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Pang KL, Li P, Yao XR, Xiao WT, Ren X, He JY. Deciphering a proliferation-essential gene signature based on CRISPR-Cas9 screening to predict prognosis and characterize the immune microenvironment in HNSCC. BMC Cancer 2025; 25:756. [PMID: 40264050 PMCID: PMC12016166 DOI: 10.1186/s12885-025-14181-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 04/17/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with a poor prognosis. Identifying reliable prognostic biomarkers and therapeutic targets is crucial for improving patient outcomes. This study aimed to systematically identify proliferation-essential genes (PEGs) associated with HNSCC prognosis using CRISPR-Cas9 screening data. METHODS CRISPR-Cas9 screening data from the DepMap database were used to identify PEGs in HNSCC cells. A prognostic PEGs signature was constructed using univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression analyses. The predictive accuracy of the signature was validated in internal and external datasets. Weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis (GSEA), and immune infiltration analysis were used to investigate the underlying mechanism between high and low-risk patients. Random forest analysis and functional experiments were conducted to investigate the role of key proliferation essential genes in HNSCC progression. RESULTS A total of 1511 PEGs were identified. A seven-gene prognostic PEGs signature (MRPL33, NAT10, PSMC1, PSMD11, RPN2, TAF7, and ZNF335) was developed and validated, demonstrating robust prognostic performance in stratifying HNSCC patients by survival risk. WGCNA and GSEA analyses revealed a marked downregulation of immune-related pathways in high-risk patients. Immune infiltration analysis validated those high-risk patients had reduced immune scores, stromal scores, and ESTIMATE scores, as well as decreased infiltration of multiple immune cell types. Among the identified genes, PSMC1 was highlighted as a pivotal regulator of HNSCC proliferation and migration, as confirmed by functional experiments. CONCLUSIONS This study identifies a novel PEGs signature that effectively predicts HNSCC prognosis and stratifies patients by survival risk. PSMC1 was identified as a key gene promoting malignant progression, offering potential as a therapeutic target for HNSCC.
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Affiliation(s)
- Ke-Ling Pang
- Department of Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Pian Li
- Department of Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Xiang-Rong Yao
- Department of Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Wen-Tao Xiao
- Department of Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Xing Ren
- Clinical Laboratory Medicine Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
| | - Jun-Yan He
- Department of Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
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Liu XH, Wang GR, Zhong NN, Wang WY, Liu B, Li Z, Bu LL. Multi-omics in immunotherapy research for HNSCC: present situation and future perspectives. NPJ Precis Oncol 2025; 9:93. [PMID: 40158059 PMCID: PMC11954913 DOI: 10.1038/s41698-025-00886-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Accepted: 03/18/2025] [Indexed: 04/01/2025] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, significantly impacting patient survival and quality of life. The recent emergence of immunotherapy has provided new hope for HNSCC patients, improving survival rates; however, only 15%-20% of patients benefit, and side effects are inevitable. With advancements in omics technologies and the growing prevalence of bioinformatics research, the immune microenvironment of HNSCC has become increasingly well understood, and the molecular mechanisms underlying immunotherapy responses continue to be elucidated. In this review, we summarize commonly used omics techniques and their applications in the research of HNSCC immunotherapy, including predicting and enhancing efficacy, formulating personalized treatment plans, establishing robust preclinical research models, and identifying new immunotherapy targets. Finally, we explore future perspective in terms of sequencing samples, data integration analysis, emerging technologies, clinicopathological features, and interdisciplinary approaches.
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Affiliation(s)
- Xuan-Hao Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
| | - Guang-Rui Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
| | - Nian-Nian Zhong
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
| | - Wei-Yu Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
- Department of Oral & Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
| | - Zheng Li
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 169, Donghu Road, Wuchang District, Wuhan, 430071, China.
| | - Lin-Lin Bu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China.
- Department of Oral & Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, 430072, China.
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Yang P, Gu H, Wu X, Chen G, Liu H, Chen Z. Tumour protein p53-activated lncRNA PGM5-AS1 suppresses lung cancer growth and stemness by targeting R-spondin1 via microRNA-1247-5p. Arch Physiol Biochem 2025:1-13. [PMID: 40035308 DOI: 10.1080/13813455.2025.2459318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/06/2024] [Accepted: 01/22/2025] [Indexed: 03/05/2025]
Abstract
OBJECTIVE This study was to investigated the inhibitory role of the tumour protein p53 (TP53)-activated PGM5-AS1 in lung cancer (LC) cell proliferation, invasion, and CSC-like properties and its underlying mechanisms. METHODS The effect of PGM5-AS1 on LC cell development was determined. Stem cell markers, aldehyde dehydrogenase activity in cells were tested, as well as the ability of stem cells to form spheroids. The interaction of PGM5-AS1 and TP53 was determined. The binding link of PGM5-AS1, miR-1247-5p, and R-spondin1 (RSPO1) was verified. RESULTS PGM5-AS1 was elevated by a combination of TP53 and PGM5-AS1 promoters. PGM5-AS1 was a molecular sponge of miR-1247-5p in LC cells, and miR-1247-5p targeted RSPO1. Elevating PGM5-AS1 or repressing miR-1247-5p restrained LC cell growth and stemness, which were reversed by depression of RSPO1. CONCLUSION This study conveys that TP53-elevated PGM5-AS1 mediates miR-1247-5p to target RSPO1, thereby inhibiting LC growth and stemness, representing a novel avenue for LC therapy.
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Affiliation(s)
- Peng Yang
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Hong Gu
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Xuanqin Wu
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Geng Chen
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Heng Liu
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Zhongliang Chen
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
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Zhai PL, Chen MM, Wang Q, Zhao JJ, Tang XM, Lu CN, Liu J, Yang QX, Xiang ML, Tang QH, Gu B, Zhang SP, Tang SP, Fu D. Multi-omics analysis identifies a liquid-liquid phase separation-related subtypes in head and neck squamous cell carcinoma. Front Oncol 2025; 15:1509810. [PMID: 40078192 PMCID: PMC11897011 DOI: 10.3389/fonc.2025.1509810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/11/2025] [Indexed: 03/14/2025] Open
Abstract
Background Growing evidence indicates that abnormal liquid-liquid phase separation (LLPS) can disrupt biomolecular condensates, contributing to cancer development and progression. However, the influence of LLPS on the prognosis of head and neck squamous cell carcinoma (HNSCC) patients and its effects on the tumor immune microenvironment (TIME) are not yet fully understood. Therefore, we aimed to categorize patients with HNSCC based on LLPS-related genes and explored their multidimensional heterogeneity. Methods We integrated the transcriptomic data of 3,541 LLPS-related genes to assess the LLPS patterns in 501 patients with HNSCC within The Cancer Genome Atlas cohort. Subsequently, we explored the differences among the three LLPS subtypes using multi-omics analysis. We also developed an LLPS-related prognostic risk signature (LPRS) to facilitate personalized and integrative assessments and then screened and validated potential therapeutic small molecule compounds targeting HNSCC via experimental analyses. Result By analyzing the expression profiles of 85 scaffolds, 355 regulators, and 3,101 clients of LLPS in HNSCC, we identified three distinct LLPS subtypes: LS1, LS2, and LS3. We confirmed notable differences among these subtypes in terms of prognosis, functional enrichment, genomic alterations, TIME patterns, and responses to immunotherapy. Additionally, we developed the LPRS, a prognostic signature for personalized integrative assessments, which demonstrated strong predictive capability for HNSCC prognosis across multiple cohorts. The LPRS also showed significant correlations with the clinicopathological features and TIME patterns in HNSCC patients. Furthermore, the LPRS effectively predicted responses to immune checkpoint inhibitor therapy and facilitated the screening of potential small-molecule compounds for treating HNSCC patients. Conclusion This study presents a new classification system for HNSCC patients grounded in LLPS. The LPRS developed in this research offers improved personalized prognosis and could optimize immunotherapy strategies for HNSCC.
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Affiliation(s)
- Peng-Lei Zhai
- Key Laboratory of Functional Organometallic Materials of College of Hunan Province, College of Chemistry and Materials Science, Hengyang Normal University, Hengyang, China
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng-Min Chen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Wang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing-Jun Zhao
- Key Laboratory of Functional Organometallic Materials of College of Hunan Province, College of Chemistry and Materials Science, Hengyang Normal University, Hengyang, China
| | - Xiao-Mei Tang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cui-Ni Lu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qin-Xin Yang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Liang Xiang
- Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing-Hai Tang
- Hunan Key Laboratory for Conservation and Utilization of Biological Resources in the Nanyue Mountainous Region, College of Life Sciences, Hengyang Normal University, Hengyang, China
| | - Biao Gu
- Key Laboratory of Functional Organometallic Materials of College of Hunan Province, College of Chemistry and Materials Science, Hengyang Normal University, Hengyang, China
| | - Shu-Ping Zhang
- Key Laboratory of Functional Organometallic Materials of College of Hunan Province, College of Chemistry and Materials Science, Hengyang Normal University, Hengyang, China
| | - Si-Ping Tang
- Key Laboratory of Functional Organometallic Materials of College of Hunan Province, College of Chemistry and Materials Science, Hengyang Normal University, Hengyang, China
| | - Da Fu
- Key Laboratory of Functional Organometallic Materials of College of Hunan Province, College of Chemistry and Materials Science, Hengyang Normal University, Hengyang, China
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Li Y, Ding Y, Wang J, Wu X, Zhang D, Zhou H, Zhang P, Shao G. A novel molecular classification system based on the molecular feature score identifies patients sensitive to immune therapy and target therapy. Front Immunol 2024; 15:1466069. [PMID: 39660131 PMCID: PMC11628386 DOI: 10.3389/fimmu.2024.1466069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC) is heterogeneous and refractory with multidimensional features. This study aims to investigate its molecular classifications based on multidimensional molecular features scores (FSs) and support classification-guided precision medicine. Methods Data of bulk RNA sequencing, single nucleotide variation, and single-cell RNA sequencing were collected. Feature scores (FSs) from hallmark pathways, regulatory cell death pathways, metabolism pathways, stemness index, immune scores, estimate scores, etc. were evaluated and screened. Then, the unsupervised clustering on the core FSs was performed and the characteristics of the resulting clusters were identified. Subsequently, machine learning algorithms were used to predict the classifications and prognoses. Additionally, the sensitivity to immune therapy and biological roles of classification-related prognostic genes were also evaluated. Results We identified four clusters with distinct characteristics. C1 is characterized by high TP53 mutations, immune suppression, and metabolic downregulation, with notable responsiveness to anti-PD1 therapy. C2 exhibited high tumor purity and metabolic activity, moderate TP53 mutations, and cold immunity. C3 represented an early phase with the most favorable prognosis, lower stemness and tumor mutations, upregulated stroma, and hypermetabolism. C4 represented a late phase with the poorest prognosis, highest stemness, higher TP53 mutations, cold immunity, and metabolic downregulation. We further developed practical software for prediction with good performance in the external validation. Additionally, FTCD was identified as a classification-specific prognostic gene with tumor-suppressing role and potential as a therapeutic target, particularly for C1 and C4 patients. Conclusions The four-layer classification scheme enhances the understanding of HCC heterogeneity, and we also provide robust predictive software for predicting classifications and prognoses. Notably, C1 is more sensitive to anti-PD1 therapies and FTCD is a promising therapeutic target, particularly for C1 and C4. These findings provide new insights into classification-guided precision medicine.
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Affiliation(s)
- Yang Li
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yinan Ding
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jinghao Wang
- School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui, China
| | - Xiaoxia Wu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Dinghu Zhang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Han Zhou
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Pengfei Zhang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Institutes of Biomedical Sciences, Inner Mongolia University, Hohhot, China
| | - Guoliang Shao
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Liu L, Liu Q. Characterization of macrophages in head and neck squamous cell carcinoma and development of MRG-based risk signature. Sci Rep 2024; 14:9914. [PMID: 38688945 PMCID: PMC11061135 DOI: 10.1038/s41598-024-60516-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 04/24/2024] [Indexed: 05/02/2024] Open
Abstract
Macrophages are immune cells in the TME that can not only inhibit angiogenesis, extracellular matrix remodeling, cancer cell proliferation, and metastasis but also mediate the phagocytosis and killing of cancer cells after activation, making them key targets in anti-tumor immunotherapy. However, there is little research on macrophages and their relation to disease prognosis in HNSCC. Initially, we collected scRNA-seq, bulk RNA-seq, and clinical data. Subsequently, we identified macrophages and distinguished MRGs. Using the K-means algorithm, we performed consensus unsupervised clustering. Next, we used ssGSEA analysis to assess immune cell infiltration in MRG clusters. A risk model was established using multivariate Cox analysis. Then, Kaplan-Meier, ROC curves, univariate and multivariate COX analyses, and C-index was used to validate the predictive power of the signature. The TIDE method was applied to assess the response to immunotherapy in patients diagnosed with HNSCC. In addition, drug susceptibility predictions were made for the GDSC database using the calcPhenotype function. We found that 8 MRGs had prognostic potential. Patients in the MRG group A had a higher probability of survival, and MRG clusters A and B had different characteristics. Cluster A had a higher degree of expression and infiltration in MRG, indicating a closer relationship with MRG. The accuracy of the signature was validated using univariate and multivariate Cox analysis, C-index, and nomogram. Immune landscape analysis found that various immune functions were highly expressed in the low-risk group, indicating an improved response to immunotherapy. Finally, drugs with high sensitivity to HNSCC (such as 5-Fluorouracil, Temozolomide, Carmustine, and EPZ5676) were explored and analyze the malignant characteristics of HNSCC. We constructed a prognostic model using multivariate Cox analysis, consisting of 8 MRGs (TGM2, STC1, SH2D3C, PIK3R3, MAP3K8, ITGA5, ARHGAP4, and AQP1). Patients in the low-risk group may have a higher response to immunotherapy. The more prominent drugs for drug selection are 5-fluorouracil, temozolomide and so on. Malignant features associated with HNSCC include angiogenesis, EMT, and the cell cycle. This study has opened up new prospects for the prognosis, prediction, and clinical treatment strategy of HNSCC.
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Affiliation(s)
- Lei Liu
- Department of Otorhinolaryngology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Qiang Liu
- Department of Otorhinolaryngology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China.
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Watanabe T, Honma Y, Yonemori K, Sunami K, Yoshimoto S, Mori T. High-grade intraductal carcinoma of the parotid gland harboring CTNNA1::ALK rearrangement: Changes in genetic status using genetic testing during treatment with an ALK inhibitor. Head Neck 2024; 46:E26-E31. [PMID: 38018800 DOI: 10.1002/hed.27587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/02/2023] [Accepted: 11/11/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Salivary gland carcinomas harboring anaplastic lymphoma kinase (ALK) rearrangements are rare. Here, we present the pathological characteristics, clinical course, and changes in the genetic status of a salivary gland carcinoma harboring a catenin alpha 1 (CTNNA1)::ALK rearrangement during treatment with an ALK tyrosine kinase inhibitor (TKI). METHODS A 59-year-old man with a parotid tumor and cervical lymph node metastases underwent total parotidectomy and radical neck dissection. One month after completion of postoperative radiotherapy, the patient experienced multiple recurrences. RESULTS Subsequent treatment with the ALK-TKI alectinib was initially effective against the intraductal carcinoma harboring CTNNA1::ALK rearrangement and TP53 mutation. However, 10 months later the patients' condition deteriorated, and an additional phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation was detected. The patient ultimately succumbed to multiple organ failure. CONCLUSION The clinical course suggested the concurrent emergence of TP53 and PIK3CA mutations and ALK-TKI drug-selective growth of non-ALK rearrangement gene tumor cells.
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Affiliation(s)
- Takane Watanabe
- Department of Head and Neck Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshitaka Honma
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kan Yonemori
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kuniko Sunami
- Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Seiichi Yoshimoto
- Department of Head and Neck Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Taisuke Mori
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
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Padam KSR, Chakrabarty S, Hunter KD, Radhakrishnan R. Exploring the regulatory interactions between mutated genes and homeobox genes in the head and neck cancer progression. Arch Oral Biol 2024; 159:105872. [PMID: 38147801 DOI: 10.1016/j.archoralbio.2023.105872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/06/2023] [Accepted: 12/11/2023] [Indexed: 12/28/2023]
Abstract
OBJECTIVE Understanding the regulatory role of homeobox (HOX) and mutated genes in the progression of head and neck cancers is essential, although their interaction remains elusive. This study aims to decipher the critical regulation of mutation driven effects on homeobox genes to enhance our understanding of head and neck cancer progression. METHODS Genomic mutation data from The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma were analyzed using VarScan2 for somatic variant detection. Mutational clustering, driver mutation identification, and cancer signaling pathway analysis were performed using the OncodriveCLUST method. Harmonizome datasets were retrieved to identify critical cancer driver genes affecting HOX genes. The effects of HPV infection on HOX and mutated genes were assessed using the oncoviral database. Altered pathway activity due to the effects of cancer drivers on HOX genes was analyzed with Gene Set Cancer Analysis. Functional enrichment analysis of gene ontology biological processes and molecular functions was conducted using the ClusterProfiler R package. RESULTS Significant alterations in HOX genes were observed in head and neck cancer cohorts with mutated TP53, FAT1, and CDKN2A. HOX genes were identified as functionally downstream targets of TP53, signifying transcriptionally mediated regulation. The interaction between HOX genes and mutated TP53, FAT1, and CDKN2A dysregulated the epithelial-to-mesenchymal transition, cell cycle, and apoptosis pathways in head and neck cancer progression. CONCLUSION The interplay between cancer driver genes and HOX genes is pivotal in regulating the oncogenic processes underlying the pathogenesis of head and neck squamous cell carcinoma.
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Affiliation(s)
- Kanaka Sai Ram Padam
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Keith D Hunter
- Liverpool Head and Neck Centre, Molecular and Clinical Cancer Medicine, University of Liverpool, UK
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, India; Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, UK.
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Zhu Y, Peng B, Luo X, Sun W, Liu D, Li N, Qiu P, Long G. High-Resolution Profiling of Head and Neck Squamous Cells Carcinoma Identifies Specific Biomarkers and Expression Subtypes of Clinically Relevant Vulnerabilities. Curr Med Chem 2024; 31:2431-2448. [PMID: 37936459 DOI: 10.2174/0109298673276128231031112655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/18/2023] [Accepted: 10/24/2023] [Indexed: 11/09/2023]
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSC) is the seventh most common cancer worldwide. Although there are several options for the treatment of HNSC, there is still a lack of better biomarkers to accurately predict the response to treatment and thus be more able to correctly treat the therapeutic modality. METHODS First, we typed cases from the TCGA-HNSC cohort into subtypes by a Bayesian non-negative matrix factorization (BayesNMF)-based consensus clustering approach. Subsequently, genomic and proteomic data from HNSC cell lines were integrated to identify biomarkers of response to targeted therapies and immunotherapies. Finally, associations between HNSC subtypes and CD8 T-cell-associated effector molecules, common immune checkpoint genes, were compared to assess the potential of HNSC subtypes as clinically predictive immune checkpoint blockade therapy. RESULTS The 500 HNSC cases from TCGA were put through a consensus clustering approach to identify six HNSC expression subtypes. In addition, subtypes with unique proteomics and dependency profiles were defined based on HNSC cell line histology and proteomics data. Subtype 4 (S4) exhibits hyperproliferative and hyperimmune properties, and S4-associated cell lines show specific vulnerability to ADAT2, EIF5AL1, and PAK2. PD-L1 and CASP1 inhibitors have therapeutic potential in S4, and we have also demonstrated that S4 is more responsive to immune checkpoint blockade therapy. CONCLUSION Overall, our HNSC typing approach identified robust tumor-expressing subtypes, and data from multiple screens also revealed subtype-specific biology and vulnerabilities. These HNSC expression subtypes and their biomarkers will help develop more effective therapeutic strategies.
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Affiliation(s)
- Yingying Zhu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bi Peng
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaoxiao Luo
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wei Sun
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dongbo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Na Li
- Department of Medical, Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, Shenzhen, 518038, China
| | - Ping Qiu
- Department of Medical, Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, Shenzhen, 518038, China
| | - Guoxian Long
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
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11
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Wei M, Zhi J, Li L, Wang W. Predicting therapeutic responses in head and neck squamous cell carcinoma from TP53 mutation detected by cell-free DNA. Transl Cancer Res 2023; 12:3604-3617. [PMID: 38197078 PMCID: PMC10774070 DOI: 10.21037/tcr-23-878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 10/08/2023] [Indexed: 01/11/2024]
Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is an epithelial malignant tumor originating from the oral cavity, oropharynx, nasal cavity, sinuses, nasopharynx, hypopharynx, or larynx. Mutations in TP53 are the most common of all somatic genomic changes in HNSCC, and TP53 mutations are associated with the response to immunotherapy and chemotherapy. Tumor-derived circulating cell-free DNA (cfDNA) is a minimally invasive method to determining genetic alterations in cancer. This study aimed to explore the therapeutic responses of patients with HNSCC with TP53 mutation and the accuracy of cfDNA for detecting TP53 mutation. Methods Information on TP53 mutations, patient survival time, and clinical data in HNSCC were downloaded from The Cancer Genome Atlas database. The difference in immune infiltration between the TP53-mutant group and the wild-type group was compared. We applied the single-sample gene set enrichment analysis method on the transcriptome of HNSCC samples to assess the distribution of immune cell types between the two groups. The chemotherapy response was constructed using the R software package, "pRRophetic". Gene set enrichment analysis was performed based on the TP53 mutation. The next-generation sequencing was executed on cfDNA from nine patients with HNSCC to detect genetic alterations. Tumor biopsy (n=9) was sequenced using the same technique. Results TP53 was the most frequently mutated gene in HNSCC. The TP53 mutation was related to immune cells and the expression of immune-associated genes. The TP53 mutation group showed lower response to immunotherapy but high sensitivity to some chemotherapies compared with the wild-type group. TP53 was the most frequently mutated gene (6/9; 66.67%) in cfDNA. Only 27.27% of TP53 mutations in tumor tissue were detected outside of cfDNA. Conclusions TP53 mutation could be used as a specific predictor of treatment response in patients with HNSCC. Using cfDNA to detect the TP53 mutations in patients with HSNCC is a feasible method. The results suggested that the therapeutic response in patients could be predicted by detecting TP53 mutations in cfDNA, and large-scale and prospective studies are needed to validate this hypothesis.
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Affiliation(s)
- Mei Wei
- Department of Otorhinolaryngology Head and Neck Surgery, Tianjin First Central Hospital, Tianjin, China
- Institute of Otolaryngology of Tianjin, Tianjin First Central Hospital, Tianjin, China
- Key Laboratory of Auditory Speech and Balance Medicine, Tianjin First Central Hospital, Tianjin, China
- Key Clinical Discipline of Tianjin (Otolaryngology), Tianjin First Central Hospital, Tianjin, China
- Otolaryngology Clinical Quality Control Centre, Tianjin First Central Hospital, Tianjin, China
| | - Jingtai Zhi
- Department of Otorhinolaryngology Head and Neck Surgery, Tianjin First Central Hospital, Tianjin, China
- Institute of Otolaryngology of Tianjin, Tianjin First Central Hospital, Tianjin, China
- Key Laboratory of Auditory Speech and Balance Medicine, Tianjin First Central Hospital, Tianjin, China
- Key Clinical Discipline of Tianjin (Otolaryngology), Tianjin First Central Hospital, Tianjin, China
- Otolaryngology Clinical Quality Control Centre, Tianjin First Central Hospital, Tianjin, China
| | - Li Li
- Department of Otorhinolaryngology Head and Neck Surgery, Tianjin First Central Hospital, Tianjin, China
- Institute of Otolaryngology of Tianjin, Tianjin First Central Hospital, Tianjin, China
- Key Laboratory of Auditory Speech and Balance Medicine, Tianjin First Central Hospital, Tianjin, China
- Key Clinical Discipline of Tianjin (Otolaryngology), Tianjin First Central Hospital, Tianjin, China
- Otolaryngology Clinical Quality Control Centre, Tianjin First Central Hospital, Tianjin, China
| | - Wei Wang
- Department of Otorhinolaryngology Head and Neck Surgery, Tianjin First Central Hospital, Tianjin, China
- Institute of Otolaryngology of Tianjin, Tianjin First Central Hospital, Tianjin, China
- Key Laboratory of Auditory Speech and Balance Medicine, Tianjin First Central Hospital, Tianjin, China
- Key Clinical Discipline of Tianjin (Otolaryngology), Tianjin First Central Hospital, Tianjin, China
- Otolaryngology Clinical Quality Control Centre, Tianjin First Central Hospital, Tianjin, China
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12
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Mishra MK, Gupta S, Shivangi, Sharma M, Sehgal S. The repertoire of mutational signatures in tobacco- and non-tobacco-induced oral cancer. Clin Transl Oncol 2023; 25:3332-3344. [PMID: 37058208 DOI: 10.1007/s12094-023-03192-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 04/04/2023] [Indexed: 04/15/2023]
Abstract
The use of tobacco products is one of the established contributors toward the development and spread of oral cancer. Additionally, recent research has indicated oral microbiome, infections with Human papilloma virus (HPV), Epstein-Barr virus (EBV), Candida as significant contributing factors to this disease along with lifestyle habits. Deregulation of cellular pathways envisaging metabolism, transcription, translation, and epigenetics caused by these risk factors either individually or in unison is manifold, resulting in the increased risk of oral cancer. Globally, this cancer continues to exist as one of the major causes of cancer-related mortalities; the numbers in the developing South Asian countries clearly indicate yearly escalation. This review encompasses the variety of genetic modifications, including adduct formation, mutation (duplication, deletion, and translocation), and epigenetic changes evident in oral squamous cell carcinoma (OSCC). In addition, it highlights the interference caused by tobacco products in Wnt signaling, PI3K/Akt/mTOR, JAK-STAT, and other important pathways. The information provided also ensures a comprehensive and critical revisit to non-tobacco-induced OSCC. Extensive literature survey and analysis has been conducted to generate the chromosome maps specifically highlighting OSCC-related mutations with the potential to act as spectacles for the early diagnosis and targeted treatment of this disease cancer.
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Affiliation(s)
- Manish Kumar Mishra
- Centre for Molecular Biology, Central University of Jammu, Jammu, J&K, India
| | - Sachin Gupta
- Department of ENT and Head and Neck Surgery, ASCOMS, Jammu, J&K, India
| | - Shivangi
- Centre for Molecular Biology, Central University of Jammu, Jammu, J&K, India
| | - Manshi Sharma
- Centre for Molecular Biology, Central University of Jammu, Jammu, J&K, India
| | - Shelly Sehgal
- Centre for Molecular Biology, Central University of Jammu, Jammu, J&K, India.
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Pan Q, Portelli S, Nguyen TB, Ascher DB. Characterization on the oncogenic effect of the missense mutations of p53 via machine learning. Brief Bioinform 2023; 25:bbad428. [PMID: 38018912 PMCID: PMC10685404 DOI: 10.1093/bib/bbad428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 10/13/2023] [Accepted: 11/05/2023] [Indexed: 11/30/2023] Open
Abstract
Dysfunctions caused by missense mutations in the tumour suppressor p53 have been extensively shown to be a leading driver of many cancers. Unfortunately, it is time-consuming and labour-intensive to experimentally elucidate the effects of all possible missense variants. Recent works presented a comprehensive dataset and machine learning model to predict the functional outcome of mutations in p53. Despite the well-established dataset and precise predictions, this tool was trained on a complicated model with limited predictions on p53 mutations. In this work, we first used computational biophysical tools to investigate the functional consequences of missense mutations in p53, informing a bias of deleterious mutations with destabilizing effects. Combining these insights with experimental assays, we present two interpretable machine learning models leveraging both experimental assays and in silico biophysical measurements to accurately predict the functional consequences on p53 and validate their robustness on clinical data. Our final model based on nine features obtained comparable predictive performance with the state-of-the-art p53 specific method and outperformed other generalized, widely used predictors. Interpreting our models revealed that information on residue p53 activity, polar atom distances and changes in p53 stability were instrumental in the decisions, consistent with a bias of the properties of deleterious mutations. Our predictions have been computed for all possible missense mutations in p53, offering clinical diagnostic utility, which is crucial for patient monitoring and the development of personalized cancer treatment.
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Affiliation(s)
- Qisheng Pan
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane Queensland 4072, Australia
- Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne Victoria 3004, Australia
| | - Stephanie Portelli
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane Queensland 4072, Australia
- Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne Victoria 3004, Australia
| | - Thanh Binh Nguyen
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane Queensland 4072, Australia
- Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne Victoria 3004, Australia
| | - David B Ascher
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane Queensland 4072, Australia
- Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne Victoria 3004, Australia
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14
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Sun H, Zhang H, Jing L, Zhao H, Chen B, Song W. FBP1 is a potential prognostic biomarker and correlated with tumor immunosuppressive microenvironment in glioblastoma. Neurosurg Rev 2023; 46:187. [PMID: 37507483 DOI: 10.1007/s10143-023-02097-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 07/10/2023] [Accepted: 07/22/2023] [Indexed: 07/30/2023]
Abstract
Hypoxia has been shown to contribute to tumor immunosuppressive microenvironment and is an effective prognostic indicator. This study aimed to screen prognostic hypoxia-related genes (HRGs) in glioblastoma and investigate the association between HRGs and tumor immunosuppressive microenvironment. The glioblastoma-related mRNA data were collected from TCGA, GEO, and CGGA databases. Totally 200 HRGs were obtained from the GSEA website. The prognostic HRGs were screened by univariate Cox regression analysis. Somatic mutation data of glioblastoma from TCGA was visualized using the "maftools" of R package. Immune cell infiltration proportions were calculated by CIBERSORT. The TISIDB online tool was applied to analyze the relationship between HRGs and immunoinhibitors as well as the HRG expression in different glioblastoma immune and molecular subtypes. Hub gene's mRNA and protein levels in cell lines were determined by qRT-PCR and western blot, respectively. The effects of hub gene knockdown on cell viability and migration ability were evaluated employing CCK8 and wound healing assays. The univariate Cox regression showed that high level of FBP1 (fructose-1,6-bisphosphatase 1) was a poor prognostic biomarker, and FBP1 was mainly expressed in lymphocyte depleted immune subtype of glioblastoma. High FBP1 mRNA and protein levels have been successfully validated in vitro. The somatic mutation analysis suggested that TP53 mutation rate was the highest in the high FBP1 glioblastoma group, while EGFR mutation rate was the highest in the low FBP1 glioblastoma group. In the high FBP1 group, the infiltration proportions and types of immune cells were less, dominated by macrophages M2, and the expression of CTLA4, LAG3, TIGIT, PDL1, and PDL2 was significantly upregulated. The expression of FBP1 was positively correlated with several immunoinhibitors, such as IL-10 and TGFβ-1. In conclusion, we demonstrated that FBP1 could serve as a prognostic biomarker for glioblastoma. The immune microenvironment in the high FBP1 group might be suppressed by up-regulating immune checkpoints and immunoinhibitors.
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Affiliation(s)
- Hu Sun
- Department of Neurosurgery, Zibo Central Hospital, 255000 Zibo, Shandong, China
| | - Hui Zhang
- Department of Cardiology, Zibo Central Hospital, 255000 Zibo, Shandong, China
| | - Lijie Jing
- Department of Neurosurgery, Zibo Central Hospital, 255000 Zibo, Shandong, China
| | - Hao Zhao
- Department of Neurosurgery, Zibo Central Hospital, 255000 Zibo, Shandong, China
| | - Bing Chen
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Huangdao District, Qingdao, 266000, Shandong, China.
| | - Wei Song
- Department of Breast and Thyroid Surgery, Zibo Central Hospital, No. 54 Gongqingtuan West Road, 255000 Zibo, Qingdao, Shandong, China.
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15
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Ji JH, Ha SY, Lee D, Sankar K, Koltsova EK, Abou-Alfa GK, Yang JD. Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:7640. [PMID: 37108802 PMCID: PMC10144688 DOI: 10.3390/ijms24087640] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has one of the highest mortality rates among solid cancers. Late diagnosis and a lack of efficacious treatment options contribute to the dismal prognosis of HCC. Immune checkpoint inhibitor (ICI)-based immunotherapy has presented a new milestone in the treatment of cancer. Immunotherapy has yielded remarkable treatment responses in a range of cancer types including HCC. Based on the therapeutic effect of ICI alone (programmed cell death (PD)-1/programmed death-ligand1 (PD-L)1 antibody), investigators have developed combined ICI therapies including ICI + ICI, ICI + tyrosine kinase inhibitor (TKI), and ICI + locoregional treatment or novel immunotherapy. Although these regimens have demonstrated increasing treatment efficacy with the addition of novel drugs, the development of biomarkers to predict toxicity and treatment response in patients receiving ICI is in urgent need. PD-L1 expression in tumor cells received the most attention in early studies among various predictive biomarkers. However, PD-L1 expression alone has limited utility as a predictive biomarker in HCC. Accordingly, subsequent studies have evaluated the utility of tumor mutational burden (TMB), gene signatures, and multiplex immunohistochemistry (IHC) as predictive biomarkers. In this review, we aim to discuss the current state of immunotherapy for HCC, the results of the predictive biomarker studies, and future direction.
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Affiliation(s)
- Jun Ho Ji
- Division of Hematology and Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Republic of Korea
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Sang Yun Ha
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
| | - Danbi Lee
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Kamya Sankar
- Division of Medical Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ekaterina K. Koltsova
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Weil Cornell Medicine, Cornell University, New York, NY 14853, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Afshari K, Sohal KS. Potential Alternative Therapeutic Modalities for Management Head and Neck Squamous Cell Carcinoma: A Review. Cancer Control 2023; 30:10732748231185003. [PMID: 37328298 DOI: 10.1177/10732748231185003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/18/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) includes malignancies of the lip and oral cavity, oropharynx, nasopharynx, larynx, and hypopharynx. It is among the most common malignancy worldwide, affecting nearly 1 million people annually. The traditional treatment options for HNSCC include surgery, radiotherapy, and conventional chemotherapy. However, these treatment options have their specific sequelae, which produce high rates of recurrence and severe treatment-related disabilities. Recent technological advancements have led to tremendous progress in understanding tumor biology, and hence the emergence of several alternative therapeutic modalities for managing cancers (including HNSCC). These treatment options are stem cell targeted therapy, gene therapy, and immunotherapy. Therefore, this review article aims to provide an overview of these alternative treatments of HNSCC.
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Affiliation(s)
- Keihan Afshari
- Department of Oral and Maxillofacial Surgery, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | - Karpal Singh Sohal
- Department of Oral and Maxillofacial Surgery, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
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17
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Qu T, Miao C, Zhang Z, Li H, Liu L, Lin W, Li C, Pan J, Ye L, Cao Y. Prognostic signature of endoplasmic reticulum stress-related long noncoding RNAs in head and neck squamous cell carcinoma: Association with somatic mutation and tumor immune microenvironment. J Dent Sci 2022; 18:541-550. [PMID: 37021255 PMCID: PMC10068581 DOI: 10.1016/j.jds.2022.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/06/2022] [Indexed: 10/14/2022] Open
Abstract
Background/purpose Analysis of endoplasmic reticulum stress (ERS)-related long noncoding RNAs (LncRNAs) may enable prognostic stratification in patients with head and neck squamous cell carcinoma (HNSCC). This study aimed to comprehensively analyze the ERS-related LncRNAs signature and its effects on the prognosis, tumorigenesis, and tumor immune microenvironment in HNSCC. Materials and methods The transcriptome data of HNSCC were obtained from TCGA. Least absolute shrinkage selection operator algorithm, and multivariate Cox regression were used to screen LncRNAs for the signature construction. Somatic mutation, gene enrichment, and immune infiltration analyses were further performed. Results 458 ERS-related LncRNAs were identified and 55 of which were correlated with HNSCC prognosis. Ten ERS-related LncRNAs were selected to establish a risk prediction signature. When dividing patients into high-risk and low-risk groups by signature score, high-risk group correlated with worse survival rates (hazard ratio = 1.211; 95% confidence interval 1.123-1.306, P < 0.001). The area under the curve was 0.751 and 0.716 in the training and validation cohorts at 3-year. Moreover, high-risk group have increased somatic mutation rates and reduced infiltration abundancy of B cells and CD8+ T cells. Conclusion The prognostic signature based on ERS-related LncRNAs may serve as a predictor of altered oncogene mutations and immune microenvironment, which provided an insight into the relationship between ERS, LncRNAs, and tumor progression.
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18
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Issa M, Klamer BG, Mladkova N, Laliotis GI, Karivedu V, Bhateja P, Byington C, Dibs K, Pan X, Chakravarti A, Grecula J, Jhawar SR, Mitchell D, Baliga S, Old M, Carrau RL, Rocco JW, Blakaj DM, Bonomi M. Update of a prognostic survival model in head and neck squamous cell carcinoma patients treated with immune checkpoint inhibitors using an expansion cohort. BMC Cancer 2022; 22:767. [PMID: 35836204 PMCID: PMC9284772 DOI: 10.1186/s12885-022-09809-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/14/2022] [Indexed: 11/15/2022] Open
Abstract
Background Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. Methods A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. Results 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. Conclusions Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.
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Affiliation(s)
- Majd Issa
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA.
| | - Brett G Klamer
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA
| | - Nikol Mladkova
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Georgios I Laliotis
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University, Baltimore, MD, 21231, USA
| | - Vidhya Karivedu
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Priyanka Bhateja
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Chase Byington
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Khaled Dibs
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Xueliang Pan
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA
| | - Arnab Chakravarti
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - John Grecula
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Sachin R Jhawar
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Darrion Mitchell
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Sujith Baliga
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Matthew Old
- Department of Otolaryngology - Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Ricardo L Carrau
- Department of Otolaryngology - Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - James W Rocco
- Department of Otolaryngology - Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Dukagjin M Blakaj
- Division of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Marcelo Bonomi
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
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Abstract
Background: Mutation of p53 is a frequent event, and mutant p53 exhibits low levels of acetylation and phosphorylation. This study aimed to investigate the effect of the histone deacetylase (HDAC) inhibitor, 4-hexylresorcinol (4HR), on the acetylation and phosphorylation of mutant p53 carcinoma cells and its therapeutic effects in a xenograft model. Methods: To determine the effect of 4HR on the acetylation and phosphorylation of p53, western blot analysis was performed using YD-9 and YD-15 cells. p53 siRNA was used to examine whether 4HR acts in a p53-dependent or independent manner. This was evaluated using a xenograft model. Results: In in vitro experiments when the concentration of 4HR was increased, the expression levels of HDAC4, acetylated p53 (Ac-p53), and phosphorylated p53 (p-p53) increased. Transfection with TP53 siRNA successfully suppressed p53 protein and TP53 mRNA expression. When 4HR was administered to a xenograft model, the tumour expansion rate was suppressed compared with the control, and the mice exhibited a higher survival rate. Conclusions: Our findings reveal that 4HR is a potential agent that restores loss of function in mutant p53 cancer cells via acetylation and phosphorylation of p53 as well as inhibition of HDAC4.
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Cai BH, Bai ZY, Lien CF, Yu SJ, Lu RY, Wu MH, Wu WC, Chen CC, Hsu YC. NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner. Biomolecules 2022; 12:biom12030438. [PMID: 35327630 PMCID: PMC8946684 DOI: 10.3390/biom12030438] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 01/25/2023] Open
Abstract
The p53 family has the following three members: p53, p63 and p73. p53 is a tumor suppressor gene that frequently exhibits mutation in head and neck cancer. Most p53 mutants are loss-of-function (LoF) mutants, but some acquire some oncogenic function, such as gain of function (GoF). It is known that the aggregation of mutant p53 can induce p53 GoF. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53 mutation cells, but we found that p73 activators were not effective in all head and neck squamous cell carcinoma (HNSCC) cell lines, with different p53 mutants. A comparison of the gene expression profiles of several regulator(s) in mutant HNSCC cells with or without aggregation of p53 revealed that nicotinamide phosphoribosyltransferase (NAMPT) is a key regulator of mutant p53 aggregation. An NAMPT inhibitor, to reduce abnormal aggregation of mutant p53, used in combination with a p73 activator, was able to effectively repress growth in HNSCC cells with p53 GoF mutants. This study, therefore, suggests a potential combination therapy approach for HNSCC with a p53 GoF mutation.
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Affiliation(s)
- Bi-He Cai
- School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan; (C.-F.L.); (M.-H.W.)
- Correspondence: (B.-H.C.); (C.-C.C.); (Y.-C.H.)
| | - Zhi-Yu Bai
- Department of Medical Laboratory Science, I-Shou University, Kaohsiung 82445, Taiwan; (Z.-Y.B.); (S.-J.Y.); (R.-Y.L.)
| | - Ching-Feng Lien
- School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan; (C.-F.L.); (M.-H.W.)
- Department of Otolaryngology-Head and Neck Surgery, E-DA Hospital, Kaohsiung 82445, Taiwan
| | - Si-Jie Yu
- Department of Medical Laboratory Science, I-Shou University, Kaohsiung 82445, Taiwan; (Z.-Y.B.); (S.-J.Y.); (R.-Y.L.)
| | - Rui-Yu Lu
- Department of Medical Laboratory Science, I-Shou University, Kaohsiung 82445, Taiwan; (Z.-Y.B.); (S.-J.Y.); (R.-Y.L.)
| | - Ming-Han Wu
- School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan; (C.-F.L.); (M.-H.W.)
| | - Wei-Chen Wu
- Department of Physical Therapy, I-Shou University, Kaohsiung 82445, Taiwan;
| | - Chia-Chi Chen
- Department of Pathology, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan
- Correspondence: (B.-H.C.); (C.-C.C.); (Y.-C.H.)
| | - Yi-Chiang Hsu
- School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan; (C.-F.L.); (M.-H.W.)
- Correspondence: (B.-H.C.); (C.-C.C.); (Y.-C.H.)
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