Upregulation of T‐cell factor‐4 isoform‐responsive target genes in hepatocellular carcinoma

Liver International - Tập 33 Số 7 - Trang 1100-1112 - 2013
Yoshito Tomimaru1, Hironori Koga2, Hirohisa Yano3, Suzanne de la Monte4, Jack R. Wands1, Miran Kim1
1Liver Research Center, Rhode Island Hospital, the Warren Alpert Medical School of Brown University, Providence, RI, USA
2Division of Gastroenterology, Department of Medicine, Kurume University of School of Medicine, Kurume, Japan
3Department of Pathology, Kurume University of School of Medicine, Kurume, Japan
4Department of Pathology, the Warren Alpert Medical School of Brown University, Providence, RI, USA

Tóm tắt

AbstractBackgroundThe Wnt/β‐catenin signalling pathway regulates genes involved in cell proliferation, survival, migration and invasion through regulation by T‐cell factor (TCF)‐4 transcription factor proteins. However, the role ofTCF‐4 isoforms generated by alternative splicing events in hepatocellular carcinoma (HCC) is unknown.AimHere, we investigatedTCF‐4 isoforms (TCF‐4J and K)‐responsive target genes that are important in hepatic oncogenesis and tumour development.MethodsGene expression microarray was performed onHCCcells overexpressingTCF‐4J and K isoforms. Expression level of selected target genes was evaluated and correlations were made between their expression level and that ofTCF‐4 isoform in 47 pairs of humanHCCtumours.ResultsComparison by gene expression microarray revealed that 447 genes were upregulated and 343 downregulated more than 2.0‐fold inTCF‐4J compared withTCF‐4K expressing cells. We validated expression of 18 selected target genes involved in Wnt/β‐catenin, insulin/IGF‐1/IRS1 and Notch signalling pathways in 47 pairs of humanHCCs and adjacent uninvolved liver tissues. It was observed that 13 genes (CLDN2,STK17B,SPP1,AXIN2,WISP2,MMP7,IRS1,ANXA1,CAMK2N1,ASPH,GPR56,CD24 andJAG1) activated byTCF‐4J isoform inHCCcells, were also upregulated inHCCtumours compared with adjacent peritumour tissue; more importantly, 10 genes exhibited a significant correlation with theTCF‐4J expression level in tumour.ConclusionTCF‐4 isoforms (TCF‐4J and K) activated different downstream target genes inHCC. The biological consequence ofTCF‐4J isoform expression was upregulation of genes associated with tripartite Wnt/β‐catenin, insulin/IGF‐1/IRS1 and Notch signal transduction pathway activation, which contribute to the pathogenesis ofHCC.

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Liver International

Tập 33 Số 7

1100-1112

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