Hypoxia-Nitric Oxide Axis and the Associated Damage Molecular Pattern in Cutaneous Melanoma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants
2.2. Laboratory Data
- -
- The DS/NT was calculated as -S-S-*100/-SH;
- -
- The DS/TT was calculated as -S-S-*100/-SH + -S-S-;
- -
- The NT/TT was calculated as -SH*100/-SH + -S-S-.
2.3. Statistical Analysis
3. Results
3.1. Groups of Characteristics
3.2. Levels of Hypoxia in Studied Groups
3.3. NO Metabolism in Studied Groups
3.4. Damage-Related Molecular Pattern in Studied Groups
3.5. Hypoxia, NO Metabolism, and Damage-Related Molecular Patterns in Relation to the Breslow Index, Clark Level, and Melanoma Stage
3.5.1. HIF-1a and HIF-2a Levels in Melanoma According to the Breslow Index, Clark Level, and Melanoma Stage
3.5.2. Serum Nitric Oxide Metabolite Levels in Melanoma According to the Breslow Index, Clark Level, and Melanoma Stage
3.5.3. Nitration and Carbonylation in Melanoma According to the Breslow Index, Clark Level, and Melanoma Stage
3.5.4. Methylated Arginine Levels in Melanoma According to the Breslow Index, Clark Level, and Melanoma Stage
3.6. The Relation between the Tumor Microenvironment, Hypoxia, and Tumor Characteristics
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Muñiz-García, A.; Romero, M.; Falcόn-Perez, J.M.; Murray, P.; Zorzano, A.; Mora, S. Hypoxia-induced HIF1α activation regulates small extracellular vesicle release in human embryonic kidney cells. Sci. Rep. 2022, 12, 1443. [Google Scholar] [CrossRef]
- Abou Khouzam, R.; Brodaczewska, K.; Filipiak, A.; Zeinelabdin, N.A.; Buart, S.; Szczylik, C.; Chouaib, S. Tumor hypoxia regulates immune escape/invasion: Influence on angiogenesis and potential impact of hypoxic biomarkers on cancer therapies. Front. Immunol. 2021, 11, 613114. [Google Scholar] [CrossRef]
- Godet, I.; Doctorman, S.; Wu, F.; Gilkes, D.M. Detection of Hypoxia in Cancer Models: Signifi-cance, Challenges, and Advances. Cells 2022, 11, 686. [Google Scholar] [CrossRef]
- Rocha, H.L.; Godet, I.; Kurtoglu, F.; Metzcar, J.; Konstantinopoulos, K.; Bhoyar, S.; Macklin, P. A persistent invasive phenotype in post-hypoxic tumor cells is revealed by fate mapping and computational modeling. Iscience 2021, 24, 102935. [Google Scholar] [CrossRef]
- Malkov, M.I.; Lee, C.T.; Taylor, C.T. Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines. Cells 2021, 10, 2340. [Google Scholar] [CrossRef]
- Arnaiz, E.; Harris, A.L. Role of hypoxia in the interferon response. Front. Immunol. 2022, 13, 821816. [Google Scholar] [CrossRef]
- Ho, J.J.; Man, H.S.; Marsden, P.A. Nitric oxide signaling in hypoxia. J. Mol. Med. 2012, 90, 217–231. [Google Scholar] [CrossRef]
- Ene, C.D.; Nicolae, I. Gangliosides and Antigangliosides in Malignant Melanoma. In Melanoma—Current Clinical Management and Future Therapeutics; Murph, M., Ed.; IntechOpen: Kenosha, WI, USA, 2015; ISBN 978-953-51-2036-0. [Google Scholar]
- Petrova, V.; Annicchiarico-Petruzzelli, M.; Melino, G.; Amelio, I. The hypoxic tumour microenvironment. Oncogenesis 2018, 7, 10. [Google Scholar] [CrossRef] [Green Version]
- Anghel, A.E.; Ene, C.D.; Nicolae, I.; Budu, V.A.; Constantin, C.; Neagu, M. Interleukin 8—Major player in cutaneous melanoma metastasic process. Rom. Biotechnol. Lett. 2015, 20, 10911–10920. [Google Scholar]
- Bedogni, B.; Welford, S.M.; Cassarino, D.S.; Nickoloff, B.J.; Giaccia, A.J.; Powell, M.B. The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation. Cancer Cell 2005, 8, 443–454. [Google Scholar] [CrossRef] [Green Version]
- Sharma, A.; Sinha, S.; Shrivastava, N. Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism. Front. Genet. 2022, 13, 849040. [Google Scholar] [CrossRef]
- Widmer, D.S.; Hoek, K.S.; Cheng, P.F.; Eichhoff, O.M.; Biedermann, T.; Raaijmakers, M.I.; Levesque, M.P. Hypoxia contributes to melanoma heterogeneity by triggering HIF1α-dependent phenotype switching. J. Investig. Dermatol. 2013, 133, 2436–2443. [Google Scholar] [CrossRef] [Green Version]
- Pardo-Sánchez, I.; García-Moreno, D.; Mulero, V. Zebrafish Models to Study the Crosstalk be-tween Inflammation and NADPH Oxidase-Derived Oxidative Stress in Melanoma. Antioxidants 2022, 11, 1277. [Google Scholar] [CrossRef]
- Corral-Gudino, L.; Bahamonde, A.; Arnaiz-Revillas, F.; Gómez-Barquero, J.; Abadía-Otero, J.; García-Ibarbia, C.; Riancho, J.A. Methylprednisolone in adults hospitalized with COVID-19 pneumonia. Wien. Klin. Wochenschr. 2021, 133, 303–311. [Google Scholar] [CrossRef]
- Ziani, L.; Buart, S.; Chouaib, S.; Thiery, J. Hypoxia increases melanoma-associated fibroblasts immunosuppressive potential and inhibitory effect on T cell-mediated cytotoxicity. OncoImmunology 2021, 10, 1950953. [Google Scholar] [CrossRef]
- McGettrick, A.F.; O’Neill, L.A. The role of HIF in immunity and inflammation. Cell Metab. 2020, 32, 524–536. [Google Scholar] [CrossRef]
- Shou, Y.; Yang, L.; Yang, Y.; Zhu, X.; Li, F.; Xu, J. Determination of hypoxia signature to predict prognosis and the tumor immune microenvironment in melanoma. Mol. Omics 2021, 17, 307–316. [Google Scholar] [CrossRef]
- Chouaib, S.; Noman, M.Z.; Kosmatopoulos, K.; Curran, M.A. Hypoxic stress: Obstacles and opportunities for innovative immunotherapy of cancer. Oncogene 2017, 36, 439–445. [Google Scholar] [CrossRef] [Green Version]
- Ene, C.D.; Nicolae, I.; Mitran, C.I.; Mitran, M.I.; Matei, C.; Caruntu, A.; Caruntu, C.; Georgescu, S.R. Antiganglioside Antibodies and Inflammatory Response in Cutaneous Melanoma. J. Immunol. Res. 2020, 2020, 2491265. [Google Scholar] [CrossRef]
- Sharma, G.D.; Thomas, A.; Paul, J. Reviving tourism industry post-COVID-19: A resilience-based framework. Tour. Manag. Perspect. 2021, 37, 100786. [Google Scholar] [CrossRef]
- Abou Khouzam, R.; Goutham, H.V.; Zaarour, R.F.; Chamseddine, A.N.; Francis, A.; Buart, S.; Chouaib, S. Integrating tumor hypoxic stress in novel and more adaptable strategies for cancer immunotherapy. In Seminars in Cancer Biology; Academic Press: Cambridge, MA, USA, 2020; Volume 65, pp. 140–154. [Google Scholar]
- Ho, T.C.; Chan, A.H.; Ganesan, A. Thirty years of HDAC inhibitors: 2020 insight and hind-sight. J. Med. Chem. 2020, 63, 12460–12484. [Google Scholar] [CrossRef]
- Li, Z.L.; Wang, B.; Wen, Y.; Wu, Q.L.; Lv, L.L.; Liu, B.C. Disturbance of hypoxia response and its implications in kidney diseases. Antioxid. Redox Signal. 2022; ahead of print. [Google Scholar] [CrossRef]
- Li, W.; Li, F.; Zhang, X.; Lin, H.K.; Xu, C. Correction: Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment. Signal Transduct. Target. Ther. 2022, 7, 31. [Google Scholar] [CrossRef]
- Lundberg, J.O.; Weitzberg, E.; Gladwin, M.T. The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug Discov. 2008, 7, 156–167. [Google Scholar] [CrossRef]
- Hendrickson, M.D.; Poyton, R.O. Crosstalk between nitric oxide and hypoxia-inducible factor signaling pathways: An update. Res. Rep. Biochem. 2015, 5, 147–161. [Google Scholar]
- Poyton, R.O.; Ball, K.A.; Castello, P.R. Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol. Metab. 2009, 20, 332–340. [Google Scholar] [CrossRef]
- Yarlagadda, K.; Hassani, J.; Foote, I.P.; Markowitz, J. The role of nitric oxide in melanoma. Biochim. Biophys. Acta Rev. Cancer 2017, 1868, 500–509. [Google Scholar] [CrossRef]
- Ball, K.A.; Nelson, A.W.; Foster, D.G.; Poyton, R.O. Nitric oxide produced by cytochrome c oxidase helps stabilize HIF-1α in hypoxic mammalian cells. Biochem. Biophys. Res. Commun. 2012, 420, 727–732. [Google Scholar] [CrossRef] [Green Version]
- Rapozzi, V.; Della Pietra, E.; Bonavida, B. Dual roles of nitric oxide in the regulation of tumor cell response and resistance to photodynamic therapy. Redox Biol. 2015, 6, 311–317. [Google Scholar] [CrossRef] [Green Version]
- Finelli, M.J. Redox post-translational modifications of protein thiols in brain aging and neuro-degenerative conditions—Focus on S-nitrosation. Front. Aging Neurosci. 2020, 12, 254. [Google Scholar] [CrossRef]
- Cortese, R.; Almendros, I.; Wang, Y.; Gozal, D. Tumor circulating DNA profiling in xenografted mice exposed to intermittent hypoxia. Oncotarget 2015, 6, 556. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, H.; Li, J.; Zhao, F.; Wang, H.; Qu, Y.; Mu, D. Nitric oxide synthase in hypoxic or ischemic brain injury. Rev. Neurosci. 2015, 26, 105–117. [Google Scholar] [CrossRef] [PubMed]
- Opländer, C.; Suschek, C.V. The role of photolabile dermal nitric oxide derivates in ultraviolet radiation (UVR)-induced cell death. Int. J. Mol. Sci. 2012, 14, 191–204. [Google Scholar] [CrossRef] [Green Version]
- Opländer, C.; Deck, A.; Volkmar, C.M.; Kirsch, M.; Liebmann, J.; Born, M.; van Abeelen, F.; van Faassen, E.E.; Kröncke, K.D.; Windolf, J.; et al. Mechanism and biological relevance of blue-light (420–453 nm)-induced nonenzymatic nitric oxide generation from photolabile nitric oxide derivates in human skin in vitro and in vivo. Free Radic. Biol. Med. 2013, 65, 1363–1377. [Google Scholar] [CrossRef]
- Lopez-Sanchez, L.M.; Aranda, E.; Rodriguez-Ariza, A. Nitric oxide and tumor metabolic reprogramming. Biochem. Pharmacol. 2020, 176, 113769. [Google Scholar] [CrossRef]
- Hu, Y.; Xiang, J.; Su, L.; Tang, X. The regulation of nitric oxide in tumor progression and therapy. J. Int. Med. Res. 2020, 48, 0300060520905985. [Google Scholar] [CrossRef] [Green Version]
- Chang, C.F.; Diers, A.R.; Hogg, N. Cancer cell metabolism and the modulating effects of nitric oxide. Free. Radic. Biol. Med. 2015, 79, 324–336. [Google Scholar] [CrossRef] [Green Version]
- D’Aguanno, S.; Mallone, F.; Marenco, M.; Del Bufalo, D.; Moramarco, A. Hypoxia-dependent drivers of melanoma progression. J. Exp. Clin. Cancer Res. 2021, 40, 159. [Google Scholar] [CrossRef]
- Bechmann, N.; Calsina, B.; Richter, S.; Pietzsch, J. Therapeutic Potential of Nitric Oxide releas-ing Selective Estrogen Receptor Modulators (NO-SERMs) in Malignant Melanoma. J.-Vestig. Dermatol. 2022, 142, 2217–2227. [Google Scholar]
- Keith, B.; Johnson, R.S.; Simon, M.C. HIF1α and HIF2α: Sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 2012, 12, 9–22. [Google Scholar] [CrossRef] [Green Version]
- Lin, Q.; Cong, X.; Yun, Z. Differential hypoxic regulation of hypoxia-inducible factors 1α and 2α. Mol. Cancer Res. 2011, 9, 757–765. [Google Scholar] [CrossRef] [Green Version]
- Moreno Roig, E.; Yaromina, A.; Houben, R.; Groot, A.J.; Dubois, L.; Vooijs, M. Prognostic role of hypoxia-inducible factor-2α tumor cell expression in cancer patients: A meta-analysis. Front. Oncol. 2018, 8, 224. [Google Scholar] [CrossRef]
- Ding, Z.; Ogata, D.; Roszik, J.; Qin, Y.; Kim, S.; Tetzlaff, M.; Grimm, E.A. iNOS Associates With Poor Survival in Melanoma: A Role for Nitric Oxide in the PI3K-AKT Pathway Stimulation and PTEN S-Nitrosylation. Front. Oncol. 2021, 11, 141. [Google Scholar] [CrossRef]
- Anghel, A.E.; Ene, C.D.; Neagu, M.; Nicolae, I. The relationship between interleukin 8 and ki67 in cutaneous malignant melanoma. Hum. Vet. Med. 2015, 7, 149–154. [Google Scholar]
- Nicolae, C.D.; Nicolae, I. Antibodies against GM1 gangliosides associated with metastatic melanoma. Acta Dermatovenerol. Croat. 2013, 21, 86–92. [Google Scholar]
- Leon, L.; Jeannin, J.F.; Bettaieb, A. Post-translational modifications induced by nitric oxide (NO): Implication in cancer cells apoptosis. Nitric Oxide 2008, 19, 77–83. [Google Scholar] [CrossRef]
- Nicolae, I.; Nicolae, C.D.; Coman, O.A.; Stefanescu, M.; Coman, L.; Ardeleanu, C. Serum total gangliosides level: Clinical prognostic implication. Rom. J. Morphol. Embryol. 2011, 52, 1277–1281. [Google Scholar]
- Schipor, S.; Caragheorgheopol, A.; Nicolae, C.D.; Nicolae, I.; Paun, D. Serum Levels of Vegf in Cutaneous Malignant Melanoma. In Clinical Chemistry And Laboratory Medicine; Walter De Gruyter & Co.: Berlin, Germany, 2011; Volume 49, p. S267. [Google Scholar]
- Nölting, S.; Bechmann, N.; Taieb, D.; Beuschlein, F.; Fassnacht, M.; Kroiss, M.; Pacak, K. Personalized management of pheochromocytoma and paraganglioma. Endocr. Rev. 2022, 43, 199–239. [Google Scholar] [CrossRef] [PubMed]
- Ene, C.D.; Anghel, A.E.; Neagu, M.; Nicolae, I. 25-OH vitamin D and interleukin-8: Emerging biomarkers in cutaneous melanoma development and progression. Mediat. Inflamm. 2015, 2015, 904876. [Google Scholar] [CrossRef] [Green Version]
- Sasabe, E.; Tomomura, A.; Hamada, M.; Kitamura, N.; Yamada, T.; Yamamoto, T. Nitric Oxide Attenuates Hypoxia-Induced 5-FU Resistance of Oral Squamous Cell Carcinoma Cells. Int. J. Cancer Clin. Res. 2015, 2, 14. [Google Scholar] [CrossRef]
- Hickok, J.R.; Thomas, D.D. Nitric oxide and cancer therapy: The emperor has NO clothes. Curr. Pharm. Des. 2010, 16, 381–391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Toberer, F.; Winkler, J.K.; Haenssle, H.A.; Heinzel-Gutenbrunner, M.; Enk, A.; Hartschuh, W.; Kutzner, H. Immunohistochemical analysis of a hypoxia-associated signature in melanomas with positive and negative sentinel lymph nodes: Hypoxia-associated signature of primary cutaneous melanomas. Der Hautarzt Z. Dermatol. Venerol. Verwandte Geb. 2022, 73, 283–290. [Google Scholar]
- Begara-Morales, J.C.; Sánchez-Calvo, B.; Chaki, M.; Valderrama, R.; Mata-Pérez, C.; Padilla, M.N.; Barroso, J.B. Antioxidant systems are regulated by nitric oxide-mediated post-translational modifications (NO-PTMs). Front. Plant Sci. 2016, 7, 152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roche, B.; Bumann, D. Single-cell reporters for pathogen responses to antimicrobial host attacks. Curr. Opin. Microbiol. 2021, 59, 16–23. [Google Scholar] [CrossRef] [PubMed]
- Ene, C.V.; Nicolae, I.; Geavlete, B.; Geavlete, P.; Ene, C.D. IL-6 Signaling Link between Inflam-matory Tumor Microenvironment and Prostatic Tumorigenesis. Anal. Cell. Pathol. 2022, 2022, 5980387. [Google Scholar] [CrossRef]
- Hu, Y.; Yu, Q.; Guo, C.; Wang, G. DNA image cytometric analysis of bronchial washings as an adjunct for the detection of lung cancer in a clinical setting. Cancer Med. 2022, 11, 1860–1868. [Google Scholar] [CrossRef] [PubMed]
- Tampa, M.; Nicolae, I.; Mitran, C.I.; Mitran, M.I.; Ene, C.; Matei, C.; Georgescu, S.R.; Ene, C.D. Serum Sialylation Changes in Actinic Keratosis and Cutaneous Squamous Cell Carcinoma Patients. J. Pers. Med. 2021, 11, 1027. [Google Scholar] [CrossRef]
- Ene, C.D.; Penescu, M.N.; Georgescu, S.R.; Tampa, M.; Nicolae, I. Posttranslational Modifica-tions Pattern in Clear Cell Renal Cell Carcinoma. Metabolites 2021, 11, 10. [Google Scholar] [CrossRef]
- Zhang, C.; Xin, L.; Li, J.; Cao, J.; Sun, Y.; Wang, X.; Huang, P. Metal–Organic Framework (MOF)-Based Ultrasound-Responsive Dual-Sonosensitizer Nanoplatform for Hypoxic Cancer Therapy. Adv. Healthc. Mater. 2022, 11, 2101946. [Google Scholar] [CrossRef]
- Seymour, R.S.; Farrell, A.P.; Christian, K.; Clark, T.D.; Bennett, M.B.; Wells, R.M.; Baldwin, J. Continuous measurement of oxygen tensions in the air-breathing organ of Pacific tarpon (Megalops cyprinoides) in relation to aquatic hypoxia and exercise. J. Comp. Physiol. B 2007, 177, 579–587. [Google Scholar] [CrossRef]
- Alique, M.; Sánchez-López, E.; Bodega, G.; Giannarelli, C.; Carracedo, J.; Ramírez, R. Hypoxia-inducible factor-1α: The master regulator of endothelial cell senescence in vascular aging. Cells 2020, 9, 195. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Godoy, L.C.; Anderson, C.T.; Chowdhury, R.; Trudel, L.J.; Wogan, G.N. Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin. Proc. Natl. Acad. Sci. USA 2012, 109, 20373–20378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nathan, S.B. Nitric oxide enhancement strategies. Future Sci. OA 2015, 1, 8. [Google Scholar] [CrossRef]
Clinical Characteristics | Melanoma | Control |
---|---|---|
(52 Subjects) | (35 Subjects) | |
Female/male | 29/23 | 19/16 |
Age (years) | 51.6 ± 10.8 | 50.8 ± 8.5 |
BMI (kg/m2) | 23.9 ± 1.9 | 22.0 ± 2.4 |
Systolic pressure (mmHg) | 121 ± 19 | 114 ± 14 |
Diastolic pressure (mmHg) | 60 ± 14 | 62 ± 13 |
Skin phototypes I-II/III-IV | 32/20 | 20/15 |
LDH (U/L) | 392.50 ± 35.70 | 197.31 ± 7.90 |
Tumor characteristics | ||
Tumor localization head-neck/trunk/limbs | 9/22/21 | - |
Histopathological type nodular/extensive in surface/lenticular /acral | 16/21/7/8 | - |
Breslow index (mm) <1.0/1.01–2.0/2.01–3.0/>3.01 | 14/17/12/9 | - |
Clark level II/III/IV/V | 12/17/12/11 | - |
Lesion ulceration | 13/39 | - |
TNM stage 0/I/II/III/IV | 5/7/18/16/6 | - |
Parameters |
Melanoma (52 Subjects) | Control (35 Subjects) | p Value |
---|---|---|---|
HIF1a (ng/mL) | 89.90 ± 32.08 | 57.63 ± 5.63 | 0.004 |
HIF2a (ng/mL) | 3.25 ± 0.41 | 1.40 ± 0.93 | 0.011 |
HIF1a/HIF2a | 27.31 ± 7.99 | 41.15 ± 4.07 | 0.001 |
Parameters |
Melanoma (52 Subjects) | Control (35 Subjects) | p Value |
---|---|---|---|
Direct nitrite (umols/L) | 34.1 ± 6.5 | 15.2 ± 3.3 | 0.002 |
Total nitrite (umols/L) | 79.5 ± 11.2 | 34.0 ± 6.2 | 0.001 |
Nitrate (umols/L) | 45.4 ± 6.2 | 18.8 ± 4.6 | 0.001 |
Parameters |
Melanoma (52 Subjects) | Control (35 Subjects) | p Value |
---|---|---|---|
Nitration | |||
Nitrotyrosine (umol/L) | 0.38 ± 0.04 | 0.13 ± 0.02 | ˂0.001 |
Carbonylation | |||
PCO (μmol/L) | 37.82 ± 5.14 | 22.51 ± 2.21 | ˂0.001 |
4-HNE (μgl/mL) | 21.15 ± 7.62 | 14.05 ± 1.39 | ˂0.001 |
TBARS (μmol/L) | 3.24 ± 0.41 | 1.97 ± 0.13 | ˂0.001 |
MDA (ng/mL) | 36.07 ± 5.40 | 20.08 ± 1.32 | ˂0.001 |
Thiol-disulphide homeostasis | |||
NT (μmol/L) | 355.92 ± 8.53 | 401.83 ± 4.89 | ˂0.001 |
TT (μmol/L) | 407.23 ± 7.40 | 440.89 ± 4.78 | ˂0.001 |
DS (μmol/L) | 25.65 ± 1.62 | 19.50 ± 0.53 | ˂0.001 |
DS/NT | 7.21 ± 0.55 | 4.85 ± 0.15 | ˂0.001 |
DS/TT | 6.30 ± 0.42 | 3.98 ±1.27 | ˂0.001 |
NT/TT | 87.39 ± 0.85 | 91.15 ± 0.25 | ˂0.001 |
Methylated arginine | |||
SDMA (μmol/L) | 0.96 ± 0.10 | 0.50 ± 0.03 | ˂0.001 |
ADMA (μmol/L) | 0.86 ± 0.09 | 0.58 ± 0.05 | ˂0.001 |
ADMA/SDMA | 0.90 ± 0.07 | 1.10 ± 0.10 | ˂0.001 |
Parameters | Breslow Index | ||||||
---|---|---|---|---|---|---|---|
<1.0 | 1.01–2.0 | 2.01–3.0 | >3.01 | ||||
HIF-1a (ng/mL) | 63.90 ± 22.70 | 84.90 ± 28.31 | p1 < 0.05 | 98.35 ± 33.66 | p1 < 0.05 p2 < 0.05 | 112.32 ± 43.69 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
HIF-2a (ng/mL) | 2.87 ± 0.26 | 3.11 ± 0.34 | p1 < 0.05 | 3.41 ± 0.47 | p1 < 0.05 p2 < 0.05 | 3.62 ± 0.58 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
HIF-1a/HIF-2a | 35.61 ± 10.37 | 28.22 ± 8.23 | p1 < 0.05 | 26.12 ± 7.77 | p1 < 0.05 p2 > 0.05 | 19.3 ± 5.62 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Parameters | Clark Level | ||||||
---|---|---|---|---|---|---|---|
II | III | IV | V | ||||
HIF-1a (ng/mL) | 61.34 ± 17.21 | 86.74 ± 26.83 | p1 < 0.05 | 99.66 ± 37.98 | p1 < 0.05 p2 < 0.05 | 111.62 ± 46.03 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
HIF-2a (ng/mL) | 2.68 ± 0.28 | 3.22 ± 0.35 | p1 < 0.05 | 3.45 ± 0.42 | p1 < 0.05 p2 ˃ 0.05 | 3.67 ± 0.59 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
HIF-1a/HIF-2a | 35.82 ± 8.86 | 28.12 ± 8.40 | p1 < 0.05 | 26.41 ± 8.02 | p1 < 0.05 p2 > 0.05 | 18.9 ± 6.69 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Parameters | Melanoma Stage | ||||||
---|---|---|---|---|---|---|---|
I | II | III | IV | ||||
HIF-1a (ng/mL) | 61.30 ± 18.21 | 86.78 ± 27.43 | p1 < 0.05 | 99.67 ± 37.16 | p1 < 0.05 p2 < 0.05 | 111.82 ± 45.53 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
HIF-2a (ng/mL) | 2.62 ± 0.31 | 3.14 ± 0.35 | p1 < 0.05 | 3.44 ± 0.39 | p1 < 0.05 p2 > 0.05 | 3.72 ± 0.61 | p1 < 0.05 p2 < 0.05 p3 > 0.05 |
HIF-1a/HIF-2a | 36.20 ± 8.82 | 26.87 ± 8.73 | p1 < 0.05 | 27.38 ± 7.87 | p1 < 0.05 p2 > 0.05 | 18.81 ± 6.55 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Parameters | Breslow Index | ||||||
---|---|---|---|---|---|---|---|
<1.0 | 1.01–2.0 | 2.01–3.0 | >3.01 | ||||
Direct nitrite (umols/L) | 28.12 ± 4.38 | 31.75 ± 6.88 | p1 < 0.05 | 36.34 ± 6.88 | p1 < 0.05 p2 < 0.05 | 40.42 ± 8.47 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Total nitrite (umols/L) | 70.52 ± 8.33 | 76.83 ± 10.62 | p1 < 0.05 | 80.9 ± 10.62 | p1 < 0.05 p2 < 0.05 | 89.77 ± 13.25 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Nitrate (umols/L) | 38.21 ± 4.77 | 39.73 ± 5.39 | p1 > 0.05 | 41.59 ± 6.52 | p1 < 0.05 p2 > 0.05 | 62.08 ± 8.11 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Parameters | Clark Level | ||||||
---|---|---|---|---|---|---|---|
II | III | IV | V | ||||
Direct nitrite (umols/L) | 28.56 ± 4.22 | 30.72 ± 5.62 | p1 < 0.05 | 36.45 ± 7.34 | p1 < 0.05 p2 < 0.05 | 40.79 ± 8.96 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Total nitrite (umols/L) | 71.38 ± 8,73 | 74.67 ± 10.34 | p1 < 0.05 | 81.49 ± 11.68 | p1 < 0.05 p2 < 0.05 | 90.52 ± 14.05 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Nitrate (umols/L) | 37.65 ± 4.82 | 39.23 ± 5.71 | p1 > 0.05 | 42.31 ± 6.02 | p1 < 0.05 p2 < 0.05 | 62.42 ± 8.27 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Parameters | Melanoma Stage | ||||||
---|---|---|---|---|---|---|---|
I | II | III | IV | ||||
Direct nitrite (umols/L) | 29.83 ± 4.57 | 30.72 ± 5.69 | p1 > 0.05 | 35.27 ± 7.78 | p1 < 0.05 p2 < 0.05 | 41.04 ± 7.93 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Total nitrite (umols/L) | 71.92 ± 9.02 | 75.15 ± 10.77 | p1 > 0.05 | 81.79 ± 11.21 | p1 < 0.05 p2 > 0.05 | 89.17 ± 13.82 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Nitrate (umols/L) | 37.19 ± 5.02 | 38.73 ± 5.51 | p1 > 0.05 | 44.21 ± 6.12 | p1 < 0.05 p2 < 0.05 | 61.69 ± 8.17 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Parameters | Breslow Index | ||||||
---|---|---|---|---|---|---|---|
<1.0 | 1.01–2.0 | 2.01–3.0 | >3.01 | ||||
Nitrotyrosine (umol/L) | 0.33 ± 0.03 | 0.36 ± 0.02 | p1 < 0.05 | 0.41 ± 0.02 | p1 < 0.05 p2 > 0.05 | 0.40 ± 0.02 | p1 < 0.05 p2 < 0.05 p3 > 0.05 |
Carbonylation | |||||||
PCO (μmol/L) | 34.28 ± 2.26 | 36.84 ± 5.86 | p1 < 0.05 | 40.85 ± 4.80 | p1 < 0.05 p2 < 0.05 | 43.01 ± 2.73 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
4-HNE (μgl/mL) | 18.44 ± 6.82 | 21.26 ± 7.92 | p1 < 0.05 | 21.84 ± 7.70 | p1 < 0.05 p2 > 0.05 | 23.08 ± 8.05 | p1 < 0.05 p2 < 0.05 p3 > 0.05 |
TBARS (μmol/L) | 3.06 ± 0.36 | 3.27 ± 0.42 | p1 < 0.05 | 3.18 ± 0. 36 | p1 < 0.05 p2 < 0.05 | 3.74 ± 0.08 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
MDA (ng/mL) | 31.92 ± 3.51 | 35.73 ± 6.19 | p1 < 0.05 | 38.85 ± 3.37 | p1 < 0.05 p2 < 0.05 | 41.20 ±1.09 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Parameters | Clark Level | ||||||
---|---|---|---|---|---|---|---|
II | III | IV | V | ||||
Nitration | |||||||
Nitrotyrosine (umol/L) | 0.35 ± 0.03 | 0.37 ± 0.04 | p1 < 0.05 | 0.40 ± 0.08 | p1 < 0.05 p2 < 0.05 | 0.39 ± 0.03 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Carbonylation | |||||||
PCO (μmol/L) | 33.26 ± 4.19 | 36.67 ± 4.28 | p1 < 0.05 | 39.52 ± 5.08 | p1 < 0.05 p2 < 0.05 | 41.85 ± 7.02 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
4-HNE (μgl/mL) | 19.44 ± 7.12 | 21.26 ± 7.90 | p1 < 0.05 | 21.60 ± 7.54 | p1 < 0.05 p2 > 0.05 | 22.31 ± 7.95 | p1 > 0.05 p2 > 0.05 p3 < 0.05 |
TBARS (μmol/L) | 3.10 ± 0.44 | 2.94 ± 0.08 | p1 > 0.05 | 3.67 ± 0.22 | p1 < 0.05 p2 < 0.05 | 3.49 ± 0.40 | p1 < 0.05 p2 < 0.05 p3 > 0.05 |
MDA (ng/mL) | 32.33 ± 5.65 | 33.66 ± 3.01 | p1 > 0.05 | 39.60 ± 5.69 | p1 < 0.05 p2 < 0.05 | 40.51 ± 2.50 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Parameters | Melanoma Stage | ||||||
---|---|---|---|---|---|---|---|
I | II | III | IV | ||||
Nitration | |||||||
Nitrotyrosine (umol/L) | 0.35 ± 0.04 | 0.37 ± 0.03 | p1 > 0.05 | 0.39 ± 0.06 | p1 < 0.05 p2 < 0.05 | 0.42 ± 0.05 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Carbonylation | |||||||
PCO (μmol/L) | 32.91 ± 3.45 | 35.84 ± 4.37 | p1 < 0.05 | 39.68 ± 5.08 | p1 < 0.05 p2 < 0.05 | 42.86 ± 7.69 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
4-HNE (μgl/mL) | 19.85 ± 6.89 | 20.67 ± 8.01 | p1 > 0.05 | 21.49 ± 7.94 | p1 < 0.05 p2 > 0.05 | 22.62 ± 7.65 | p1 < 0.05 p2 < 0.05 p3 > 0.05 |
TBARS (μmol/L) | 3.06 ± 0.37 | 3.27 ± 0.42 | p1 < 0.05 | 3.15 ± 0.34 | p1 < 0.05 p2 > 0.05 | 3.61 ± 0.32 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
MDA (ng/mL) | 31.46 ± 3.51 | 36.01 ± 6.5 | p1 < 0.05 | 38.06 ± 3.76 | p1 < 0.05 p2 < 0.05 | 41.01 ± 1.09 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
Parameters | Breslow Index | ||||||
---|---|---|---|---|---|---|---|
<1.0 | 1.01–2.0 | 2.01–3.0 | >3.01 | ||||
SDMA (μmol/L) | 0.88 ± 0.07 | 0.93 ± 0.07 | p1 < 0.05 | 0.97 ± 0.08 | p1 < 0.05 p2 < 0.05 | 1.04 ± 0.07 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
ADMA (μmol/L) | 0.78 ± 0.07 | 0.84 ± 0.09 | p1 < 0.05 | 0.90 ± 0.09 | p1 < 0.05 p2 < 0.05 | 0.94 ± 0.11 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
ADMA/SDMA | 0.88 ± 0.05 | 0.90 ± 0.06 | p1 > 0.05 | 0.92 ± 0.08 | p1 > 0.05 p2 > 0.05 | 0.90 ± 0.09 | p1 > 0.05 p2 > 0.05 p3 > 0.05 |
Parameters | Clark Level | ||||||
---|---|---|---|---|---|---|---|
II | III | IV | V | ||||
SDMA (μmol/L) | 0.91 ± 0.08 | 0.92 ± 0.04 | p1 > 0.05 | 0.97 ± 0.05 | p1 < 0.05 p2 < 0.05 | 1.02 ± 0.05 | p1 < 0.05 p2 < 0.05 p3 > 0.05 |
ADMA (μmol/L) | 0.79 ± 0.07 | 0.83 ± 0.08 | p1 < 0.05 | 0.91 ± 0.1 | p1 < 0.05 p2 < 0.05 | 0.94 ± 0.12 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
ADMA/SDMA | 0.88 ± 0.06 | 0.90 ± 0.05 | p1 > 0.05 | 0.94 ± 0.07 | p1 > 0.05 p2 > 0.05 | 0.87 ± 0.07 | p1 > 0.05 p2 > 0.05 p3 < 0.05 |
Parameters | Melanoma Stage | ||||||
---|---|---|---|---|---|---|---|
I | II | III | IV | ||||
SDMA (μmol/L) | 0.90 ± 0.07 | 0.93 ± 0.05 | p1 < 0.05 | 0.97 ± 0.04 | p1 < 0.05 p2 < 0.05 | 1.02 ± 0.07 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
ADMA (μmol/L) | 0.77 ± 0.06 | 0.83 ± 0.08 | p1 < 0.05 | 0.91 ± 0.10 | p1 < 0.05 p2 < 0.05 | 0.95 ± 0.12 | p1 < 0.05 p2 < 0.05 p3 < 0.05 |
ADMA/SDMA | 0.88 ± 0.05 | 0.88 ± 0.07 | p1 > 0.05 | 0.93 ± 0.09 | p1 > 0.05 p2 > 0.05 | 0.89 ± 0.09 | p1 > 0.05 p2 > 0.05 p3 < 0.05 |
Parameters | LDH | Clark | Breslow | TNM | Ulceration | |
---|---|---|---|---|---|---|
HIF-1a | r | 0.250 | 0.690 | 0.400 | 0.410 | 0.010 |
p | 0.061 | 0.020 | 0.031 | 0.055 | 0.890 | |
HIF-2a | r | 0.554 | 0.192 | 0.206 | 0.484 | 0.040 |
p | 0.002 | 0.150 | 0.154 | 0.041 | 0.895 | |
HIF-1a/ HIF-2a | r | 0.257 | −0.189 | −0.200 | −0.250 | −0.030 |
p | 0.070 | 0.050 | 0.002 | 0.040 | 0.760 | |
Direct nitrite | r | 0.401 | 0.630 | 0.390 | 0.350 | 0.120 |
p | 0.030 | 0.001 | 0.020 | 0.040 | 0.290 | |
Nitrate | r | 0.380 | 0.580 | 0.460 | 0.460 | −0.020 |
p | 0.005 | 0.010 | 0.001 | 0.001 | 0.780 | |
3-nitrotirosine | r | 0.290 | 0.290 | 0.360 | 0.190 | 0.140 |
p | 0.030 | 0.010 | 0.009 | 0.170 | 0.200 | |
Carbonylic groups | r | 0.280 | 0.640 | 0.419 | 0.190 | 0.140 |
p | 0.040 | 0.010 | 0.001 | 0.150 | 0.200 | |
4-HNE | r | 0.400 | 0.600 | 0.420 | 0.350 | 0.030 |
p | 0.003 | 0.010 | 0.001 | 0.005 | 0.790 | |
TBARS | r | 0.450 | 0.050 | 0.306 | 0.200 | 0.180 |
p | 0.001 | 0.001 | 0.020 | 0.130 | 0.150 | |
MDA | r | 0.240 | 0.620 | 0.470 | 0.300 | 0.070 |
p | 0.080 | 0.010 | 0.001 | 0.010 | 0.500 | |
NT | r | −0.381 | 0.420 | −0.450 | −0.110 | 0.040 |
p | 0.009 | 0.020 | 0.001 | 0.400 | 0.730 | |
TT | r | −0.331 | −0.450 | −0.480 | 0.010 | 0.040 |
p | 0.010 | 0.010 | 0.001 | 0.950 | 0.710 | |
DS | r | 0.170 | 0.080 | 0.800 | 0.270 | 0.030 |
p | 0.200 | 0.550 | 0.580 | 0.600 | 0.950 | |
DS/NT | r | 0.250 | 0.190 | 0.200 | 0.250 | 0.010 |
p | 0.061 | 0.160 | 0.151 | 0.080 | 0.890 | |
DS/TT | r | 0.254 | 0.192 | 0.206 | 0.260 | 0.040 |
p | 0.062 | 0.150 | 0.154 | 0.081 | 0.895 | |
NT/TT | r | 0.257 | 0.189 | −0.200 | −0.250 | 0.030 |
p | 0.070 | 0.150 | 0.152 | 0.080 | 0.760 | |
SDMA | r | 0.010 | 0.570 | −0.280 | 0.180 | 0.106 |
p | 0.430 | 0.010 | 0.050 | 0.200 | 0.010 | |
ADMA | r | 0.340 | 0.640 | 0.284 | 0.284 | 0.040 |
p | 0.010 | 0.010 | 0.030 | 0.010 | 0.950 | |
ADMA/SDMA | p | 0.156 | 0.280 | 0.100 | 0.230 | 0.120 |
r | 0.050 | 0.030 | 0.480 | 0.120 | 0.754 |
Metabolites | HIF1a | HIF2a | HIF1a/HIF2a | Direct Nitrite | Nitrate | |
---|---|---|---|---|---|---|
Direct nitrite | r | 0.654 | 0.331 | 0.342 | - | - |
p | 0.018 | 0.036 | 0.004 | - | - | |
Nitrate | r | 0.730 | 0.470 | 0.375 | - | - |
p | 0.020 | 0.006 | 0.030 | - | - | |
3-nitrotirosine | r | 0.311 | 0.490 | 0.578 | 0.870 | 0.860 |
p | 0.028 | 0.041 | 0.001 | 0.001 | 0.002 | |
Carbonylic groups | r | 0.401 | 0.720 | 0.653 | 0.520 | 0.430 |
p | 0.018 | 0.006 | 0.001 | 0.001 | 0.001 | |
4-HNE | r | 0.392 | 0.822 | 0.720 | 0.510 | 0.470 |
p | 0.002 | 0.001 | 0.001 | 0.001 | 0.008 | |
TBARS | r | 0.412 | 0.630 | 0.750 | 0.376 | 0.609 |
p | 0.001 | 0.001 | 0.001 | 0.022 | 0.010 | |
MDA | r | 0.371 | 0.520 | 0.540 | 0.510 | 0.420 |
p | 0.002 | 0.010 | 0.002 | 0.002 | 0.040 | |
NT | r | −0.530 | −0.491 | 0.320 | −0.510 | −0.150 |
p | 0.001 | 0.004 | 0.020 | 0.001 | 0.260 | |
TT | r | −0.553 | −0.367 | 0.450 | −0.422 | −0.110 |
p | 0.002 | 0.038 | 0.020 | 0.003 | 0.650 | |
DS | r | 0.287 | 0.281 | 0.140 | 0.768 | 0.297 |
p | 0.043 | 0.002 | 0.420 | 0.040 | 0.030 | |
DS/NT | r | −0.301 | −0.250 | 0.090 | 0.130 | 0.310 |
p | 0.015 | 0.072 | 0.470 | 0.201 | 0.140 | |
DS/TT | r | −0.404 | −0.221 | 0.212 | 0.176 | 0.130 |
p | 0.041 | 0.059 | 0.320 | 0.177 | 0.111 | |
NT/TT | r | 0.398 | 0.306 | 0.169 | 0.160 | −0.340 |
p | 0.051 | 0.040 | 0.350 | 0.432 | 0.020 | |
SDMA | r | 0.110 | 0.146 | 0.210 | 0.195 | 0.211 |
p | 0.010 | 0.176 | 0.210 | 0.360 | 0.342 | |
ADMA | r | 0.490 | 0.587 | 0.730 | 0.684 | 0.810 |
p | 0.031 | 0.028 | 0.002 | 0.001 | 0.001 | |
ADMA/SDMA | r | −0.098 | 0.203 | 0.320 | 0.126 | 0.260 |
p | 0.520 | 0.043 | 0.033 | 0.218 | 0.430 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ene, C.D.; Nicolae, I. Hypoxia-Nitric Oxide Axis and the Associated Damage Molecular Pattern in Cutaneous Melanoma. J. Pers. Med. 2022, 12, 1646. https://doi.org/10.3390/jpm12101646
Ene CD, Nicolae I. Hypoxia-Nitric Oxide Axis and the Associated Damage Molecular Pattern in Cutaneous Melanoma. Journal of Personalized Medicine. 2022; 12(10):1646. https://doi.org/10.3390/jpm12101646
Chicago/Turabian StyleEne, Corina Daniela, and Ilinca Nicolae. 2022. "Hypoxia-Nitric Oxide Axis and the Associated Damage Molecular Pattern in Cutaneous Melanoma" Journal of Personalized Medicine 12, no. 10: 1646. https://doi.org/10.3390/jpm12101646