. Discrepancy of uterine leiomyoma and myometrium to hypoxia-induced endoplasmic reticulum stress after uterine occlusion therapy accounts for therapeutic effect. Archives of Gynecology and Obstetrics. 2014; 289: 1039–1045.

[36] Xu Q, Ohara N, Liu J, Nakabayashi K, DeManno D, Chwalisz K, et al. Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells. American Journal of Physiology-Endocrinology and Metabolism. 2007; 293: E1002–E1011.

[37] Lin L, Chang H, Kuo T, Chen H, Liu W, Lo Y, et al. Oxidative stress mediates the inhibitory effects of Manzamine a on uterine leiomyoma cell proliferation and extracellular matrix deposition via SOAT inhibition. Redox Biology. 2023; 66: 102861.