RRC ID 38444
Author Wu D, Matsushita K, Matsubara H, Nomura F, Tomonaga T.
Title An alternative splicing isoform of eukaryotic initiation factor 4H promotes tumorigenesis in vivo and is a potential therapeutic target for human cancer.
Journal Int J Cancer
Abstract Deregulation of protein synthesis plays a critical role in cell transformation. Several translation initiation factors (eIFs) have been implicated in malignant transformation; thus, suppression of eIFs could be a potential cancer therapy if cancer cells are selectively killed without damaging healthy cells. One of the potential molecular targets is a cancer-specific splicing variant. We have previously shown that one of the splicing variants of eIF4H (isoform 1) was overexpressed in primary human colorectal cancer. Our study aimed to explore whether eIF4H isoform 1 contributes to carcinogenesis and could be an efficient molecular target for human cancer therapy. We found that its overexpression in immortalized mouse fibroblasts, NIH3T3 cells, generated tumors in nude mice. Conversely, suppression of eIF4H isoform 1 expression using specific siRNA inhibited the proliferation of colon cancer cells in vitro and subcutaneously implanted tumor in vivo. Strikingly, eIF4H isoform 1 specific siRNA showed no effect on the growth of immortalized human fibroblasts. More interestingly, ectopic expression of eIF4H isoform 1 greatly increased the cyclin D1 level. On the other hand, cyclin D1 decreased by shRNA-mediated suppression of eIF4H isoform 1. Moreover, cotransfection of eIF4H isoform 1 siRNA and cyclin D1 expression plasmid was able to reverse the growth suppression effect of eIF4H isoform 1 knockdown. These results suggest that eIF4H isoform 1 plays an important role in carcinogenesis through the activation of oncogenic signaling and could be a promising molecular target for cancer therapy.
Volume 128(5)
Pages 1018-30
Published 2011-3-1
DOI 10.1002/ijc.25419
PMID 20473909
MeSH Aged Alternative Splicing* Animals Base Sequence Blotting, Western Cell Transformation, Neoplastic* Colorectal Neoplasms / genetics* Esophageal Neoplasms / genetics* Eukaryotic Initiation Factors / drug effects Eukaryotic Initiation Factors / genetics Eukaryotic Initiation Factors / physiology* Female Humans Male Mice Mice, Inbred BALB C Mice, Nude Middle Aged NIH 3T3 Cells Polymerase Chain Reaction Protein Isoforms / drug effects Protein Isoforms / genetics Protein Isoforms / physiology* RNA, Small Interfering
IF 4.982
Times Cited 16
Human and Animal Cells