Identify and validate circadian regulators as potential prognostic markers and immune infiltrates in head and neck
Yi Jin1,2, Zhanwang Wang3, Siwei Huang4
1Department of Radiation Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
Abstract:
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneity pathological malignant cancer with leading causes of morbidity and mortality. EGFR inhibitors, immune checkpoint inhibitors have become novel treatments. However, the mechanism still remained uncertain. Several studies have confirmed that the circadian rhythms induce multiple malignancies developing. We utilized multi-omics analysis to demonstrate the crosstalk between circadian clock genes and tumor microenvironment in HNSCC. Firstly, we performed the LASSO Cox regression analysis based on the 16 important clock genes. A 7-gene risk model was successfully established in TCGA and validated in GEO datasets. Next, CIBERSORT and ESTIMATE methods were performed to display the immune landscape of high risk and low risk groups, and the results showed that high abundance of mast cells activated, dendritic cells activated and neutrophils were positively correlated with poor OS. To further identify hub genes, Kaplan Meier plot was applied in all TCGA and GEO datasets and two hub genes (PER2, and PER3) were identified, especially PER3, which was found strongly associated with immune score, PDCD1, CD4 + and CD8 + T cells in HNSCCC. Moreover, to explore the innate mechanism of circadian-induced pathway, we constructed a circadian-related ceRNA regulatory network containing 34 lncRNAs, 3 miRNAs and 4 core circadian genes. In-vitro experiments also verified that Per2 or Per3 could suppressed the proliferation, migration and invasion of HNSC. This study unraveled the association between PER3 and prognosis in patients with HNSC and the innate mechanism remains to be elucidated.
Insights
This study reveals circadian clock genes, particularly PER3, are linked to head and neck squamous cell carcinoma (HNSCC) prognosis and immune cell infiltration. Circadian clock gene dysregulation impacts tumor microenvironment and patient outcomes in HNSCC.
Area of Science:
- Oncology
- Circadian Biology
- Immunology
Background:
- Head and neck squamous cell carcinoma (HNSCC) is a significant cause of cancer morbidity and mortality.
- Novel treatments like EGFR and immune checkpoint inhibitors show promise, but underlying mechanisms require further elucidation.
- Emerging evidence links circadian rhythm disruption to various malignancies, including HNSCC.
Purpose of the Study:
- To investigate the interplay between circadian clock genes and the tumor microenvironment in HNSCC.
- To identify key circadian clock genes associated with HNSCC prognosis and immune cell infiltration.
- To explore the molecular mechanisms underlying circadian clock gene influence on HNSCC progression.
Main Methods:
- Multi-omics analysis including LASSO Cox regression and Kaplan-Meier plots on TCGA and GEO datasets.
- Immune landscape analysis using CIBERSORT and ESTIMATE.
- Construction of a circadian-related competing endogenous RNA (ceRNA) regulatory network.
- In-vitro experiments to validate the functional role of identified clock genes.
Main Results:
- A 7-gene risk model was established, identifying specific circadian clock genes associated with HNSCC.
- High abundance of activated mast cells, activated dendritic cells, and neutrophils correlated with poorer overall survival (OS).
- PER3 was identified as a hub gene strongly associated with immune scores and T cell populations (CD4+, CD8+).
- In-vitro studies confirmed that PER2 and PER3 suppressed HNSCC cell proliferation, migration, and invasion.
Conclusions:
- Circadian clock genes, particularly PER3, play a crucial role in HNSCC progression and are associated with patient prognosis.
- The study highlights the significant crosstalk between circadian rhythms and the tumor immune microenvironment in HNSCC.
- PER3 may serve as a potential prognostic biomarker and therapeutic target in HNSCC, warranting further mechanistic investigation.
