Gene expression profiling in hepatocellular carcinoma: upregulation of genes in amplified chromosome regions

Skawran, Britta; Steinemann, Doris; Weigmann, Anja; Flemming, Peer; Becker, Thomas; Flik, J.; Kreipe, Hans; Schlegelberger, Brigitte; Wilkens, Ludwig

doi:10.1038/modpathol.3800998

Cited by 81 publications

(69 citation statements)

References 22 publications

(27 reference statements)

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“…Some of the 161 sense transcripts have been already demonstrated to be candidates for markers of HCC (23)(24)(25)(26)(27)(28)(29)(30). This fact provided support for the assumption that the microarray results accurately reflect gene expression of HCC and non-cancerous tissues.…”

Section: Identification Of Sense and Antisense Transcripts Differentisupporting

confidence: 58%

Differential expression profiles of sense and antisense transcripts between HCV-associated hepatocellular carcinoma and corresponding non-cancerous liver tissue

et al. 2012

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Abstract. Recent studies have demonstrated that natural antisense transcripts, which are complementary sequences to messenger RNA, have important cellular functions such as the stabilization and silencing of mRNA. However, the possible contribution of antisense transcripts in hepatocellular carcinoma (HCC) development has not been described. Therefore, we simultaneously investigated the sense and antisense transcripts of HCC and non-cancerous tissues to explore the possible contribution of antisense transcripts to HCC progression. RNA was prepared from 15 HCV-associated HCCs and from 6 corresponding non-cancerous tissues and was subjected to expression profile analysis of sense and antisense transcripts using a human custom microarray. Differential expression of 161 sense and 25 antisense transcripts was observed with more than 2-fold between HCC and non-cancerous tissue (p<0.001). The expression of the sense and antisense transcripts was used to cluster cancer and non-cancerous tissues, and the cancer and non-cancerous tissues were found to be clearly separated into different clusters. Additionally, the sense and antisense expression profiles were analyzed with regard to HCC differentiation (p<0.001), resulting in 71 sense and 43 antisense transcripts. These unique transcripts did not overlap with those found in the discrimination of HCC from non-cancerous tissues. When the HCC tissues were clustered by transcript expression, the antisense transcripts resulted in clustering of HCC that was consistent with grouping based on histology. These findings strongly indicate that the antisense transcripts together with the sense transcripts are involved in liver tumorigenesis.

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Section: Identification Of Sense and Antisense Transcripts Differentisupporting

confidence: 58%

Differential expression profiles of sense and antisense transcripts between HCV-associated hepatocellular carcinoma and corresponding non-cancerous liver tissue

et al. 2012

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“…Tumor specimens from these patients were analyzed with regard to mRNA expression in hepatocellular adenoma in an earlier study. 22 Tumor material was obtained as surgical specimens taken for diagnostic purposes as permitted by the Ethics Committee of Hannover Medical School. Unfixed tissue samples of 0.5 cm in diameter were snap-frozen within 30 min after resection and stored at À801C.…”

Section: Methodsmentioning

confidence: 99%

“…Gains of 8q were observed in 14 cases (64%), losses of 8p in 11 cases (50%), gains of 20q in 9 cases Methods cDNA microarray analysis cDNA microarray experiments were carried out as previously described. 22 In brief, total RNA was isolated using Trizol (Invitrogen, Karlsruhe, Germany) followed by RNeasy Mini Kit (Qiagen, Hilden, Germany) and linearly amplified (MessageAmp aRNA Kit; Ambion, Huntingdon, UK). Aliquots of 1.5 mg of amplified RNA from the tumors and the human reference were reverse transcriptase labeled with Cy3 (reference) and Cy5 (tumor) (Amersham Biosciences, Little Chalfont, UK).…”

Section: Methodsmentioning

confidence: 99%

“…Hepatocellular adenoma can also be distinguished from carinoma based on global gene expression profiling. 22 Comparing aCGH and gene expression data, it was possible to define a set of seven upregulated genes localized on chromosome band 1q22. As histological dedifferentiation is accompanied by loss of 13q, 11,16 we focused on gene expression in different grades of hepatocellular carcinoma bearing 13q or not.…”

Section: -31mentioning

confidence: 99%

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Loss of 13q is associated with genes involved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma

et al. 2008

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Dedifferentiation of hepatocellular carcinoma implies aggressive clinical behavior and is associated with an increasing number of genomic alterations, eg deletion of 13q. Genes directly or indirectly deregulated due to these genomic alterations are mainly unknown. Therefore this study compares array comparative genomic hybridization and whole genome gene expression data of 23 well, moderately, or poorly dedifferentiated hepatocellular carcinoma, using unsupervised hierarchical clustering. Dedifferentiated carcinoma clearly branched off from well and moderately differentiated carcinoma (Po0.001 v 2 -test). Within the dedifferentiated group, 827 genes were upregulated and 33 genes were downregulated. Significance analysis of microarrays for hepatocellular carcinoma with and without deletion of 13q did not display deregulation of any gene located in the deleted region. However, 531 significantly upregulated genes were identified in these cases. A total of 6 genes (BIC, CPNE1, RBPMS, RFC4, RPSA, TOP2A) were among the 20 most significantly upregulated genes both in dedifferentiated carcinoma and in carcinoma with loss of 13q. These genes are involved in cell-cycle control and proliferation. Of 33 downregulated genes in the dedifferentiated subgroup, 4 metallothioneins had the lowest fold change, most probably mediated through inactivation of C/EBPa by the PI3K/AKT cascade. In conclusion dedifferentiation of hepatocellular carcinoma is associated with upregulation of genes involved in cell-cycle control and proliferation. Notably, a significant portion of these genes is also upregulated in carcinoma with deletion of 13q. As no downregulated genes were identified and microRNAs (mir-621, mir-16-1, mir-15a) are located within the deleted region of 13q and may be lost, we speculate that these miRNAs may induce the upregulation of critical cell-cycle control genes.

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“…By applying the recently published methods for the comparison of simultaneous cDNA microarray and CGH data (Skawran et al, 2008), the implication of chromosomal aberrations in adrenocortical tumour pathogenesis could be revealed.…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

et al. 2010

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Gene expression profiling in hepatocellular carcinoma: upregulation of genes in amplified chromosome regions

Cited by 81 publications

References 22 publications

Differential expression profiles of sense and antisense transcripts between HCV-associated hepatocellular carcinoma and corresponding non-cancerous liver tissue

Differential expression profiles of sense and antisense transcripts between HCV-associated hepatocellular carcinoma and corresponding non-cancerous liver tissue

Loss of 13q is associated with genes involved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

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