Abstract
Colorectal cancer (CRC) is the third most common cause of cancer related death worldwide. Furthermore, with more than 1.2 million cases registered per year, it constitutes the third most frequent diagnosed cancer entity worldwide. Deregulation of protein synthesis has received considerable attention as a major step in cancer development and progression. Eukaryotic translation initiation factors (eIFs) are involved in the regulation of protein synthesis and are functionally linked to the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway.The identification of factors accounting for colorectal carcinoma (CRC) development is a major gap in the field. Besides the importance of eIF3 subunits and the eIF4 complex, eIF1, eIF5 and eIF6 were found to be altered in primary and metastatic CRC. We observed significant difference in the expression profile between low and high grade CRC. eIF1, eIF5 and eIF6 are involved in translational control in CRC. Our findings also indicate a probable clinical impact when separating them into low and high grade colon and rectum carcinoma.eIF and mTOR expression were analysed on protein and mRNA level in primary low and high grade colon carcinoma (CC) and rectum carcinoma (RC) samples in comparison to non-neoplastic tissue without any disease-related pathology. To assess the therapeutic potential of targeting eIF1, eIF5 and eIF6 siRNA knockdown in HCT116 and HT29 cells was performed. We evaluated the eIF knockdown efficacy on protein and mRNA level and investigated proliferation, apoptosis, invasion, as well as colony forming and polysome associated fractions.These results indicate that eIFs, in particular eIF1, eIF5 and eIF6 play a major role in translational control in colon and rectum cancer.
Highlights
Colorectal cancer (CRC) is the third most common cause of cancer related death and with more than one million cases annually the third most frequently diagnosed cancer entity worldwide [1,2,3]
There were no significant differences in overall survival between RC low and high grade groups (Supplementary Figure 6A 6E) for eIF2S1, eIF3A, eIF3B, eIF3C, eIF3D and eIF3H
We investigated the effect on protein expression of primary carcinomas of the colon (CC) and RC tumors compared to the respective liver metastasis for mammalian target of rapamycin (mTOR) pathway members and Eukaryotic translation initiation factors (eIFs) subunits
Summary
Colorectal cancer (CRC) is the third most common cause of cancer related death and with more than one million cases annually the third most frequently diagnosed cancer entity worldwide [1,2,3]. 20% of CRC patients have liver metastases at the time of diagnosis and 60% of patients develop liver metastases during the course of disease [6,7,8]. Current clinical management strategies include surgery, chemotherapy, radiation and palliative care, but they are not as effective as previously expected [4]. Various drugs have been reported to be effective against primary or metastatic CRC, but still the efficacy of current medications needs to be further improved. Biologically similar, it needs to be taken into account, that carcinomas of the colon (CC) and rectum (RC) are treated differently with respect to surgery and radiotherapy [9]
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