Alternative mRNA splicing of liver intestine-cadherin in hepatocellular carcinoma

Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):483-9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Base Sequence
  • COS Cells
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Chlorocebus aethiops
  • Exons / genetics
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestines / pathology
  • Liver / metabolism
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Molecular Sequence Data
  • Neoplasm Recurrence, Local / pathology
  • Polymorphism, Genetic*
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Transfection

Substances

  • CDH17 protein, human
  • Cadherins
  • RNA, Messenger
  • RNA, Neoplasm