The Mitochondrial DNA Common Deletion Is Present in Most Basal and Squamous Cell Carcinoma Samples Isolated by Laser Capture Microdissection but Generally at Reduced Rather than Increased Levels

Kamenisch, York; Wenz, Julia; Metzler, Gisela; Bauer, Jakob; Neubauer, Hans; Garbe, Claus; Röcken, Martin; Berneburg, Mark

doi:10.1038/sj.jid.5700552

Cited by 16 publications

(11 citation statements)

References 23 publications

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“…It was shown that the common 4977-bp deletion in mitochondrial DNA (mtDNA) occurred in the two most common skin cancers, basal cell carcinoma and squamous cell carcinoma. 4 Arsenic acts like a double-sided sword in manipulating cell growth. On the one hand, it has been reported that arsenic induced aberrant cell proliferation, leading to human cancers 5 through several survival pathways, including the extracellular signal-regulated kinase signaling pathway.…”

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confidence: 99%

Aberrant Cell Proliferation by Enhanced Mitochondrial Biogenesis via mtTFA in Arsenical Skin Cancers

Lee

Wu²,

Hong

et al. 2011

The American Journal of Pathology

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Arsenic-induced Bowen's disease (As-BD), a cutaneous carcinoma in situ, is thought to arise from gene mutation and uncontrolled proliferation. However, how mitochondria regulate the arsenic-induced cell proliferation remains unclear. The aim of this study was to clarify whether arsenic interfered with mitochondrial biogenesis and function, leading to aberrant cell proliferation in As-BD. Skin biopsy samples from patients with As-BD and controls were stained for cytochrome c oxidase (Complex IV), measured for mitochondrial DNA (mtDNA) copy number and the expression levels of mitochondrial biogenesis-related genes, including peroxisome proliferator-activated receptor gamma coactivator-1␣ (PGC-1␣), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (mtTFA). The results showed that expression of cytochrome c oxidase, mtTFA, NRF-1, and PGC-1␣ was increased in As-BD compared with in healthy subjects. Treatment of primary keratinocytes with arsenic at concentrations lower than 1.0 mol/L induced cell proliferation, along with enhanced mitochondrial biogenesis. Furthermore, we observed that the mitochondrial oxygen consumption rate and intracellular ATP level were increased in arsenic-treated keratinocytes. Blocking of mitochondrial function by oligomycin A (Complex V inhibitor) or knockdown of mtTFA by RNA interference abrogated arsenic-induced cell proliferation without affecting cyclin D1 expression. We concluded that mtTFA up-regulation, augmented mitochondrial biogenesis, and enhanced mitochondrial functions may contribute to arsenic-induced cell proliferation. Targeting mitochondrial biogenesis may help treat arsenical cancers at the stage of cell proliferation.

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confidence: 99%

Aberrant Cell Proliferation by Enhanced Mitochondrial Biogenesis via mtTFA in Arsenical Skin Cancers

Lee

Wu²,

Hong

et al. 2011

The American Journal of Pathology

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“…The characteristics of each case-control study are listed in Table 1 . Of the 38 studies, sample sizes ranged from 7 to 130, in which nine studies focusing on breast cancer [25], [31]–[38], five studies focusing on hepatocellular carcinoma [39]–[43], four focusing on gastric cancer [38], [44]–[46], three focusing on colorectal cancer [25], [38], [47], three focusing on esophageal cancer [48]–[50], three focusing on oral cancer [51]–[53], two focusing on thyroid cancer [25], [54], two focusing on skin cancer [55], [56] and seven studies of other cancers (one endometrial carcinoma [57], one lung cancer [58], one Warthin’s cancer [59], one cervix cancer [60], one acute lymphoblastic leukemia [61], one prostate cancer [62] and one head and neck cancer [38]). Because some controls in two researches [25], [38] were shared by several cancers, it was defined as four studies (breast cancer, colorectal cancer, gastric cancer and head and neck cancer) and three studies (thyroid cancer, breast cancer and colorectal cancer) in the analysis stratified by cancer type but defined as one study in the overall analysis and stratification analysis by ethnicity, sample size, measurement method and DNA source.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Common Deletion, a Potential Biomarker for Cancer Occurrence, Is Selected against in Cancer Background: A Meta-Analysis of 38 Studies

et al. 2013

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Mitochondrial dysfunction has been long proposed to play a major role in tumorigenesis. Mitochondrial DNA (mtDNA) mutations, especially the mtDNA 4,977 bp deletion has been found in patients of various types of cancer. In order to comprehend the mtDNA 4,977 bp deletion status in various cancer types, we performed a meta-analysis composed of 33 publications, in which a total of 1613 cancer cases, 1516 adjacent normals and 638 healthy controls were included. When all studies were pooled, we found that cancerous tissue carried a lower mtDNA 4,977 bp deletion frequency than adjacent non-cancerous tissue (OR = 0.43, 95% CI = 0.20–0.92, P = 0.03 for heterogeneity test, I2 = 91.5%) among various types of cancer. In the stratified analysis by cancer type the deletion frequency was even lower in tumor tissue than in adjacent normal tissue of breast cancer (OR = 0.19, 95% CI = 0.06–0.61, P = 0.005 for heterogeneity test, I2 = 82.7%). Interestingly, this observation became more significant in the stratified studies with larger sample sizes (OR = 0.70, 95% CI = 0.58–0.86, P = 0.0005 for heterogeneity test, I2 = 95.1%). Furthermore, when compared with the normal tissue from the matched healthy controls, increased deletion frequencies were observed in both adjacent non-cancerous tissue (OR = 3.02, 95% CI = 2.13–4.28, P<0.00001 for heterogeneity test, I2 = 53.7%), and cancerous tissue (OR = 1.36, 95% CI = 1.04–1.77, P = 0.02 for heterogeneity test, I2 = 83.5%). This meta-analysis suggests that the mtDNA 4,977 bp deletion is often found in cancerous tissue and thus has the potential to be a biomarker for cancer occurrence in the tissue, but at the same time being selected against in various types of carcinoma tissues. Larger and better-designed studies are still warranted to confirm these findings.

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“…In total, 27 benign skin lesions (8 SK, 14 LS and 5 EN) and 27 corresponding normal tissues were analysed for the frequency of the mtDNA common deletion by quantitative real‐time PCR. Because the frequency of the common deletion may depend on the localization of the analyzed skin (sun‐exposed versus sun‐protected), the corresponding normal tissues served as an internal control to eliminate site‐specific effects (14). The mean age of the patients was 66 years for SK, 69 years for SL and 11 years for EN, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…The analysis of the mtDNA 4,977 bp common deletion was performed as described previously (13–15). In brief, DNA isolated from SL, SK and EN probes was subjected to real‐time PCR for detection of the level of common deletion and the level of mitochondrial reference fragment.…”

Section: Experimental Designmentioning

confidence: 99%

Distinct profile of the mitochondrial DNA common deletion in benign skin lesions

Hafner

Kamenisch

Landthaler

et al. 2011

Experimental Dermatology

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production of TSLP, thus activating dendritic cells and mast cells; this results in Th2-type allergic immune responses via the stimulation of DCs and mast cells (11). Besides, filaggrin expression is frequently downregulated in AD patients with no FLG mutations owing to the Th2 cytokines, . Thus, we measured and compared the levels of TSLP expression in filaggrin knockdown epidermal cells. In Fig. 2, TSLP expression in the human epidermal layer was increased under filaggrin knockdown conditions and enhanced in response to poly(I:C) stimuli. This suggests that the filaggrin knockdown conditions induced TSLP secretion and might result in Th2 immune reaction, thus resulting in the propagation of filaggrin reduction in the inflammatory area of the skin of atopic dermatitis patients. AcknowledgementsWe thank Professor Tae Supporting InformationAdditional Supporting Information may be found in the online version of this article: Figure S1. Detection of TLR mRNA by RT-PCR in cultured HaCaT cells. Figure S2. Quantification of IL-1a and IL-1b from cellular lysates as well as IL-6 from the culture supernatants of TLR agonist-treated HaCaT cells with siRNA transfection. Figure S3. H&E staining of NeoDerm-E Ò transduced with control or filaggrin shRNA with or without TLR3 ligand stimulation. Abstract: Mutations of mitochondrial (mt) DNA, particularly the 4977 bp long common deletion, are increased in aging tissues and preferentially found in chronologically and photoaged skin. Mutations of human mitochondrial DNA (mtDNA) have also been identified in malignant tumors of the skin and of other organs. However, benign skin lesions have not yet been investigated. We analyzed the frequency of the common deletion in 27 benign skin lesions [8 seborrheic keratoses (SK), 5 epidermal nevi (EN), 14 solar lentigos (SL)] by quantitative realtime PCR, because SK and especially SL have been related to (photo)aged skin. All SK and four of five EN displayed reduced common deletion levels compared with adjacent normal skin. In contrast, 50% of SL revealed a higher percentage of the common deletion than the adjacent normal skin, and some SL showed very high absolute common deletion levels up to 14% of total mtDNA. Our results show that the amount of the common deletion is significantly different in benign skin lesions and raise further questions regarding the pathogenesis of SL and its possible role as a precursor lesion of SK.

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The Mitochondrial DNA Common Deletion Is Present in Most Basal and Squamous Cell Carcinoma Samples Isolated by Laser Capture Microdissection but Generally at Reduced Rather than Increased Levels

Cited by 16 publications

References 23 publications

Aberrant Cell Proliferation by Enhanced Mitochondrial Biogenesis via mtTFA in Arsenical Skin Cancers

Aberrant Cell Proliferation by Enhanced Mitochondrial Biogenesis via mtTFA in Arsenical Skin Cancers

Mitochondrial Common Deletion, a Potential Biomarker for Cancer Occurrence, Is Selected against in Cancer Background: A Meta-Analysis of 38 Studies

Distinct profile of the mitochondrial DNA common deletion in benign skin lesions

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