tRNA-Derived Fragments (tRFs) in Bladder Cancer: Increased 5′-tRF-LysCTT Results in Disease Early Progression and Patients’ Poor Treatment Outcome

Abstract

The heterogeneity of bladder cancer (BlCa) prognosis and treatment outcome requires the elucidation of tumors’ molecular background towards personalized patients’ management. tRNA-derived fragments (tRFs), although originally considered as degradation debris, represent a novel class of powerful regulatory non-coding RNAs. In silico analysis of the TCGA-BLCA project highlighted 5′-tRF-LysCTT to be significantly deregulated in bladder tumors, and 5′-tRF-LysCTT levels were further quantified in our screening cohort of 230 BlCa patients. Recurrence and progression for non-muscle invasive (NMIBC) patients, as well as progression and patient’s death for muscle-invasive (MIBC) patients, were used as clinical endpoint events. TCGA-BLCA were used as validation cohort. Bootstrap analysis was performed for internal validation and the clinical net benefit of 5′-tRF-LysCTT on disease prognosis was assessed by decision curve analysis. Elevated 5′-tRF-LysCTT was associated with unfavorable disease features, and significant higher risk for early progression (multivariate Cox: HR = 2.368; p = 0.033) and poor survival (multivariate Cox: HR = 2.151; p = 0.032) of NMIBC and MIBC patients, respectively. Multivariate models integrating 5′-tRF-LysCTT with disease established markers resulted in superior risk-stratification specificity and positive prediction of patients’ progression. In conclusion, increased 5′-tRF-LysCTT levels were strongly associated with adverse disease outcome and improved BlCa patients’ prognostication.

tRNAGlyGCC-Derived Internal Fragment (i-tRF-GlyGCC) in Ovarian Cancer Treatment Outcome and Progression

“…Unsurprisingly, numerous research groups have identified tRFs as potential prognostic molecular markers in various cancer types [ 42 , 43 ]. Particularly, a high ratio of 5′-tRF-LysCTT/3′-tRF-PheGAA has been correlated with a worse prognosis in prostate cancer [ 44 ], while increased 5′-tRF-LysCTT levels were strongly linked to a poor disease outcome in bladder cancer [ 45 ]. Additionally, the reduced serum levels of 5′-half-ValCAC were associated with adverse clinicopathological characteristics [ 46 ], whereas the elevation of two i-tRFs derived from tRNA CysGCA was correlated to trastuzumab resistance and worse prognosis of breast cancer patients [ 47 ].…”

Emerging Functions for snoRNAs and snoRNA-Derived Fragments

“…Additionally, there are literally hundreds of studies purporting that dysregulation of tRFs is related to cancers of various types [ 108 , 109 , 110 ]; however, the underlying mechanisms remain largely unknown, both in terms of what alters tRNA processing and what signaling cascades are triggered by tRF dysregulation [ 20 ]. In addition to their potential utility as biomarkers, tRF levels might also indicate how well cells will respond to various kinds of therapy, though again mechanistic explanations remain poorly understood [ 103 , 111 ].…”

Transfer RNA-Derived Small RNAs: Novel Regulators and Biomarkers of Cancers

“…Likewise, Papadimitriou et al. reported a significant elevation of the tRF-Lys-CTT in bladder tumors and a positive association with clinical prognosis ( 115 ). Interestingly, data demonstrated diverse expression of three different tRF-5s in the testicular germinoma ( 120 ).…”