Despite improvements in treatment strategies, colorectal cancer (CRC) still has high mortality rates. Most CRCs develop from adenopolyps via the adenoma-carcinoma sequence. A mechanism for inhibition of this sequence in individuals with a high risk of developing CRC is urgently needed. Differential studies of mitochondrial (mt) gene expressions in the progressive stages of CRC with villous architecture are warranted to reveal early risk assessments and new targets for chemoprevention of the disease. In the present study, reverse transcription-quantitative PCR (RT-qPCR) was used to determine the relative amount of the transcripts of six mt genes [MT-RNR1, MT-ND1, MT-COI, MT-ATP6, MT-ND6, and MT-CYB (region 648–15887)] which are involved in the normal metabolism of mitochondria. A total of 42 pairs of tissue samples obtained from colorectal adenopolyps, adenocarcinomas, and their corresponding adjacent normal tissues were examined. Additionally, electron transport chain (ETC), complexes I (NADH: ubiquinone oxidoreductase) and III (CoQH2-cytochrome C reductase), and carbonyl protein group contents were analyzed. Results indicate that there were differential expressions of the six mt genes and elevated carbonyl protein contents among the colorectal adenopolyps compared to their paired adjacent normal tissues (p < 0.05). The levels of complexes I and III were higher in tumor tissues relative to adjacent normal tissues. Noticeably, the expression of MT-COI was overexpressed in late colorectal carcinomas among all studied transcripts. Our data suggest that increased expressions in certain mt genes and elevated levels of ROS may potentially play a critical role in the colorectal tumors evolving from adenopolyps to malignant lesions.
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- 12S/MT-RNR1 :
Mitochondrial encoded 12S ribosomal RNA
- ATCB :
- CA :
- Cp :
- CRC :
- DNPH :
- ETC :
Electron transport chain
- FAP :
Familial adenomatous polyposis
- GAPDH :
Glyceraldehyde 3 phosphate dehydrogenase
- HILF1α :
Hypoxia inducible factor 1-alpha
- MT :
- MT-ATP6 :
ATP synthase F0 subunit 6
- MT-COI :
Mitochondrial encoded cytochrome oxidase I
- MT-CYB :
Mitochondrial encoded cytochrome b
- MT-DNA :
- MT-ND1 :
Mitochondrial encoded NADH dehydrogenase 1
- MT-ND6 :
Mitochondrial encoded NADH dehydrogenase 6
- ROS :
Reactive oxygen species
- RT-qPCR :
Reverse transcription quantitative polymerase chain reaction
- TA :
- TV :
- UBC :
- V :
Duarte FV, Palmeira CM, Rolo AP. The Role of microRNAs in mitochondria: small players acting wide. Genes (Basel). 2014;5:865–86.
Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol Mech Dis. 2011;6:479–507.
Winawer SJ, Zauber AG, Ho MN, O’Brien MJ, Gottlieb LS, Sternberg SS, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med. 1993;329:1977–81.
Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends in Genetics. 1993;9:138–41.
Czarnecka A, Golik P, Bartnik E. Mitochondrial DNA mutations in human neoplasia. J Appl Genet. 2006;47:67–78.
Weren RDA, Ligtenberg MJL, Kets CM, de Voer RM, Verwiel ETP, Spruijt L, et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet. 2015;47:668–71.
Bettington M, Walker N, Clouston A, Brown I, Leggett B, Whitehall V. The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology. 2013;62:367–86.
Adams G, Mehrabi S, Vatcharapijarn Y, Iyamu OI, Akwe JA, Grizzle WE, et al. Frequencies of mtDNA mutations in primary tissue of colorectal adenopolyps. Front Biosci (Elite Ed). 2013;5:809–13.
Aikhionbare F, Khan M, Carey D, Okoli J, Go R. Is cumulative frequency of mitochondrial DNA variants a biomarker for colorectal tumor progression? Mol Cancer. 2004;3:30.
Polyak K, Li Y, Zhu H, Lengauer C, Willson JKV, Markowitz SD, et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet. 1998;20:291–3.
Sun C, Reimers LL, Burk RD. Methylation of HPV16 genome CpG sites is associated with cervix precancer and cancer. Gynecol Oncol. 2011;121:59–63.
Mehrabi S, Partridge EE, Seffens W, Yao X, Aikhionbare FO. Oxidatively modified proteins in the serous subtype of ovarian carcinoma. Biomed Res Int. 2014;2014:585083.
Chester KA, Robson L, Begent RHJ, Pringle H, Primrose L, Talbot IC, et al. In situ and slot hybridization analysis of RNA in colorectal tumours and normal colon shows distinct distributions of mitochondrial sequences. J Pathol. 1990;162:309–15.
Lee HC, Yin PH, Lin JC, Wu CC, Chen CY, Wu CW, et al. Mitochondrial Genome Instability and mtDNA Depletion in Human Cancers. Annals of the New York Academy of Sciences. 2005;1042:109–22.
Lu X, Walker T, MacManus JP, Seligy VL. Differentiation of HT-29 human colonic adenocarcinoma cells correlates with increased expression of mitochondrial RNA: effects of trehalose on cell growth and maturation. Cancer Research. 1992;52:3718–25.
Yamamoto A, Horai S, Yuasa Y. Increased level of mitochondrial gene expression in polyps of familial polyposis coli patients. Biochemical and Biophysical Research Communications. 1989;159:1100–6.
Abril J, De Heredia ML, González L, Cléries R, Nadal M, Condom E, et al. Altered expression of 12S/MT-RNR1, MT-CO2/COX2, and MT-ATP6 mitochondrial genes in prostate cancer. Prostate. 2008;68:1086–96.
Evans P, Lyras L, Halliwell B. Measurement of protein carbonyls in human brain tissue. In: Methods in Enzymology Oxidants and Antioxidants Part B.Academic Press. 1999. p. 145–56.
Beal MF. Oxidatively modified proteins in aging and disease1,2. Free Radical Biology and Medicine. 2002;32:797–803.
Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, et al. Determination of carbonyl content in oxidatively modified proteins. In: Methods in enzymology oxygen radicals in biological systems part B: oxygen radicals and antioxidants. Academic Press. 1990. p. 464–78.
Bragoszewski P, Kupryjanczyk J, Bartnik E, Rachinger A, Ostrowski J. Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer. BMC Cancer. 2008;8:292.
Rubie C, Kempf K, Hans J, Su T, Tilton B, Georg T, et al. Housekeeping gene variability in normal and cancerous colorectal, pancreatic, esophageal, gastric and hepatic tissues. Molecular and Cellular Probes. 2005;19:101–9.
Andersen CL, Jensen JL, Ørntoft TF. Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Research. 2004;64:5245–50.
Mehrabi S, Wallace L, Cohen S, Yao X, Aikhionbare FO. Differential measurements of oxidatively modified proteins in colorectal adenopolyps. Int J Clin Med. 2015;6:288–99.
Carew JS, Huang P. Mitochondrial defects in cancer. Mol Cancer. 2002;1:9.
Grzybowska-Szatkowska L, Slaska B, Rzymowska J, Brzozowska A, Floriańczyk B. Novel mitochondrial mutations in the ATP6 and ATP8 genes in patients with breast cancer. Mol Med Rep. 2014;10:1772–8.
Sun AS, Cederbaum AI. Oxidoreductase activities in normal rat liver, tumor-bearing rat liver, and hepatoma HC-252. Cancer Research. 1980;40:4677–81.
Chandra D, Singh KK. Genetic insights into OXPHOS defect and its role in cancer. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 2011;1807:620–5.
Akouchekian M, Houshmand M, Akbari MHH, Kamalidehghan B, Dehghan M. Analysis of mitochondrial ND1 gene in human colorectal cancer. J Res Med Sci. 2011;16:50–5.
Rigoulet M, Yoboue ED, Devin A. Mitochondrial ROS generation and its regulation: mechanisms involved in H2O2 signaling. Antioxidants & Redox Signaling. 2010;14:459–68.
Zhang Y, Marcillat O, Giulivi C, Ernster L, Davies KJ. The oxidative inactivation of mitochondrial electron transport chain components and ATPase. Journal of Biological Chemistry. 1990;265:16330–6.
Saybaşili H, Yϋksel M, Haklar G, Yalϛin AS. Effect of mitochondrial electron transport chain inhibitors on superoxide radical generation in rat hippocampal and striatal slices. Antioxid Redox Signal. 2001;3(6):1099–104.
Dasgupta S, Hoque MO, Upadhyay S, Sidransky D. Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer. Cancer Research. 2008;68:700–6.
Pelicano H, Zhang W, Liu J, Hammoudi N, Dai J, Xu RH, et al. Mitochondrial dysfunction in some triple-negative breast cancer cell lines: role of mTOR pathway and therapeutic potential. Breast Cancer Research. 2014;16:434.
Heerdt BG, Halsey HK, Lipkin M, Augenlicht LH. Expression of mitochondrial cytochrome c oxidase in human colonic cell differentiation, transformation, and risk for colonic cancer. Cancer Research. 1990;50:1596–600.
Herrmann PC, Gillespie JW, Charboneau L, Bichsel VE, Paweletz CP, Calvert VS, et al. Mitochondrial proteome: altered cytochrome c oxidase subunit levels in prostate cancer. PROTEOMICS. 2003;3:1801–10.
Sun AS, Sepkowitz K, Geller SA. A study of some mitochondrial and peroxisomal enzymes in human colonic adenocarcinoma. Laboratory Investigation. 1981;44:13–7.
Dmitrenko V, Shostak K, Boyko O, Khomenko O, Rozumenko V, Malisheva T, et al. Reduction of the transcription level of the mitochondrial genome in human glioblastoma. Cancer Letters. 2005;218:99–107.
Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia: a mechanism of O2 sensing. Journal of Biological Chemistry. 2000;275(33):25130–8.
Oppenheimer SR, Mi D, Sanders ME, Caprioli RM. A Molecular Analysis of Tumor Margins by MALDI Mass Spectrometry in Renal Carcinoma. J Proteome Res. 2010;9:2182–90.
Higuchi M. Roles of Mitochondrial DNA Changes on Cancer Initiation and Progression. Cell Biol (Henderson, NV). 2012;1:109.
Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JR, Ackrell BA, Brand MD. Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem. 2012;287:27255–64.
Musatov A, Robinson NC. Susceptibility of mitochondrial electron-transport complexes to oxidative damage. Focus on cytochrome c oxidase. Free Radical Research. 2012;46:1313–26.
Poyton RO, McEwen JE. Crosstalk between nuclear and mitochondrial genomes. Annu Rev Biochem. 1996;65:563–607.
Delsite R, Kachhap S, Anbazhagan R, Gabrielson E, Singh K. Nuclear genes involved in mitochondria-to-nucleus communication in breast cancer cells. Mol Cancer. 2002;1:1–10.
Baracca A, Chiaradonna F, Sgarbi G, Solaini G, Alberghina L, Lenaz G. Mitochondrial complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 2010;1797:314–23.
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.
De Rasmo D, Panelli D, Sardanelli AM, Papa S. cAMP-dependent protein kinase regulates the mitochondrial import of the nuclear encoded NDUFS4 subunit of complex I. Cellular Signalling. 2008;20:989–97.
Puurand M, Peet N, Piirsoo A, Peetsalu M, Soplepmann J, Sirotkina M, et al. Deficiency of the complex I of the mitochondrial respiratory chain but improved adenylate control over succinate-dependent respiration are human gastric cancer-specific phenomena. Mol Cell Biochem. 2012;370:69–78.
Lim HY, Ho QS, Low J, Choolani M, Wong KP. Respiratory competent mitochondria in human ovarian and peritoneal cancer. Mitochondrion. 2011;11:437–43.
Simonnet H, Demont J, Pfeiffer K, Guenaneche L, Bouvier R, Brandt U, et al. Mitochondrial complex I is deficient in renal oncocytomas. Carcinogenesis. 2003;24:1461–6.
Bonora E, Porcelli AM, Gasparre G, Biondi A, Ghelli A, Carelli V, et al. Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial dna mutations affecting complexes I and III. Cancer Research. 2006;66:6087–96.
Chandran UR, Dhir R, Ma C, Michalopoulos G, Becich M, Gilbertson J. Differences in gene expression in prostate cancer, normal appearing prostate tissue adjacent to cancer and prostate tissue from cancer free organ donors. BMC Cancer. 2005;5:1–11.
Prakash K, Pirozzi G, Elashoff M, Munger W, Waga I, Dhir R, et al. Symptomatic and asymptomatic benign prostatic hyperplasia: molecular differentiation by using microarrays. Proceedings of the National Academy of Sciences. 2002;99:7598–603.
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.
We acknowledge the RCMI G12 MBRC Program from the National Institute of Minority Health and Health Disparities, Grant Number 8G12MD007602. To those investigators whose meritorious works could not be cited due to space limitations, we honestly apologize. This work was supported by grant NIH-NIGMS GM099663 awarded to Dr. Felix O Aikhionbare. We would also like to acknowledge William Roth and Saravanakumar Muthusamy for their technical and editing support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH-NIMHD and NIGMS.
Conception and design: L. Wallace, F.O. Aikhionbare, and S. Mehrabi; development of methodology: L. Wallace, S. Mehrabi, and F.O. Aikhionbare; acquisition of data: L. Wallace, S. Mehrabi, and M. Bacanamwo; analysis and interpretation of data: L. Wallace, S. Mehrabi, X. Yao, and F.O. Aikhionbare; writing: L. Wallace, S. Mehrabi, and F.O. Aikhionbare.
Conflicts of interest
The authors declare no conflicts of interest.
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Wallace, L., Mehrabi, S., Bacanamwo, M. et al. Expression of mitochondrial genes MT-ND1, MT-ND6, MT-CYB, MT-COI, MT-ATP6, and 12S/MT-RNR1 in colorectal adenopolyps. Tumor Biol. 37, 12465–12475 (2016). https://doi.org/10.1007/s13277-016-5101-3