# Oxidative Stress and Antioxidant Defense in Endometriosis and Its Malignant Transformation

**Authors:** Takuya Iwabuchi, Chiharu Yoshimoto, Hiroshi Shigetomi, Hiroshi Kobayashi

PMC · DOI: 10.1155/2015/848595 · 2015-06-21

## TL;DR

This study explores how oxidative stress and antioxidant defenses contribute to endometriosis and its progression to cancer.

## Contribution

It identifies how redox balance shifts from promoting cell death in benign endometriosis to supporting cancer in its malignant form.

## Key findings

- Oxidative stress from hemoglobin and iron derivatives causes DNA damage in benign endometriosis.
- Enhanced antioxidant defenses may promote malignant transformation in endometriosis-associated ovarian cancer.
- Redox balance acts as a double-edged sword, influencing both cell death and carcinogenesis.

## Abstract

The aim of this study was to investigate the role of redox status in endometriosis and its malignant transformation. A search was conducted between 1990 and 2014 through the English language literature (online MEDLINE PubMed database) using the keywords endometriosis combined with malignant transformation, oxidative stress, and antioxidant defense. In benign endometriosis, autoxidation and Fenton reaction of hemoglobin from the ferrous Fe2+ (oxyhemoglobin) state to the ferric Fe3+ (methemoglobin) state lead to production of excess reactive oxygen species (ROS) such as
O2
− and ∙OH. Hemoglobin, heme, and iron derivatives in endometriotic cysts cause distortion in the homeostatic redox balance. Excess oxidative stress could trigger DNA damage and cell death. In contrast, endometriosis-associated ovarian cancer (EAOC) might be associated with an effective antioxidant defense, including heme oxygenases, cytochrome P450 family, and glutathione transferase family. The pattern of redox balance supports that enhanced antioxidants may be involved in the pathogenesis of malignant transformation. In conclusion, oxidant/antioxidant balance function is a double-edged sword, promoting cell death or carcinogenesis. Upregulation of antioxidant functions in endometriotic cyst may result in restoration of cell survival and subsequent malignant transformation.

## Linked entities

- **Proteins:** HB1 (hemoglobin 1), CYP71B9 (cytochrome P450, family 71, subfamily B, polypeptide 9), GSTF9 (glutathione S-transferase PHI 9)
- **Chemicals:** O2− (PubChem CID 977), ∙OH (PubChem CID 961), Fe2+ (PubChem CID 23925), Fe3+ (PubChem CID 29936)
- **Diseases:** endometriosis (MONDO:0005133)

## Full-text entities

- **Genes:** BAX (BCL2 associated X, apoptosis regulator) [NCBI Gene 581] {aka BCL2L4}, CYP4F3 (cytochrome P450 family 4 subfamily F member 3) [NCBI Gene 4051] {aka CPF3, CYP4F, CYPIVF3, LTB4H}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50}, HBG2 (hemoglobin subunit gamma 2) [NCBI Gene 3048] {aka HBG-T1, TNCY}, TF (transferrin) [NCBI Gene 7018] {aka HEL-S-71p, PRO1557, PRO2086, TFQTL1}, CYP1A1 (cytochrome P450 family 1 subfamily A member 1) [NCBI Gene 1543] {aka AHH, CP11, CYP1, CYPIA1, P1-450, P450-C}, NQO1 (NAD(P)H quinone dehydrogenase 1) [NCBI Gene 1728] {aka DHQU, DIA4, DTD, NMOR1, NMORI, QR1}, BAD (BCL2 associated agonist of cell death) [NCBI Gene 572] {aka BBC2, BCL2L8}, EGR1 (early growth response 1) [NCBI Gene 1958] {aka AT225, G0S30, KROX-24, NGFI-A, TIS8, ZIF-268}, HMOX1 (heme oxygenase 1) [NCBI Gene 3162] {aka HMOX1D, HO-1, HSP32, bK286B10}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, MAFK (MAF bZIP transcription factor K) [NCBI Gene 7975] {aka NFE2U, P18}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, GCLC (glutamate-cysteine ligase catalytic subunit) [NCBI Gene 2729] {aka CNSHA7, GCL, GCS, GLCL, GLCLC}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, PRDX1 (peroxiredoxin 1) [NCBI Gene 5052] {aka MSP23, NKEF-A, NKEFA, PAG, PAGA, PAGB}, GSTP1 (glutathione S-transferase pi 1) [NCBI Gene 2950] {aka DFN7, FAEES3, GST3, GSTP, GSTP1-1, HEL-S-22}, CAT (catalase) [NCBI Gene 847], NPRL3 (NPR3 like, GATOR1 complex subunit) [NCBI Gene 8131] {aka C16orf35, CGTHBA, FFEVF3, HS-40, MARE, NPR3}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, BACH2 (BACH transcriptional regulator 2) [NCBI Gene 60468] {aka BTBD25, IMD60}, GSTM1 (glutathione S-transferase mu 1) [NCBI Gene 2944] {aka GST1, GSTM1-1, GSTM1a-1a, GSTM1b-1b, GTH4, GTM1}, BACH1 (BTB domain and CNC homolog 1) [NCBI Gene 571] {aka BACH-1, BTBD24}, CYP2D6 (cytochrome P450 family 2 subfamily D member 6 (gene/pseudogene)) [NCBI Gene 1565] {aka CPD6, CYP2D, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2}, GSTT1 (glutathione S-transferase theta 1) [NCBI Gene 2952], CUBN (cubilin) [NCBI Gene 8029] {aka IFCR, IGS, IGS1, MGA1, gp280}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, GSTK1 (glutathione S-transferase kappa 1) [NCBI Gene 373156] {aka GST, GST 13-13, GST13, GST13-13, GSTK1-1, hGSTK1}
- **Diseases:** DNA damage (MESH:D004266), malignant mesotheliomas (MESH:D000086002), adenosarcoma (MESH:D018195), Alzheimer's and Parkinson's diseases (MESH:D010300), hemolysis (MESH:D006461), cancer (MESH:D009369), carcinogenesis (MESH:D063646), EAOC (MESH:D010051), clear cell carcinoma (MESH:D002292), atherosclerotic (MESH:D050197), Endometriosis (MESH:D004715), Inflammation (MESH:D007249), gastric cancer (MESH:D013274), sarcomas (MESH:D012509), hepatocellular carcinoma (MESH:D006528), Mullerian-type tumors (MESH:D018200), Alzheimer's disease (MESH:D000544), liver, thyroid, breast, colon, and pancreas (MESH:D061325), dysmenorrhea (MESH:D004412), endometrial stromal sarcoma (MESH:D018203), ischemia (MESH:D007511), amyotrophic lateral sclerosis (MESH:D000690), bleeding (MESH:D006470), aneuploidy (MESH:D000782), cyst (MESH:D003560), neurodegenerative diseases (MESH:D019636), gynecologic diseases (MESH:D005831), carcinogens (MESH:D011230), ovarian carcinogenesis (MESH:D010049), intracerebral hemorrhage (MESH:D002543), mucinous borderline tumor (MESH:D018297), infertility (MESH:D007246), endometriotic lesion (MESH:D009059)
- **Chemicals:** Iron (MESH:D007501), 8-OHdG (MESH:D000080242), H2O2 (MESH:D006861), hydroxyl radical (MESH:D017665), Heme (MESH:D006418), biliverdin (MESH:D001664), OH (MESH:C031356), free radical (MESH:D005609), oxygen (MESH:D010100), Superoxide (MESH:D013481), Ferrous iron (-), CO (MESH:D002248), cGMP (MESH:D006152), bilirubin (MESH:D001663), ROS (MESH:D017382), lipid (MESH:D008055),  (MESH:D000975)
- **Species:** Homo sapiens (human, species) [taxon 9606]
- **Mutations:** C609T

## Figures

1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC4491397/full.md

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Source: https://tomesphere.com/paper/PMC4491397