Separation of low and high grade colon and rectum carcinoma by eukaryotic translation initiation factors 1, 5 and 6

Abstract

Copyright: Golob-Schwarzl et al. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACTColorectal 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 www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 60), pp: 101224-101243 Research PaperOncotarget 101225 www.impactjournals.com/oncotarget 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.

Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression

“…45,46 It is overexpressed in multiple tumor types, 47,48 including CRC, where expression of EIF6 has been shown to increase from normal colon, through adenoma to CRC. 45,46 It is overexpressed in multiple tumor types, 47,48 including CRC, where expression of EIF6 has been shown to increase from normal colon, through adenoma to CRC.…”

“…EIF6 is a translation initiation factor that plays a role in ribosome complex formation and protein synthesis downstream of PI3K/Akt/mTOR signaling pathway. 45,46 It is overexpressed in multiple tumor types, 47,48 including CRC, where expression of EIF6 has been shown to increase from normal colon, through adenoma to CRC. 49 Functional studies on EIF6 suggest its oncogenic activity through increasing cancer cell motility and invasion.…”

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

“…Interestingly, the PI3K/AKT/mTOR signaling activity is related with an upregulation of eIF3B [ 121 ]. Golob-Schwarzl and colleagues showed the expression of eIFs family members, bringing eIF1, eIF5, and eIF6 to attention, together with components of the PI3K/AKT/mTOR signaling cascade in colorectal cancer (CRC) [ 122 ]. These eIF subunits and the PI3K/AKT/mTOR signaling members had a significant influence on the overall survival of CRC patients [ 122 ].…”

“…mTOR regulates the assembly of eIF4f to manage translation initiation. The PI3K/AKT/mTOR pathway affects tumorigenesis through eIFs, reported in HCC [ 119 ], GC [ 121 ], CRC [ 122 ], and other cancer types [ 117 , 134 ]. In summary, eIFs integrate the signals from the PI3K/AKT/mTOR pathway, which may be a promising target for tumor therapy in future.…”

The Prognostic Significance of Eukaryotic Translation Initiation Factors (eIFs) in Endometrial Cancer

“…In recent years, the role of eukaryotic translation initiation factors (eIFs) in carcinogenesis has been steadily uncovered [15][16][17]. They are involved in tumour development, progression and invasion.…”