Global alterations in mRNA polysomal recruitment in a cell model of colorectal cancer progression to metastasis.
Tumour onset and progression are due to the accumulation of genomic lesions, which alter gene expression and ultimately proteome activities. These lesions are thought to affect primarily the transcriptional control of gene expression. In the present study, we aimed at evaluating the genome-wide occurrence of alterations in the translational control exploiting an isogenic, phenotypically validated cellular model of colorectal cancer (CRC) transition from invasive carcinoma to metastasis. In this model, microarray profiling shows that changes in the level of messenger ribonucleic acid (mRNA) association with polysomes occur more than 2-fold than changes in the level of total cellular mRNA. When common to both the total and polysomal compartments, these changes are also homodirectional, being amplified in magnitude at the polysomal level. Comparison between the transcriptional and the translational fluctuations revealed distinct signatures of statistically over-represented gene functions, involving the program of cell proliferation for both levels of analysis, while the apoptosis and the translation programs were affected mainly at translation. Looking for an upstream determinant of translational deregulation, we found an increase in the hyperphosphorylated form of the 4E-BP1 protein in the metastatic cell line, possibly resulting in an increased activation of cap-dependent translation due to increased activity of the eIF4E protein. Analysis of the distribution profiles for the 5' untranslated region (5'-UTR) length of the changed genes showed an association between longer 5'-UTRs and the probability for the relevant gene to be altered translationally, consistent with enhanced eIF4E function. This genome-wide analysis is in favour of a model of profound alteration of translational control in late CRC progression. It also suggests polysomal mRNA profiles as a new, informative dimension for the study of transcriptome imbalance in cancer.
Fiorgen Foundation, Via Sacconi 6, 50019 Florence, Italy.
Alessandro
A
Provenzani
Raffaele
R
Fronza
Fabrizio
F
Loreni
Alessia
A
Pascale
Marialaura
M
Amadio
Alessandro
A
Quattrone
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D018450:Disease Progression; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism; D011132:Polyribosomes / Q000235:genetics*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D010750:Phosphoproteins; D012333:RNA, Messenger