Codon misreading tRNAs promote tumor growth in mice

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Deregulation of transfer RNAs (tRNAs), aminoacyl-tRNA synthetases, and tRNA modifying enzymes is frequently observed in cancer.
• This deregulation suggests that protein synthesis efficiency and accuracy may be compromised in tumors.

Purpose of the Study:

• To investigate the role of protein mistranslation in tumor biology.
• To determine if specific types of amino acid misincorporations influence cancer progression.

Main Methods:

• Generated NIH3T3 cells expressing mutant Ser-tRNAs causing serine-to-alanine and serine-to-leucine misincorporations.
• Quantified mistranslation frequency in human colon tumors and mouse xenografts.
• Assessed cell transformation, angiogenesis, tumor growth, Akt pathway activation, and unfolded protein response (UPR).

Main Results:

• Human colon tumors and xenografts showed 2- to 4-fold higher mistranslation rates than normal tissues.
• Serine-to-alanine misreading tRNA was a more potent inducer of cell transformation, angiogenesis, and faster tumor growth compared to serine-to-leucine.
• Upregulation of the Akt pathway and UPR was observed.
• Relative expression of misreading tRNAs increased during tumor growth.

Conclusions:

• Protein mistranslation is significantly elevated in tumors and appears advantageous for cancer progression.
• Specific mistranslation events, like serine-to-alanine, can drive key oncogenic processes.
• The study reveals novel aspects of protein synthesis deregulation in the context of tumor biology.