Bioinformatic analysis identifies HPV-related tumor microenvironment remodeling prognostic biomarkers in head and neck squamous cell carcinoma

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are highly aggressive tumors with rapid progression and poor prognosis. Human papillomavirus (HPV) infection has been identified as one of the most important carcinogens for HNSCC. As an early event in HNSCC, infection with HPV leads to altered immune profiles in the tumor microenvironment (TME). The TME plays a key role in the progression and transformation of HNSCC. However, the TME in HNSCC is a complex and heterogeneous mix of tumor cells, fibroblasts, different types of infiltrating immune cells, and extracellular matrix. Biomarkers relevant to the TME, and the biological role of these biomarkers, remain poorly understood. To this end, we performed comprehensive analysis of the RNA sequencing (RNA-Seq) data from tumor tissue of 502 patients with HNSCC and healthy tissue of 44 control samples. In total, we identified 4,237 differentially expressed genes, including 2,062 upregulated and 2,175 downregulated genes. Further in-depth bioinformatic analysis suggested 19 HNSCC tumor tissue-specific genes. In the subsequent analysis, we focused on the biomarker candidates shown to be significantly associated with unfavorable patient survival: ITGA5, PLAU, PLAUR, SERPINE1, TGFB1, and VEGFC. We found that the expression of these genes was negatively regulated by DNA methylation. Strikingly, all of these potential biomarkers are profoundly involved in the activation of the epithelial–mesenchymal transition (EMT) pathway in HNSCCs. In addition, these targets were found to be positively correlated with the immune invasion levels of CD4+ T cells, macrophages, neutrophils, and dendritic cells, but negatively correlated with B-cell infiltration and CD8+ T-cell invasion. Notably, our data showed that the expression levels of ITGA5, PLAU, PLAUR, SERPINE1, and TGFB1 were significantly overexpressed in HPV-positive HNSCCs compared to normal controls, indicating the potential role of these biomarkers as transformation and/or malignant progression markers for HNSCCs in patients with HPV infection. Taken together, the results of our study propose ITGA5, PLAU, PLAUR, SERPINE1, and TGFB1 as potential prognostic biomarkers for HNSCCs, which might be involved in the HPV-related TME remodeling of HNSCC. Our findings provide important implications for the development and/or improvement of patient stratification and customized immunotherapies in HNSCC.

Transcriptomic analysis of Porphyromonas gingivalis‐infected head and neck cancer cells: Identification of PLAU as a candidate prognostic biomarker

“…In addition, the up‐regulated expression of PLAU was associated with HPV positivity and the neck node status 50 . ITGA5, PLAU, PLAUR, SERPINE1 and TGFB1 have potential as prognostic biomarkers for HNSCC mediated by HPV infection 48 . Expression of PLAU in HNSCC was also detected by immunohistochemical staining.…”

“…PLAU has been associated with the prognosis of patients with head and neck cancer. [47][48][49][50] In a HNSCC bioinformatics study, PLAU, SERPINE1, and ACTA1 were linked to the prognosis of patients. Among them, the labelling score of PLAU significantly 51 In the present study, we attempt to detect changes in PLAU protein expression due to P. gingivalis infection and found a transient increase of PLAU protein (Figure 6A).…”

“…Moreover, CCL20 and PLAU were suggested by the Kaplan–Meier method. PLAU has been associated with the prognosis of patients with head and neck cancer 47–50 . In a HNSCC bioinformatics study, PLAU, SERPINE1, and ACTA1 were linked to the prognosis of patients.…”

An Investigation of the Prognostic Role of Genes Related to Lipid Metabolism in Head and Neck Squamous Cell Carcinoma

“…Furthermore, bioinformatics tools have been widely used to identify novel molecular markers of cancer. In HNSCC, many scholars use bioinformatics methods to identify biomarker candidates for diagnosis and prognosis, such as the biomarkers of tumour-infiltrating lymphocytes and HPVrelated tumour microenvironment remodelling [30][31][32]. However, the biomarkers obtained from bioinformatics represent only the starting point, further experimental and functional studies would have to be performed in order to validate their predictive role [33].…”

Pan-cancer analysis of SERPINE family genes as biomarkers of cancer prognosis and response to therapy

“…Pei et al developed a hypoxia risk score model based on SERPINE1 revealing the correlation between hypoxia and tumor immune microenvironment ( Pei et al, 2021 ). In addition, numerous studies published in the past few decades reported that SERPINE1 is one of the most reliable biomarkers and prognostic markers in many cancer types, including breast cancer ( Harbeck et al, 2004 ; Palmirotta et al, 2009 ; Duffy et al, 2014 ; Duffy et al, 2016 ; Jevrić et al, 2019 ), ovarian cancer ( Mashiko et al, 2015 ; Nakatsuka et al, 2017 ), renal cell carcinoma ( Ahluwalia et al, 2021 ), head and neck squamous cell carcinoma ( Pavón et al, 2015 ; Guo et al, 2022 ; Zhou et al, 2022 ; Li et al, 2023 ), bladder cancer ( Chan et al, 2017 ), colorectal cancer ( Sakakibara et al, 2005 ), gastric cancer ( Khan et al, 2022 ; Xu et al, 2022 ) and non-small cell lung cancers ( Sotiropoulos et al, 2019 ). Previous studies also demonstrated that SERPINE1 can promote cancer progression and metastasis as it is promoting the tumor migration, invasion, and angiogenesis ( Dellas and Loskutoff, 2005 ; Li et al, 2018 ; Kubala and DeClerck, 2019 ).…”