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Alternative mRNA Splicing of Liver Intestine-Cadherin in Hepatocellular Carcinoma

¹ Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong and ² Department of Microbiology and Molecular Genetics, University of California, Irvine, California

Requests for reprints: John M. Luk, Department of Surgery, University of Hong Kong, Faculty of Medicine Building LB9-52, 21 Sassoon Road, Pokfulam, Hong Kong. Phone: 852-2819-9628; Fax: 852-2819-9636; E-mail: jmluk{at}hkucc.hku.hk.

Purpose: To identify alternative splicing of the liver intestine-cadherin (LI-cadherin) gene in hepatocellular carcinoma (HCC) and correlate its aberrant expression with clinical outcomes.

Experimental Design: Reverse transcription-PCR (RT-PCR) and quantitative real-time RT-PCR were used to examine alternative mRNA splicing and mRNA level of LI-cadherin in 50 paired tumor-peritumor tissues of 50 HCC and 8 normal liver specimens. The minigene exon-trapping strategy was employed to investigate the splicing mechanism introduced by nucleotide polymorphisms. Association of LI-cadherin splicing with tumor venous infiltration, first-year tumor recurrence, and overall survival after partial hepatectomy were determined.

Results: Alternative mRNA splicing of LI-cadherin was identified in half of the HCC specimens. Sequencing analysis indicated the loss of exon 7 in the spliced LI-cadherin gene. LI-cadherin mRNA was up-regulated from 2.58-fold to 800-fold in over 80% of HCC samples when compared with normal liver by quantitative PCR. Furthermore, nucleotide polymorphisms were identified in putative branch point at IVS6 + 35 (intron 6) as well as in coding sequence 651 (exon 6) in HCC tissues, which may affect alternative mRNA splicing. Clinically, those patients who harbored the alternative splicing of LI-cadherin were strongly associated with shorter overall survival time (P < 0.01) as well as higher incidences of tumor recurrences and venous infiltration (both P < 0.05) after hepatectomy.

Conclusions: Over-expression of LI-cadherin was frequently detected in liver cancer patients. Aberrant alternative splicing of LI-cadherin was detected in 50% of HCC specimens and its clinical significance hinted at early tumor recurrence and poor overall survival of HCC patients.

Key Words: Alternative splicing • LI-cadherin • Hepatocellular carcinoma

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