Abstract
Background
The incidence of skin cutaneous melanoma (SKCM), one of the most aggressive and lethal skin tumors, is increasing worldwide. However, for advanced SKCM, we still lack an accurate and valid way to predict its prognosis, as well as novel theories to guide the planning of treatment options for SKCM patients. Lactylation (LAC), a novel post-translational modification of histones, has been shown to promote tumor growth and inhibit the antitumor response of the tumor microenvironment (TME) in a variety of ways. We hope that this study will provide new ideas for treatment options for SKCM patients, as well as research on the molecular mechanisms of SKCM pathogenesis and development.
Methods
At the level of the RNA sequencing set (TCGA, GTEx), we used differential expression analysis, LASSO regression analysis, and multifactor Cox regression analysis to screen for prognosis-related genes and calculate the corresponding LAC scores. The content of TME cells in the tumor tissue was calculated using the CIBERSORT algorithm, and the TME score was calculated based on its results. Finally, the LAC–TME classifier was established and further analyzed based on the two scores, including the construction of a prognostic model, analysis of clinicopathological characteristics, and correlation analysis of tumor mutation burden (TMB) and immunotherapy. Based on single-cell RNA sequencing data, this study analyzed the cellular composition in SKCM tissues and explored the role of LAC scores in intercellular communication. To validate the functionality of the pivotal gene CLPB in the model, cellular experiments were ultimately executed.
Results
We screened a total of six prognosis-related genes (NDUFA10, NDUFA13, CLPB, RRM2B, HPDL, NARS2) and 7 TME cells with good prognosis. According to Kaplan–Meier survival analysis, we found that the LAClow/TMEhigh group had the highest overall survival (OS) and the LAChigh/TMElow group had the lowest OS (p value < 0.05). In further analysis of immune infiltration, tumor microenvironment (TME), functional enrichment, tumor mutational load and immunotherapy, we found that immunotherapy was more appropriate in the LAClow/TMEhigh group. Moreover, the cellular assays exhibited substantial reductions in proliferation, migration, and invasive potentials of melanoma cells in both A375 and A2058 cell lines upon CLPB knockdown.
Conclusions
The prognostic model using the combined LAC score and TME score was able to predict the prognosis of SKCM patients more consistently, and the LAC–TME classifier was able to significantly differentiate the prognosis of SKCM patients across multiple clinicopathological features. The LAC–TME classifier has an important role in the development of immunotherapy regimens for SKCM patients.
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Data availability
All the data in our study can be accessed from the online databases.
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Acknowledgements
This study was funded by the National Natural Science Foundation of China (82072182, 82002061).
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This research was funded by National Natural Science Foundation of China, Grant numbers [82002061, 82072182].
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Conception and design: YZ, BS; data curation and methodology: ZY and YP; BS carried out the in vitro studies. Analysis and interpretation of data: ZC; writing of the manuscript: YZ, BS; review of the manuscript: ZY, YP and ZC; study supervision: LC and BS. All authors read and approved the final manuscript.
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Zhu, Y., Song, B., Yang, Z. et al. Integrative lactylation and tumor microenvironment signature as prognostic and therapeutic biomarkers in skin cutaneous melanoma. J Cancer Res Clin Oncol 149, 17897–17919 (2023). https://doi.org/10.1007/s00432-023-05483-7
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DOI: https://doi.org/10.1007/s00432-023-05483-7