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 METTL1 and WDR4, the two key components of the tRNA 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.
The tumor microenvironment is distinctive in primary and secondary liver cancer. B cells represent an important component of immune infiltrates. Here, we demonstrated that B cells are an important regulator in hepatocellular carcinoma (HCC) and colorectal cancer liver metastasis (CRLM) microenvironments. B cells displayed distinct developmental trajectories in HCC and CRLM. Single-cell analysis revealed that IgG+ plasma cells preferentially accumulated in HCC while IgA+ plasma cells were preferentially enriched in CRLM. Mechanistically, IgG+ plasma cells in HCC were recruited by tumor-associated macrophages via the CXCR3-CXCL10 axis, whereas IgA+ plasma cells in CRLM were recruited by metastatic tumor cells via CCR10-CCL28 signaling. Functionally, IgG+ plasma cells preferentially promoted pro-tumorigenic macrophages formation in HCC, and IgA+ plasma cells preferentially induced granulocytic myeloid-derived suppressor cells activation in CRLM. Clinically, increased infiltration of IgG+ plasma cells and macrophages in HCC was correlated to worse survival, while increased intratumoral IgA+ plasma cells and neutrophils in CRLM indicated poor prognosis. Taken together, this study demonstrated plasma and myeloid cell-mediated immunosuppression in HCC and CRLM, suggesting that selectively modulating primary or secondary tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating liver cancer.
Purpose: miR-500a-3p has been extensively reported to be implicated in the development and progression in several human cancer types. This study aimed to investigate the diagnostic and prognostic significance of miR-500a-3p as a biomarker in hepatocellular carcinoma (HCC). Methods: miR-500a-3p expression was evaluated by in situ hybridization (ISH) and real-time PCR in 10 adjacent normal tissues (ANT), 21 liver fibrosis tissues, and 110 HCC tissues. Statistical analysis was used to investigate the correlation of miR-500a-3p expression with clinicopathological features in HCC patients. Kaplan-Meier survival analysis was performed to evaluate the prognostic significance of miR-500a-3p in overall survival and recurrence-free survival in HCC patients. Results: In this study, we found that expression levels of miR-500a-3p were enhanced in HCC tissues. High miR-500a-3p levels were positively correlated with multiple clinicopathological features, including advanced clinical stage, distant metastatic status, increased AFP levels and poor tumor differentiation degree. More importantly, high miR-500a-3p levels predicted poor overall survival and early recurrence in HCC patients. Finally, a strong and positive correlation of miR-500a-3p mRNA expression with ISH staining scores was observed in clinical HCC tissues. Conclusion: Our findings suggest that miR-500a-3p might be used as a novel biomarker to facilitate early diagnosis and predict prognosis in HCC patients.
<div>Abstract<p>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 N<sup>7</sup>-methylguanosine (m<sup>7</sup>G) 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 m<sup>7</sup>G tRNA modification in promoting lenvatinib resistance <i>in vivo</i>. Mechanistically, METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m<sup>7</sup>G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance.</p>Significance:<p>Upregulation of tRNA m<sup>7</sup>G 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.</p></div>
<p>This file describes supplementary figures.</p>
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