RRC ID |
38444
|
著者 |
Wu D, Matsushita K, Matsubara H, Nomura F, Tomonaga T.
|
タイトル |
An alternative splicing isoform of eukaryotic initiation factor 4H promotes tumorigenesis in vivo and is a potential therapeutic target for human cancer.
|
ジャーナル |
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.
|
巻・号 |
128(5)
|
ページ |
1018-30
|
公開日 |
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 |
5.145
|
引用数 |
16
|
WOS 分野
|
ONCOLOGY
|
リソース情報 |
ヒト・動物細胞 |
|