Aberrant splicing of Hugl-1 is associated with hepatocellular carcinoma progression - PubMed (original) (raw)
. 2009 May 15;15(10):3287-96.
doi: 10.1158/1078-0432.CCR-08-2078. Epub 2009 May 15.
Xiujing Feng, Xiaobo Man, Guang Yang, Liang Tang, Dan Du, Fan Zhang, Haixin Yuan, Qin Huang, Zhe Zhang, Yinkun Liu, Dennis Strand, Zhengjun Chen
Affiliations
- PMID: 19447873
- DOI: 10.1158/1078-0432.CCR-08-2078
Aberrant splicing of Hugl-1 is associated with hepatocellular carcinoma progression
Xuefeng Lu et al. Clin Cancer Res. 2009.
Erratum in
- Clin Cancer Res. 2009 Jul 15;15(14):4786
Abstract
Purpose: Lethal giant larvae functions as a cell polarity regulator and a tumor suppressor in Drosophila. Its evolutionary conservation implies a tumor suppressor role for its human homologue, Hugl-1. The aims of this study were to characterize Hugl-1 and to determine the clinical significance of Hugl-1 alterations in hepatocellular carcinoma (HCC).
Experimental design: Sequence alterations of Hugl-1 from 80 HCC specimens and 5 HCC cell lines were characterized by reverse transcription-PCR and sequence analysis. Western blot was used for determining Hugl-1 expression. The biological activities of Hugl-1 and its aberrant variants were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wound healing assay, Boyden chamber assay, and tumorigenicity assay.
Results: In 32.5% (26 of 80) of the specimens and 20.0% (one of five) of HCC cell lines, 23 unique aberrant Hugl-1 transcripts were identified, most of which resulted from skipping part of and/or entire exon or insertion of intron sequences. The majority of these aberrant Hugl-1 transcripts encoded truncated proteins lacking one or more conserved WD-40 repeat motifs. Two truncated Hugl-1 proteins were found exclusively in HCC tissues. Aberrant Hugl-1 transcripts (78.3%, 20 of 23) had a short "direct repeat" sequence flanking their deleted regions. The abnormal Hugl-1 was significantly correlated with poor differentiation and large tumor size of HCC. Overexpression of two representative HCC-derived aberrant Hugl-1 variants promoted HCC cell migration, invasion, and tumorigenicity in nude mice.
Conclusions: We provide the first evidence that Hugl-1 mRNA is frequently mutated by aberrant splicing exclusively in HCC, which may be involved in HCC progression.
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