Background and Aims:
Radiotherapy is an increasingly essential therapeutic strategy in the management of hepatocellular carcinoma (HCC). Nevertheless, resistance to radiotherapy is one of the primary obstacles to successful treatment outcomes. Hence, we aim to elucidate the mechanisms underlying radioresistance and identify reliable biotargets that would be inhibited to enhance the efficacy of radiotherapy in HCC.
Approach and Results:
From a label‐free quantitative proteome screening, we identified transfer RNA (tRNA; guanine‐N [7]‐) methyltransferase 1 (METTL1), a key enzyme for N7‐methylguanosine (m7G) tRNA modification, as an essential driver for HCC cells radioresistance. We reveal that METTL1 promotes DNA double‐strand break (DSB) repair and renders HCC cells resistant to ionizing radiation (IR) using loss‐of‐function and gain‐of‐function assays in vitro and in vivo. Mechanistically, METTL1‐mediated m7G tRNA modification selectively regulates the translation of DNA‐dependent protein kinase catalytic subunit or DNA ligase IV with higher frequencies of m7G‐related codons after IR treatment, thereby resulting in the enhancement of nonhomologous end‐joining (NHEJ)–mediated DNA DSB repair efficiency. Clinically, high METTL1 expression in tumor tissue is significantly correlated with poor prognosis in radiotherapy‐treated patients with HCC.
Conclusions:
Our findings show that METTL1 is a critical enhancer for HCC cell NHEJ‐based DNA repair following IR therapy. These findings give insight into the role of tRNA modification in messenger RNA translation control in HCC radioresistance.
Background and Purpose. Follow-up intervals after radiofrequency ablation (RFA) varied in different international guidelines. This study aimed to compare the cost-effectiveness of different follow-up intervals for hepatocellular carcinoma (HCC) following RFA. Methods. A Markov model was established to evaluate the cost-effectiveness of every 2 months or 2-3 months (2- to 3-month group) versus every 3 months or 3-4 months (3- to 4-month group) posttreatment surveillance in the first two years for HCC after RFA. Transition probabilities and utility values were derived from the literature review. Costs of follow-up were estimated from our institution. The incremental cost-effectiveness ratio (ICER), which was less than $10888 per quality-adjusted life-year (QALY), was considered cost-effective. Sensitivity analyses were performed to determine the uncertainty of the model. Results. The 2- to 3-month group gained 1.196 QALYs at a cost of $2212.66, while the effectiveness and cost of the 3- to 4-month group were 1.029 QALYs and $1268.92, respectively. The ICER of the 2- to 3-month group versus the 3- to 4-month group was $5651.14 per QALY gained, which was less than the willingness-to-pay threshold of 1-time gross domestic product per capita of China ($10888/QALY). One-way sensitivity analysis showed that the model was most sensitive to the utility of progression-free survival. The probabilistic sensitivity analysis demonstrated that the 2- to 3-month group had a higher probability of being more cost-effective than the 3- to 4-month group when willingness to pay was over $1088.8. Conclusions. Every 2 months or 2-3 months of follow-up intervals were more cost-effective than 3 months or 3-4 months of follow-up intervals. Thus, the intensive follow-up interval in the first two years was recommended for Child-Pugh class A or B HCC patients within the Milan criteria following RFA.
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