An alternative splicing isoform of eukaryotic initiation factor 4H promotes tumorigenesis in vivo and is a potential therapeutic target for human cancer

Deregulation of protein synthesis plays a critical role in cell transformation. Several translation initiation factors (elFs) have been implicated in malignant transformation; thus, suppression of elFs 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 elF4H (isoform 1) was overexpressed in primary human colorectal cancer. Our study aimed to explore whether elF4H 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 elF4H isoform 1 expression using specific siRNA inhibited the proliferation of colon cancer cells in vitro and subcutaneously implanted tumor in vivo. Strikingly, elF4H isoform 1 specific siRNA showed no effect on the growth of immortalized human fibroblasts. More interestingly, ectopic expression of elF4H isoform 1 greatly increased the cyclin D1 level. On the other hand, cyclin D1 decreased by shRNA-mediated suppression of elF4H isoform 1. Moreover, cotransfection of elF4H isoform 1 siRNA and cyclin D1 expression plasmid was able to reverse the growth suppression effect of elF4H isoform 1 knockdown. These results suggest that elF4H isoform 1 plays an important role in carcinogenesis through the activation of oncogenic signaling and could be a promising molecular target for cancer therapy.