Dataset Information

Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma.

ABSTRACT: Somatic mutations in mitochondrial DNA (mtDNA) have been detected in hepatocellular carcinoma (HCC). However, it remains unclear whether mtDNA copy number and mitochondrial biogenesis are altered in HCC. In this study, we found that mtDNA copy number and the content of mitochondrial respiratory proteins were reduced in HCCs as compared with the corresponding non-tumorous livers. MtDNA copy number was significantly reduced in female HCC but not in male HCC. Expression of the peroxisome proliferator-activated receptor gamma coactivator-1 was significantly repressed in HCCs (P<0.005), while the expression of the mitochondrial single-strand DNA-binding protein was upregulated, indicating that the regulation of mitochondria biogenesis is disturbed in HCC. Moreover, 22% of HCCs carried a somatic mutation in the mtDNA D-loop region. The non-tumorous liver of the HCC patients with a long-term alcohol-drinking history contained reduced mtDNA copy number (P<0.05) and higher level of the 4977 bp-deleted mtDNA (P<0.05) as compared with non-alcohol patients. Our results suggest that reduced mtDNA copy number, impaired mitochondrial biogenesis and somatic mutations in mtDNA are important events during carcinogenesis of HCC, and the differential alterations in mtDNA of male and female HCC may contribute to the differences in the clinical manifestation between female and male HCC patients.

SUBMITTER: Yin PH

PROVIDER: S-EPMC2409531 | biostudies-literature | 2004 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma.

Yin P H PH Lee H C HC Chau G Y GY Wu Y T YT Li S H SH Lui W Y WY Wei Y H YH Liu T Y TY Chi C W CW

British journal of cancer 20040601 12

Somatic mutations in mitochondrial DNA (mtDNA) have been detected in hepatocellular carcinoma (HCC). However, it remains unclear whether mtDNA copy number and mitochondrial biogenesis are altered in HCC. In this study, we found that mtDNA copy number and the content of mitochondrial respiratory proteins were reduced in HCCs as compared with the corresponding non-tumorous livers. MtDNA copy number was significantly reduced in female HCC but not in male HCC. Expression of the peroxisome proliferat ...[more]

PMID: 15150555

Similar Datasets

Project description:We investigated the role of mitochondrial DNA (mtDNA) copy number alteration in human renal cell carcinoma (RCC). The mtDNA copy numbers of paired cancer and non-cancer parts from five resected RCC kidneys after radical nephrectomy were determined by quantitative polymerase chain reaction (Q-PCR). An RCC cell line, 786-O, was infected by lentiviral particles to knock down mitochondrial transcriptional factor A (TFAM). Null target (NT) and TFAM-knockdown (TFAM-KD) represented the control and knockdown 786-O clones, respectively. Protein or mRNA expression levels of TFAM; mtDNA-encoded NADH dehydrogenase subunit 1 (ND1), ND6 and cytochrome c oxidase subunit 2 (COX-2); nuclear DNA (nDNA)-encoded succinate dehydrogenase subunit A (SDHA); v-akt murine thymoma viral oncogene homolog 1 gene (AKT)-encoded AKT and v-myc myelocytomatosis viral oncogene homolog gene (c-MYC)-encoded MYC; glycolytic enzymes including hexokinase II (HK-II), glucose 6-phosphate isomerase (GPI), phosphofructokinase (PFK), and lactate dehydrogenase subunit A (LDHA); and hypoxia-inducible factors the HIF-1? and HIF-2?, pyruvate dehydrogenase kinase 1 (PDK1), and pyruvate dehydrogenase E1 component ? subunit (PDHA1) were analyzed by Western blot or Q-PCR. Bioenergetic parameters of cellular metabolism, basal mitochondrial oxygen consumption rate (mOCRB) and basal extracellular acidification rate (ECARB), were measured by a Seahorse XF(e)-24 analyzer. Cell invasiveness was evaluated by a trans-well migration assay and vimentin expression. Doxorubicin was used as a chemotherapeutic agent. The results showed a decrease of mtDNA copy numbers in resected RCC tissues (p = 0.043). The TFAM-KD clone expressed lower mtDNA copy number (p = 0.034), lower mRNA levels of TFAM (p = 0.008), ND1 (p = 0.007), and ND6 (p = 0.017), and lower protein levels of TFAM and COX-2 than did the NT clone. By contrast, the protein levels of HIF-2?, HK-II, PFK, LDHA, AKT, MYC and vimentin; trans-well migration activity (p = 0.007); and drug resistance to doxorubicin (p = 0.008) of the TFAM-KD clone were significantly higher than those of the NT clone. Bioenergetically, the TFAM-KD clone expressed lower mOCRB (p = 0.009) but higher ECARB (p = 0.037) than did the NT clone. We conclude that a reduction of mtDNA copy number and decrease of respiratory function of mitochondria in RCC might be compensated for by an increase of enzymes and factors that are involved in the upregulation of glycolysis to confer RCC more invasive and a drug-resistant phenotype in vitro.

Project description:Genome-wide DNA copy number profiles of multiple hepatocellular carcinoma tumors and non-tumor liver tissues from the same patients. Introduction: Hepatocellular Carcinoma (HCC) is the second cause of cancer-related death worldwide. Understanding tumor heterogeneity is relevant for the pathogenesis and treatment of this neoplasm. Particularly, whether multinodular tumors result from intrahepatic metastasis (IM or clonal tumors) or de novo cancers (synchronic tumors) have direct implications in treatment decisionmaking for resection and transplantation. We aimed to assess the genomic heterogeneity of multifocal HCC using single-nucleotide polymorphism (SNP) and gene expression analyses. Methods: Among 544 HCC patients consecutively transplanted at Mount Sinai Hospital between 1990- 2007, we selected 18 patients with a total of 42 multinodular tumors (2-3 non-satellite foci HCCs) for this molecular study. Formalin-fixed blocks were collected for each tumor along with corresponding clinico-pathological data. SNP array and gene expression profiling was generated. Clonality was defined by measuring the similarity of genome-wide copy number variation (CNV) profiles between two nodules. Unsupervised hierarchical clustering based on gene expression data was performed to measure genetic proximity between each tumor. Prediction of previously published signatures was performed using Nearest Template Prediction (NTP). Association of clonality with clinic-pathological parameters was assessed. Results: A total of 42 tumors have been analyzed (10 patients- 2 tumors; 8- 3 tumors). Most patients were male (17/18, 95%) with median age of 53-yr-old (range 39–67), HCV (10/18, 56%) or HBV infection (6/18, 33%). Median tumor size was 3 cm (range 1.5-6.5), satellites were present in 3 (17%) and vascular invasion in 11 patients (61%), respectively. CNV profiles predicted clonal tumors in 38% (6/16) and non-clonality in 62% of cases (10/16). CNV profiles of the remaining 2 cases were not informative. Clonal tumors were significantly associated with HCV infected patients (5/6 vs 3/10, p=0.007), whereas all HBV-induced HCC were synchronic tumors (0/6 vs 6/10, p=0.03). Furthermore, clonal tumors were significantly associated with presence of satellites and shorter time-torecurrence. Assessment of genetic proximity based on gene expression revealed that each clonal tumor showed proximity to its paired tumor and clustered around the same node (6/6,100%) as opposed to non-clonal (2/9,22%). When exploring molecular subclasses within clonal tumors (intrahepatic metastases), while half of them retained the molecular fingerprint, the other half switch to more aggressive subclasses. Conversely, all non-clonal tumors within the same patient belonged to distinct molecular subclasses. Conclusion: Multinodular HCCs undergoing transplantation are molecularly heterogeneous. Using CNV profiling we identified clonal multinodular tumors (true intrahepatic metastasis) in 40% of cases and de novo tumors in 60%. Clonal tumors were significantly associated with HCV infection, satellites and recurrence. Genetic proximity was observed in clonal tumors, but molecular subclasses prediction revealed that intrahepatic metastases share more aggressive subclasses in half of cases.

Dataset Information

Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma.

Publications

Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets