High Leukocyte Mitochondrial DNA Content Contributes to Poor Prognosis in Glioma Patients Through Its Immunosuppressive Effect

Overview

Journal Br J Cancer

Specialty Oncology

Date 2015 May 30

PMID 26022928

Citations 11

Authors

Y Chen

X Huang

J Zhang

X Zhou

J Hu

G Li

S He

J Xing

Affiliations

Soon will be listed here.

Abstract

Background: Epidemiological studies have indicated significant associations of leukocyte mitochondrial DNA (mtDNA) copy number with risk of several malignancies, including glioma. However, whether mtDNA content can predict the clinical outcome of glioma patients has not been investigated.

Methods: The mtDNA content of peripheral blood leukocytes from 336 glioma patients was examined using a real-time PCR-based method. Kaplan-Meier curves and Cox proportional hazards regression model were used to examine the association of mtDNA content with overall survival (OS) and progression-free survival (PFS) of patients. To explore the potential mechanism, the immune phenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines from another 20 glioma patients were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively.

Results: Patients with high mtDNA content showed both poorer OS and PFS than those with low mtDNA content. Multivariate Cox regression analysis demonstrated that mtDNA content was an independent prognostic factor for both OS and PFS. Stratified analyses showed that high mtDNA content was significantly associated with poor prognosis of patients with younger age, high-grade glioma or adjuvant radiochemotherapy. Immunological analysis indicated that patients with high mtDNA content had significantly lower frequency of natural killer cells in PBMCs and higher plasma concentrations of interleukin-2 and tumour necrosis factor-α, suggesting an immunosuppression-related mechanism involved in mtDNA-mediated prognosis.

Conclusions: Our study for the first time demonstrated that leukocyte mtDNA content could serve as an independent prognostic marker and an indicator of immune functions in glioma patients.

Citing Articles

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High leukocyte mitochondrial DNA copy number contributes to poor prognosis in breast cancer patients.

Zhang W, Lin S, Zeng B, Chen X, Chen L, Chen M BMC Cancer. 2023; 23(1):377.

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References

Yu Q, Nie S, Wang J, Yin P, Huang D, Li W . Toll-like receptor 4-mediated ROS signaling pathway involved in Ganoderma atrum polysaccharide-induced tumor necrosis factor-α secretion during macrophage activation. Food Chem Toxicol. 2014; 66:14-22. DOI: 10.1016/j.fct.2014.01.018. View

Hosgood 3rd H, Liu C, Rothman N, Weinstein S, Bonner M, Shen M . Mitochondrial DNA copy number and lung cancer risk in a prospective cohort study. Carcinogenesis. 2010; 31(5):847-9. PMC: 2864414. DOI: 10.1093/carcin/bgq045. View

Qu F, Liu X, Zhou F, Yang H, Bao G, He X . Association between mitochondrial DNA content in leukocytes and colorectal cancer risk: a case-control analysis. Cancer. 2011; 117(14):3148-55. DOI: 10.1002/cncr.25906. View

Li J, Li J, Yue Y, Hu Y, Cheng W, Liu R . Genistein suppresses tumor necrosis factor α-induced inflammation via modulating reactive oxygen species/Akt/nuclear factor κB and adenosine monophosphate-activated protein kinase signal pathways in human synoviocyte MH7A cells. Drug Des Devel Ther. 2014; 8:315-23. PMC: 3962316. DOI: 10.2147/DDDT.S52354. View

Yang Y, Bazhin A, Werner J, Karakhanova S . Reactive oxygen species in the immune system. Int Rev Immunol. 2013; 32(3):249-70. DOI: 10.3109/08830185.2012.755176. View

Gomez G, Kruse C . Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene Ther Mol Biol. 2006; 10(A):133-146. PMC: 1474813. View

Capps G, Samuels D, Chinnery P . A model of the nuclear control of mitochondrial DNA replication. J Theor Biol. 2003; 221(4):565-83. DOI: 10.1006/jtbi.2003.3207. View

Brandsma D, van den Bent M . Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol. 2009; 22(6):633-8. DOI: 10.1097/WCO.0b013e328332363e. View

Zhang J, Li D, Qu F, Chen Y, Li G, Jiang H . Association of leukocyte mitochondrial DNA content with glioma risk: evidence from a Chinese case-control study. BMC Cancer. 2014; 14:680. PMC: 4177174. DOI: 10.1186/1471-2407-14-680. View

10.

Cavalli L, Varella-Garcia M, Liang B . Diminished tumorigenic phenotype after depletion of mitochondrial DNA. Cell Growth Differ. 1998; 8(11):1189-98. View

11.

Koochekpour S, Marlowe T, Singh K, Attwood K, Chandra D . Reduced mitochondrial DNA content associates with poor prognosis of prostate cancer in African American men. PLoS One. 2013; 8(9):e74688. PMC: 3781126. DOI: 10.1371/journal.pone.0074688. View

12.

Furnari F, Fenton T, Bachoo R, Mukasa A, Stommel J, Stegh A . Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007; 21(21):2683-710. DOI: 10.1101/gad.1596707. View

13.

Hsu C, Yin P, Lee H, Chi C, Tseng L . Mitochondrial DNA content as a potential marker to predict response to anthracycline in breast cancer patients. Breast J. 2010; 16(3):264-70. DOI: 10.1111/j.1524-4741.2010.00908.x. View

14.

Mizumachi T, Muskhelishvili L, Naito A, Furusawa J, Fan C, Siegel E . Increased distributional variance of mitochondrial DNA content associated with prostate cancer cells as compared with normal prostate cells. Prostate. 2008; 68(4):408-17. PMC: 2268637. DOI: 10.1002/pros.20697. View

15.

Lin C, Chang S, Wang L, Chou T, Hsu W, Wu Y . The role of mitochondrial DNA alterations in esophageal squamous cell carcinomas. J Thorac Cardiovasc Surg. 2009; 139(1):189-197.e4. DOI: 10.1016/j.jtcvs.2009.04.007. View

16.

Tatla S, Woodhead V, Foreman J, Chain B . The role of reactive oxygen species in triggering proliferation and IL-2 secretion in T cells. Free Radic Biol Med. 1999; 26(1-2):14-24. DOI: 10.1016/s0891-5849(98)00133-6. View

17.

Lan Q, Lim U, Liu C, Weinstein S, Chanock S, Bonner M . A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma. Blood. 2008; 112(10):4247-9. PMC: 2582005. DOI: 10.1182/blood-2008-05-157974. View

18.

Wen P, Kesari S . Malignant gliomas in adults. N Engl J Med. 2008; 359(5):492-507. DOI: 10.1056/NEJMra0708126. View

19.

Guo W, Yang D, Xu H, Zhang Y, Huang J, Yang Z . Mutations in the D-loop region and increased copy number of mitochondrial DNA in human laryngeal squamous cell carcinoma. Mol Biol Rep. 2012; 40(1):13-20. DOI: 10.1007/s11033-012-1939-7. View

20.

Kaminski M, Sauer S, Klemke C, Suss D, Okun J, Krammer P . Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. J Immunol. 2010; 184(9):4827-41. DOI: 10.4049/jimmunol.0901662. View