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

Abstract

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.

Curcumin inhibits cell proliferation and promotes apoptosis of laryngeal cancer cells through Bcl-2 and PI3K/Akt, and by upregulating miR-15a

“…miRNAs serve a negative role primarily through the inhibition of its target genes; a previous study has demonstrated that miR-15a induces the apoptosis of laryngeal carcinoma cells by activating Bcl-2 (26). It has been confirmed that miRNA-15a is able to inhibit the proliferation of laryngeal cancer cells by directly inhibiting PI3K/Akt expression (27). In the present study, it was identified that curcumin significantly increased miR-15a expression in AMC-HN-8 cells.…”

Protocadherin 9 inhibits epithelial–mesenchymal transition and cell migration through activating GSK-3β in hepatocellular carcinoma

“…Published studies on HCC have shown that chromosome region 13q is one of the most frequently affected chromosome arms in a number of cancers including HCC [22,23]. A recently published study has reported that allelic losses on 13q can result in more aggressive tumor behavior, suggesting that this chromosomal region is likely to contain TSGs [24,25]. In this study, we provide direct evidence for the tumor-suppressing role of PCDH9, which is located on chromosome 13q21.32 and frequently deleted in HCC.…”

Hepatocellular and Cholangiolar Carcinoma-Derived Cell Lines Reveal Distinct Sets of Chromosomal Imbalances

“…Losses of 13q have been reported in 27% of surgical specimens of HCC as a sign of dedifferentiation [12] . The loss is also seen in the context of increasing chromosomal instability [16,17] . Deletion of 13q has been reported in other solid tumors, but with a frequency of less than 5% [18] .…”