Mitochondrial reactive oxygen species and complex II levels are associated with the outcome of hepatocellular carcinoma

Wu,Jianhua; Zhao,Fei; Zhao,Yufei; Guo,Zhanjun

doi:10.3892/ol.2015.3621

Mitochondrial reactive oxygen species and complex II levels are associated with the outcome of hepatocellular carcinoma

Authors:
- Jianhua Wu
- Fei Zhao
- Yufei Zhao
- Zhanjun Guo
View Affiliations

Affiliations: Experimental Animal Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China, Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
Published online on: August 18, 2015 https://doi.org/10.3892/ol.2015.3621
Pages: 2347-2350

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In the present study, two oxidative stress parameters, reactive oxygen species (ROS) and mitochondrial respiratory complex II, were evaluated in the mitochondria of hepatocellular carcinoma (HCC) cells to determine the association between these parameters and the carcinogenesis and clinical outcome of HCC. High levels of ROS and low levels of complex II were found to be associated with reduced post‑operative survival in HCC patients using the log‑rank test. Furthermore, multivariate analysis confirmed that the levels of ROS [relative risk (RR)=2.867; 95% confidence interval (CI), 1.062‑7.737; P=0.038] and complex II (RR=5.422; 95% CI, 1.273‑23.088; P=0.022) were independent predictors for the survival of patients with HCC. Therefore, the analysis of ROS and complex II levels may provide a useful research and therapeutic tool for the prediction of HCC prognosis and treatment.

View Figures

View References

1	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
2	El-Serag HB: Hepatocellular carcinoma. N Engl J Med. 365:1118–1127. 2011. View Article : Google Scholar : PubMed/NCBI
3	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
4	Hoshida Y, Villanueva A and Llovet JM: Molecular profiling to predict hepatocellular carcinoma outcome. Expert Rev Gastroenterol Hepatol. 3:101–103. 2009. View Article : Google Scholar : PubMed/NCBI
5	Okada S, Shimada K, Yamamoto J, Takayama T, Kosuge T, Yamasaki S, Sakamoto M and Hirohashi S: Predictive factors for postoperative recurrence of hepatocellular carcinoma. Gastroenterology. 106:1618–1624. 1994.PubMed/NCBI
6	Csiszar A, Podlutsky A, Podlutskaya N, Sonntag WE, Merlin SZ, Philipp EE, Doyle K, Davila A, Recchia FA, Ballabh P, et al: Testing the oxidative stress hypothesis of aging in primate fibroblasts: Is there a correlation between species longevity and cellular ROS production? J Gerontol A Biol Sci Med Sci. 67:841–852. 2012. View Article : Google Scholar : PubMed/NCBI
7	Park J, Lee J and Choi C: Mitochondrial network determines intracellular ROS dynamics and sensitivity to oxidative stress through switching inter-mitochondrial messengers. PLoS One. 6:e232112011. View Article : Google Scholar : PubMed/NCBI
8	Kawanishi S, Hiraku Y and Oikawa S: Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging. Mutat Res. 488:65–76. 2001. View Article : Google Scholar : PubMed/NCBI
9	Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M and Telser J: Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 39:44–84. 2007. View Article : Google Scholar : PubMed/NCBI
10	DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, et al: Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 475:106–109. 2011. View Article : Google Scholar : PubMed/NCBI
11	DiMauro S and Schon EA: Mitochondrial DNA mutations in human disease. Am J Med Genet. 106:18–26. 2001. View Article : Google Scholar : PubMed/NCBI
12	Lightowlers RN, Chinnery PF, Turnbull DM and Howell N: Mammalian mitochondrial genetics: Heredity, heteroplasmy and disease. Trends Genet. 13:450–455. 1997. View Article : Google Scholar : PubMed/NCBI
13	Yang L, Wang P, Wang H, Li Q, Teng H, Liu Z, Yang W, Hou L and Zou X: Fucoidan derived from Undaria pinnatifida induces apoptosis in human hepatocellular carcinoma SMMC-7721 cells via the ROS-mediated mitochondrial pathway. Mar Drugs. 11:1961–1976. 2013. View Article : Google Scholar : PubMed/NCBI
14	Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JR, Ackrell BA and Brand MD: Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem. 287:27255–27264. 2012. View Article : Google Scholar : PubMed/NCBI
15	Moreno-Sánchez R, Hernández-Esquivel L, Rivero-Segura NA, Marín-Hernández A, Neuzil J, Ralph SJ and Rodríguez Enríquez S: Reactive oxygen species are generated by the respiratory complex II - evidence for lack of contribution of the reverse electron flow in complex I. FEBS J. 280:927–938. 2013.PubMed/NCBI
16	Hoekstra AS and Bayley JP: The role of complex II in disease. Biochim Biophys Acta. 1827:543–551. 2013. View Article : Google Scholar : PubMed/NCBI
17	Halliwell B: Can oxidative DNA damage be used as a biomarker of cancer risk in humans? Problems, resolutions and preliminary results from nutritional supplementation studies. Free Radic Res. 29:469–486. 1998. View Article : Google Scholar : PubMed/NCBI
18	Li S, Wang X, Wu Y, Zhang H, Zhang L, Wang C, Zhang R and Guo Z: 8-Hydroxy-2′-deoxyguanosine expression predicts hepatocellular carcinoma outcome. Oncol Lett. 3:338–342. 2012.PubMed/NCBI
19	Cheng CW, Kuo CY, Fan CC, Fang WC, Jiang SS, Lo YK, Wang TY, Kao MC and Lee AY: Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species. Cell Death Dis. 4:e6812013. View Article : Google Scholar : PubMed/NCBI
20	Inoue S and Kawanishi S: Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett. 371:86–88. 1995. View Article : Google Scholar : PubMed/NCBI
21	Erhola M, Toyokuni S, Okada K, Tanaka T, Hiai H, Ochi H, Uchida K, Osawa T, Nieminen MM, Alho H, et al: Biomarker evidence of DNA oxidation in lung cancer patients: Association of urinary 8-hydroxy-2′-deoxyguanosine excretion with radiotherapy, chemotherapy, and response to treatment. FEBS Lett. 409:287–291. 1997. View Article : Google Scholar : PubMed/NCBI
22	Miyake H, Hara I, Gleave ME and Eto H: Protection of androgen-dependent human prostate cancer cells from oxidative stress-induced DNA damage by overexpression of clusterin and its modulation by androgen. Prostate. 61:318–323. 2004. View Article : Google Scholar : PubMed/NCBI
23	Kluckova K, Bezawork-Geleta A, Rohlena J, Dong L and Neuzil J: Mitochondrial complex II, a novel target for anti-cancer agents. Biochim Biophys Acta. 1827:552–564. 2013. View Article : Google Scholar : PubMed/NCBI
24	Albayrak T, Scherhammer V, Schoenfeld N, Braziulis E, Mund T, Bauer MK, Scheffler IE and Grimm S: The tumor suppressor cybL, a component of the respiratory chain, mediates apoptosis induction. Mol Biol Cell. 14:3082–3096. 2003. View Article : Google Scholar : PubMed/NCBI