Source: The First Affiliated Hospital
Edited by: Tan Rongyu, Wang Dongmei

Recently, Prof. Kuang Ming’s team (Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University) and Prof. Lin Shuibin’s team (Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University) co-published a research article named “N7-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression”. It was published as the cover article in Molecular Cell, a top journal in the field of molecular biology. This article was based on a novel tRNA modification sequencing technology (TRAC-seq) developed by Prof. Lin Shuibin (published in Nature Protocols in 2019). TRAC-seq broke through the technical bottleneck of tRNA sequencing and applied to identify the new function of tRNA m7G modification in the regulation of tumor progression. This article provided a new mechanism for the abnormal translation of tumor mRNA and opened up avenues for developing therapeutic strategies for effective cancer treatment. It is a highlight in the combination of cutting-edge technology and clinical needs and also a great success of our long-term strategy in encouraging precision medicine, translational research and inter-disciplinary talents.

Intrahepatic cholangiocarcinoma (ICC) is the second most common and devastating primary liver cancer, accounting for 10%–20% of primary hepatic tumors. Even with surgical resection and highly aggressive chemotherapy, the 5-year survival of ICC patients is only 5%–40%. The synthesis of protein in ICC is quite active, which further promotes its proliferation and metastasis, but the underlying mechanisms are poorly understood.

Based on the liver cancer database in the First Affiliated Hospital, Sun Yat-sen University, Prof. Kuang Ming’s team found the core m7G tRNA methyltransferase complex components METTL1 and WDR4 are both highly upregulated in ICC tumors. The patients with higher METTL1/WDR4 expression have poorer survival status and develop more frequent recurrence. In vitro results uncovered a critical role of METTL1/WDR4 in the regulation of ICC proliferation, invasion and metastasis. A total of 22 tRNAs that contain m7G modification were identified by tRNA reduction and cleavage sequencing and these tRNA selectively regulated the translation of cell cycle and EGFR signaling pathway genes via a codon-frequency-dependent mechanism.

In conclusion, we provide evidence supporting the oncogenic function of METTL1-mediated m7G tRNA modification in ICC development and uncover the molecular mechanisms underlying the tRNA-modification-mediated selective regulation of oncogene expression in cancer. These findings could open up avenues for developing therapeutic strategies for effective cancer treatment.

The first authors of this paper are Dai Zihao, Liu Haining and Liao Junbin, from the Department of Liver Surgery. The corresponding author is Prof. Kuang Ming, Director of the Liver Surgery and Tumor Center. Prof. Lin Shuibin from the Center for Translational Medicine and the Institute of Precision Medicine is the co-corresponding author.

Link to the paper: https://www.sciencedirect.com/science/article/abs/pii/S1097276521005554