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Background Insufficient post-operative future liver remnant (FLR) limits the feasibility of hepatectomy for patients. Staged hepatectomy is an effective surgical approach that can improve the resection rate of hepatocellular carcinoma (HCC). This study aimed to compare the safety and efficacy of laparoscopic microwave ablation and portal vein ligation for staged hepatectomy (LAPS) and classical associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in the treatment of hepatitis B virus (HBV)-related HCC. Methods Clinical data of patients with HBV-related HCC who underwent LAPS or ALPPS in our institute between January 2017 and May 2022 were retrospectively analysed. Results A total of 18 patients with HBV-related HCC were retrospectively analysed and divided into the LAPS group (n  =   9) and ALPPS group (n  =   9). Eight patients in the LAPS group and eight patients in the ALPPS group proceeded to a similar resection rate (88.9% vs 88.9%, P  =   1.000). The patients undergoing LAPS had a lower total comprehensive complication index than those undergoing ALPPS but there was not a significant different between the two groups (8.66 vs 35.87, P  =   0.054). The hypertrophy rate of FLR induced by ALPPS tended to be more rapid than that induced by LAPS (24.29 vs 13.17 mL/d, P  =   0.095). The 2-year recurrence-free survival (RFS) was 0% for ALPPS and 35.7% for LAPS (P  =   0.009), whereas the 2-year overall survival for ALPPS and LAPS was 33.3% and 100.0% (P  =   0.052), respectively. Conclusions LAPS tended to induce lower morbidity and FLR hypertrophy more slowly than ALPPS, with a comparable resection rate and better long-term RFS in HBV-related HCC patients. [ABSTRACT FROM AUTHOR]

The tyrosine kinase inhibitor lenvatinib is a first-line drug for treating patients with advanced hepatocellular carcinoma (HCC). However, its efficacy is severely hampered by drug resistance. Insights into the molecular mechanisms underlying lenvatinib resistance could provide new strategies to improve and prolong responses. Here, we performed unbiased proteomic screening of parental and lenvatinib-resistant HCC cells and discovered that methyltransferase-like protein-1 (METTL1) and WD repeat domain 4 protein (WDR4), the two key components of the tRNA N7-methylguanosine (m7G) methyltransferase complex, were dramatically upregulated in lenvatinib-resistant cells. METTL1 knockdown overrode resistance by impairing the proliferation capacity of HCC cells and promoting apoptosis under lenvatinib treatment. In addition, overexpression of wild-type METTL1 but not its catalytic dead mutant induced lenvatinib resistance. Animal experiments including hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models further demonstrated the critical function of METTL1/WDR4-mediated m7G tRNA modification in promoting lenvatinib resistance in vivo. Mechanistically, METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m7G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance., Significance: Upregulation of tRNA m7G methyltransferase complex components METTL1 and WDR4 promotes lenvatinib resistance in HCC and confers a sensitivity to METTL1 targeting, providing a promising strategy to override resistance., (©2022 American Association for Cancer Research.)

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N 7 -methylguanosine (m 7 G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m 7 G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m 7 G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m 7 G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m 7 G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)