CCNE1 promotes the progression of hepatic precancerous lesion and the malignant phenotype of hepatocellular carcinoma

Background and Aims

The diagnosis of hepatic precancerous lesions (HPC) and early hepatocellular carcinoma (HCC) has significant public health implications and holds the potential to reduce the global burden of HCC. This study aimed to identify molecular features and biomarkers associated with HPC progression and early HCC development.

Methods

RNA sequencing was used to identify differentially expressed genes in mouse HPC tissues and normal liver tissues. Cyclin E1 (CCNE1) expression in HPC tissues and HCC cells was assessed using immunohistochemistry, Western blotting, and real-time polymerase chain reaction. The effects of CCNE1 on HCC cell proliferation, migration, invasion, and apoptosis were evaluated using colony formation, wound healing, Transwell assays, and flow cytometry. The mechanism of CCNE1 was explored through Kyoto Encyclopedia of Genes and Genomes pathway analysis and gene set enrichment analysis and further validated through in vitro experiments. The interaction between CCNE1 and tumor-associated macrophages (TAMs) was investigated by co-culturing HCC cells with macrophages.

Results

RNA sequencing and TCGA database analysis showed that CCNE1 expression was significantly elevated in mouse HPC tissues and human HCC samples and was associated with reduced survival rates. In vitro assays demonstrated that CCNE1 promoted HCC cell proliferation, migration, invasion, and survival by activating the PI3K/Akt signaling pathway. Additionally, CCNE1 induced TAM polarization toward the M2 phenotype by promoting the expression of CCL2 and CCL5 in HCC cells.

Conclusions

This study identifies CCNE1 as a pivotal driver of HPC-to-HCC progression, playing multifaceted roles in tumor cell survival, invasion, and immune evasion. Its expression is positively correlated with early vascular invasion and late distant metastasis in HCC. Mechanistically, CCNE1 promotes tumorigenesis via PI3K/Akt pathway activation and fosters an immunosuppressive microenvironment through CCL2/CCL5-mediated TAM infiltration and M2 polarization. These findings highlight CCNE1 as a promising biomarker for early HCC diagnosis and a potential therapeutic target for disrupting both tumor-intrinsic signaling and the immunosuppressive microenvironment. However, several limitations must be acknowledged. First, although our bioinformatic analyses of TCGA and GEO datasets validate CCNE1’s clinical relevance, prospective studies with longitudinal HPC-to-HCC cohorts are needed to confirm its predictive value. Second, the functional crosstalk between CCNE1 and other signaling pathways or molecules remains unexplored. Finally, preclinical models (e.g., CCNE1-transgenic mice) are essential to validate its causal role in HPC progression and to evaluate targeted therapies in vivo. Future studies should confirm these findings in longitudinal cohorts and preclinical models to translate CCNE1’s diagnostic and therapeutic potential into clinical practice. By bridging mechanistic insights with clinical needs, this work lays the foundation for precision medicine strategies to intercept HCC at its precancerous stage.

Full text

https://www.xiahepublishing.com/2310-8819/JCTH-2024-00428

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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