Role of mitochondrial DNA copy number alteration in non-small cell lung cancer

Lin, Cheng‐Chieh; Yeh, Yi‐Chen; Pan, Siao-Cian; Lu, Shih-Yu; Chen, Yann-Jang; Chueh, Wen-Yu; Wei, Yau‐Huei

doi:10.4103/fjs.fjs_15_20

Cited by 4 publications

(12 citation statements)

References 41 publications

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“…However, some confounding results happened. During TFAM knockdown, we found an increase in migration activity in RCC, NSCLC, and GAC (Figure 2E) cells [27,33], but a decrease in migration activity in ESCC and CRC cells [22,38]. Although we did not evaluate the protein levels of TFAM in GAC patients' specimens in this study, relevant results have been reported in other human cancers.…”

Section: Discussionsupporting

confidence: 49%

“…This observation suggests that a decrease of the mtDNA copy number may be involved in the carcinogenesis of gastric cancer [31]. Additionally, a decrease in the mtDNA copy number has been reported in the progression of esophageal squamous cell carcinomas [32] and non-small lung cancers [33,34], poor prognosis of breast cancer [35], the development of Borrmann's types III/IV GAC [4], and advanced stage III/IV GAC [30], as well as advanced T-/N-/M-status and poorer prognosis of GAC, observed in the current study (Tables 3 and 4; Figure 1A). Taken together, a decrease in the mtDNA copy number plays a role in the carcinogenesis, progression, and poor prognosis of GAC.…”

Section: Discussionmentioning

confidence: 68%

“…Although we did not evaluate the protein levels of TFAM in GAC patients' specimens in this study, relevant results have been reported in other human cancers. In a previous study, we found that a low level of TFAM protein expression was associated with the progression and poor prognosis in NSCLC [33]. In contrast, Mo et al [50] reported that a high level of TFAM protein expression was associated with the progression of bladder cancer.…”

Section: Discussionmentioning

confidence: 77%

“…To evaluate the consequences of decreased mtDNA copy number in human cancers, we have focused on the TFAM-mtDNA pathway in the past 10 or more years. We knocked down TFAM to decrease the mtDNA copy number in several human cancer cell lines, including esophageal squamous cell carcinoma (ESCC) [42], renal cell carcinoma (RCC) [27], colorectal cancer (CRC) [43], and non-small cell lung cancer (NSCLC) [33] as well as GAC (Figure 2 & Supplementary Figure S3; Table 5) in the current study. A decrease in the mtDNA copy number did cause a decrease in mitochondrial biogenesis as reflected by lower expression levels of mtDNA-encoded polypeptides in ESCC, RCC, CRC, and NSCLC cells or lower rates of oxygen consumption in ESCC, RCC, CRC, and GAC (Figure 2C) cells.…”

Section: Discussionmentioning

confidence: 99%

“…Thin sections about 5 µm in thickness were cut from the corresponding tissue blocks for DNA extraction. After the de-wax and re-hydration procedures, the tissue sections were mixed with 500 µL of QuickExtract TM DNA extraction solution (Epicenter, Madison, WI, USA) to extract total cellular DNA at 65 • C for 3 h as described [18,19,33]. The DNA samples thus obtained were kept at −20 • C until use.…”

Section: Study Participants Tissue Preparation and Dna Extractionmentioning

confidence: 99%

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Metabolic Reprogramming in Response to Alterations of Mitochondrial DNA and Mitochondrial Dysfunction in Gastric Adenocarcinoma

Chang

Lee

Pan

et al. 2022

IJMS

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We used gastric cancer cell line AGS and clinical samples to investigate the roles of mitochondrial DNA (mtDNA) alterations and mitochondrial respiratory dysfunction in gastric adenocarcinoma (GAC). A total of 131 clinical samples, including 17 normal gastric mucosa (N-GM) from overweight patients who had received sleeve gastrectomy and 57 paired non-cancerous gastric mucosae (NC-GM) and GAC from GAC patients who had undergone partial/subtotal/total gastrectomy, were recruited to examine the copy number and D310 sequences of mtDNA. The gastric cancer cell line AGS was used with knockdown (KD) mitochondrial transcription factor A (TFAM) to achieve mitochondrial dysfunction through a decrease of mtDNA copy number. Parental (PT), null-target (NT), and TFAM-KD-(A/B/C) represented the parental, control, and TFAM knocked-down AGS cells, respectively. These cells were used to compare the parameters reflecting mitochondrial biogenesis, glycolysis, and cell migration activity. The median mtDNA copy numbers of 17 N-GM, 57 NC-GM, and 57 GAC were 0.058, 0.055, and 0.045, respectively. The trend of decrease was significant (p = 0.030). In addition, GAC had a lower mean mtDNA copy number of 0.055 as compared with the paired NC-GM of 0.078 (p < 0.001). The mean mtDNA copy number ratio (mtDNA copy number of GAC/mtDNA copy number of paired NC-GM) was 0.891. A total of 35 (61.4%) GAC samples had an mtDNA copy number ratio ≤0.804 (p = 0.017) and 27 (47.4%) harbored a D310 mutation (p = 0.047), and these patients had shorter survival time and poorer prognosis. After effective knockdown of TFAM, TFAM-KD-B/C cells expressed higher levels of hexokinase II (HK-II) and v-akt murine thymoma viral oncogene homolog 1 gene (AKT)-encoded AKT, but lower levels of phosphorylated pyruvate dehydrogenase (p-PDH) than did the NT/PT AGS cells. Except for a higher level of p-PDH, the expression levels of these proteins remained unchanged in TFAM-KD-A, which had a mild knockdown of TFAM. Compared to those of NT, TFAM-KD-C had not only a lower mtDNA copy number (p = 0.050), but also lower oxygen consumption rates (OCR), including basal respiration (OCRBR), ATP-coupled respiration (OCRATP), reserve capacity (OCRRC), and proton leak (OCRPL)(all with p = 0.050). In contrast, TFAM-KD-C expressed a higher extracellular acidification rate (ECAR)/OCRBR ratio (p = 0.050) and a faster wound healing migration at 6, 12, and 18 h, respectively (all with p = 0.050). Beyond a threshold, the decrease in mtDNA copy number, the mtDNA D310 mutation, and mitochondrial dysfunction were involved in the carcinogenesis and progression of GACs. Activation of PDH might be considered as compensation for the mitochondrial dysfunction in response to glucose metabolic reprogramming or to adjust mitochondrial plasticity in GAC.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Study Participants Tissue Preparation and Dna Extractionmentioning

confidence: 99%

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Metabolic Reprogramming in Response to Alterations of Mitochondrial DNA and Mitochondrial Dysfunction in Gastric Adenocarcinoma

Chang

Lee

Pan

et al. 2022

IJMS

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Tobacco, Second-Hand Smoke and Cancer

Pinkaew,

Dammad,

Bitar

et al. 2023

Environmental Oncology

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The Role of Plasma Cell-Free Mitochondrial DNA and Nuclear DNA in Systemic Lupus Erythematosus

Lee¹,

Lin²,

Pan³

et al. 2022

Front. Biosci. (Landmark Ed)

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Background:The roles of plasma cell-free (pcf) mitochondrial DNA (mtDNA pcf ) and nuclear DNA (nDNA pcf ) in the pathogenesis of systemic lupus erythematosus (SLE) remain unclear. We analyzed the relative copies of mtDNA pcf and nDNA pcf and investigated their association with the levels of plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasma malondialdehyde (MDA) and mRNA of leukocyte C-type lectin domain family 5 member A (CLEC5A) in SLE patients. Methods: A total of 80 SLE patients and 43 healthy controls (HCs) were enrolled. Their plasma samples were subjected to the measurements of mtDNA pcf copies, nDNA pcf copies, 8-OHdG and MDA, respectively. Their leukocytes were analyzed for CLEC5A mRNA expression. Results: SLE patients had higher nDNA pcf copies (2.84 ± 1.99 vs. 2.00 ± 0.88, p = 0.002), lower mtDNA pcf copies (4.81 ± 6.33 vs. 9.83 ± 14.20, p = 0.032), higher plasma 8-OHdG (0.227 ± 0.085 vs. 0.199 ± 0.041 ng/mL, p = 0.016), lower plasma MDA (3.02 ± 2.20 vs. 4.37 ± 2.16 µM, p = 0.001) and similar leukocyte CLEC5A mRNA expression levels (1.21 ± 1.17 vs. 1.26 ± 1.05, p = 0.870), as compared with those of HCs. Among the HCs, SLE patients with SLE Disease Activity Index (SLEDAI) ≤8, and SLE patients with SLEDAI >8, their respective mtDNA pcf copies decreased stepwisely (9.83 ± 14.20 vs. 6.28 ± 7.91 vs. 3.19 ± 3.35, p = 0.054). The nDNA pcf copies of HCs, SLE patients without nephritis, and SLE patients with nephritis were increased stepwisely (2.00 ± 0.88 vs. 2.63 ± 1.74 vs. 3.16 ± 2.34, p = 0.043). Among SLE patients, higher nDNA pcf copies were associated with higher levels of plasma 8-OHdG (p < 0.001) but lower plasma MDA (p = 0.019). Among HCs but not SLE patients, higher nDNA pcf copies (p = 0.013) or lower mtDNA pcf copies (p < 0.001) were related to higher levels of leukocyte CLEC5A mRNA expression. Conclusions: Higher nDNA pcf , lower mtDNA pcf , increased ROS-elicited oxidative DNA damage and dysregulated leukocyte CLEC5A expression might be implicated in the pathogenesis of SLE.Keywords: plasma cell-free mitochondrial DNA (mtDNA pcf ); plasma cell-free nuclear DNA (nDNA pcf ); malondialdehyde (MDA); 8-hydroxy-2'-deoxyguanosine (8-OHdG); C-type lectin domain family 5 member A (CLEC5A); systemic lupus erythematosus (SLE)

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Role of mitochondrial DNA copy number alteration in non-small cell lung cancer

Cited by 4 publications

References 41 publications

Metabolic Reprogramming in Response to Alterations of Mitochondrial DNA and Mitochondrial Dysfunction in Gastric Adenocarcinoma

Metabolic Reprogramming in Response to Alterations of Mitochondrial DNA and Mitochondrial Dysfunction in Gastric Adenocarcinoma

Tobacco, Second-Hand Smoke and Cancer

The Role of Plasma Cell-Free Mitochondrial DNA and Nuclear DNA in Systemic Lupus Erythematosus

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