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MicroRNA induction by copy number gain is associated with poor outcome in squamous cell carcinoma of the lung.

ABSTRACT: Copy number gains in cancer genomes have been shown to induce oncogene expression and promote carcinogenesis; however, their role in regulating oncogenic microRNAs (onco-miRNAs) remains largely unknown. Our aim was to identify onco-miRNAs induced by copy number gains in human squamous cell carcinoma (Sq) of the lung. We performed a genome-wide screen of onco-miRNAs from 245 Sqs using data sets from RNA-sequencing, comparative genomic hybridization, and the corresponding clinical information from The Cancer Genome Atlas. Among 1001 miRNAs expressed in the samples, 231 were correlated with copy number alternations, with only 11 of these being highly expressed in Sq compared to adenocarcinoma and normal tissues. Notably, miR-296-5p, miR-324-3p, and miR-3928-3p expression was significantly associated with poor prognosis. Multivariate analysis using the Cox proportional hazards model showed that miRNA expression and smoking were independent prognostic factors and were associated with poor prognosis. Furthermore, the three onco-miRNAs inhibited FAM46C to induce MYC expression, promoting proliferation of Sq cells. We found that copy number gains in Sq of the lung induce onco-miRNA expression that is associated with poor prognosis.

SUBMITTER: Xia E

PROVIDER: S-EPMC6194131 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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MicroRNA induction by copy number gain is associated with poor outcome in squamous cell carcinoma of the lung.

Xia Endi E Kanematsu Sotaro S Suenaga Yusuke Y Elzawahry Asmaa A Kondo Hitomi H Otsuka Noriko N Moriya Yasumitsu Y Iizasa Toshihiko T Kato Mamoru M Yoshino Ichiro I Yokoi Sana S

Scientific reports 20181018 1

Copy number gains in cancer genomes have been shown to induce oncogene expression and promote carcinogenesis; however, their role in regulating oncogenic microRNAs (onco-miRNAs) remains largely unknown. Our aim was to identify onco-miRNAs induced by copy number gains in human squamous cell carcinoma (Sq) of the lung. We performed a genome-wide screen of onco-miRNAs from 245 Sqs using data sets from RNA-sequencing, comparative genomic hybridization, and the corresponding clinical information from ...[more]

PMID: 30337605

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Project description:c-MYC copy number gain (c-MYC gain) has been associated with aggressive behaviour in several cancers. However, the role of c-MYC gain has not yet been determined in lung adenocarcinomas classified by genetic alterations in epidermal growth factor receptor (EGFR), KRAS, and anaplastic lymphoma kinase (ALK) genes. We investigated the clinicopathologic and prognostic significance of c-MYC gain for disease-free survival (DFS) and overall survival (OS) according to EGFR, KRAS, and ALK gene status and stages in lung adenocarcinomas.In 255 adenocarcinomas resected in Seoul National University Bundang Hospital from 2003 to 2009, fluorescence in situ hybridisation (FISH) with c-MYC probe and centromeric enumeration probe 8 (CEP8) was analysed using tissue microarray containing single representative core per each case. EGFR (codon 18 to 21) and KRAS (codon 12, 13, and 61) mutations were analysed by polymerase chain reaction and direct sequencing method from formalin-fixed, paraffin-embedded tissue sections. ALK rearrangement was determined by FISH method. c-MYC gain was defined as >2 copies per nucleus, chromosome 8 gain as ?3 copies per nucleus, and gain of c-MYC:CEP8 ratio (hereafter, c-MYC amplification) as ?2.We observed c-MYC gain in 20% (51 out of 255), chromosome 8 gain in 5.5% (14 out of 255), c-MYC amplification in 2.4% (6 out of 255), EGFR mutation in 49.4% (118 out of 239), KRAS mutation in 5.7% (7 out of 123), and ALK rearrangement in 4.9% (10 out of 205) of lung adenocarcinomas. c-MYC gain was observed in 19% (22 out of 118) of patients with lung adenocarcinomas with an EGFR mutation, but not in any patients with a KRAS mutation, or an ALK rearrangement. c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor in the full cohort of lung adenocarcinoma (P=0.022, hazard ratio (HR)=1.71, 95% confidence interval (CI), 1.08-2.69 for DFS; P=0.032, HR=2.04, 95% CI, 1.06-3.91 for OS), as well as in stage I subgroup (P=0.023, HR=4.70, 95% CI, 1.24-17.78 for DFS; P=0.031, HR=4.65, 95% CI, 1.15-18.81 for OS), and in EGFR-mutant subgroup (P=0.022; HR=2.14; 95% CI, 1.11-4.10 for DFS).c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor for DFS and OS in lung adenocarcinomas, both in full cohort and stage I cancer, and possibly for DFS in EGFR-mutant adenocarcinomas. Additional studies are required to determine if patients with lung adenocarcinoma with c-MYC gain are candidates for additional first-line treatment to mitigate their increased risk for disease progression and death.

Project description:Alterations in mitochondrial DNA (mtDNA) copy numbers in various human cancers have been studied, but any such changes in esophageal squamous cell carcinoma (ESCC) are not established. In the present study, we investigated the correlation of mtDNA copy number with clinicopathologic features, prognosis, and malignant potential of ESCC. MtDNA copy numbers of resected specimens from 80 patients treated with radical esophagectomy were measured by quantitative real-time PCR analyses. Human ESCC cells, TE8 and TE11, were cultured, and depletion of mtDNA content was induced by knockdown of mitochondrial transcription factor A expression or treatment with ethidium bromide. The mRNA and protein expression, proliferation, invasion, and cell cycle were investigated. The results showed that the mtDNA copy number of cancerous portions was 56.0 (37.4-234.5) percent that of non-cancerous parts and significantly lower (p<0.01). Low mtDNA copy number in resected cancerous tissues was significantly correlated with pathological depth of tumor invasion (p = 0.045) and pathological stage (p = 0.025). Patients with lower mtDNA copy number had significantly poorer 5-year overall survival compared to patients with higher levels (p<0.01). The mtDNA-depleted TE8 and TE11 cells had morphological changes and proliferated more slowly than control cells under normoxia but proliferated at almost the same rate under hypoxic conditions. In mtDNA-depleted cells, E-cadherin mRNA expression was decreased, and N-cadherin, vimentin, zeb-1, and cd44 mRNA expression was increased. Immunoblotting and flow cytometry analysis also showed downregulated E-cadherin and upregulated N-cadherin and CD44 protein in mtDNA-depleted cells. Moreover, mtDNA-depleted cells had enhanced invasion, migration, and sphere formation abilities, and the cell cycle arrest at G0/G1 phase was induced in these cells. These results suggested that mtDNA-depleted ESCC cells had mesenchymal characteristics, cancer stemness, and tolerance to hypoxia, which played important role in cancer progression. In conclusion, a low copy number of mtDNA is associated with tumor progression in ESCC.

Dataset Information

MicroRNA induction by copy number gain is associated with poor outcome in squamous cell carcinoma of the lung.

Publications

MicroRNA induction by copy number gain is associated with poor outcome in squamous cell carcinoma of the lung.

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