CEACAM5 inhibits the lymphatic metastasis of head and neck squamous cell carcinoma by regulating epithelial–mesenchymal transition via inhibiting MDM2

Abstract Lymph node (LN) metastasis affects both the management and prognosis of head and neck squamous cell carcinoma (HNSCC). Here, we explored the relationship between lymphatic metastasis and CEA family member 5 (CEACAM5), including its possible regulatory role in HNSCC. The levels of CEACAM5 in tissues from patients with HNSCC, with and without LN metastases, were assessed by transcriptome sequencing. The associations between CEACAM5 and the N stage of LN metastasis in HNSCC were predicted through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and a pan-cancer analysis of CEACAM5 expression in 33 common human tumors was conducted. CEACAM5 levels were analyzed in tumor and normal tissue specimens from HNSCC patients and the correlation between CEACAM5 levels and prognosis was evaluated. The influence of CEACAM5 on cell proliferation, invasion, migration, and apoptosis was investigated in HNSCC cell lines, as were the downstream regulatory mechanisms. A mouse model of LN metastasis was constructed. CEACAM5 levels were significantly higher in HNSCC tissue without LN metastasis than in that with LN metastasis. Similar findings were obtained for the clinical specimens. CEACAM5 levels were associated with better clinical prognosis. CEACAM5 was found to inhibit the proliferation and migration and promote the apoptosis of HNSCC cells. A mouse xenograft model showed that CEACAM5 inhibited LN metastasis. In conclusions, CEACAM5 inhibited epithelial–mesenchymal transition (EMT) in HNSCC by reducing murine double minute 2 (MDM2) expression and thereby suppressing LN metastasis. CEACAM5 has potential as both a prognostic marker and a therapeutic target in HNSCC.

[1]  J. O’Leary,et al.  The Role of HPV in Determining Treatment, Survival, and Prognosis of Head and Neck Squamous Cell Carcinoma , 2022, Cancers.

[2]  Xiaofeng Yang,et al.  Application and prospect of single-cell sequencing in cancer metastasis. , 2022, Future oncology.

[3]  Juan Wang,et al.  IDO1 plays a tumor-promoting role via MDM2-mediated suppression of the p53 pathway in diffuse large B-cell lymphoma , 2022, Cell Death & Disease.

[4]  A. Tyagi.  Underlying Facets of Cancer Metastasis , 2022, Cancers.

[5]  S. Narayan,et al.  Therapeutics Targeting p53-MDM2 Interaction to Induce Cancer Cell Death , 2022, International journal of molecular sciences.

[6]  D. Pegtel,et al.  More than a Bubble: Extracellular Vesicle microRNAs in Head and Neck Squamous Cell Carcinoma , 2022, Cancers.

[7]  Weiqi Wang,et al.  Downregulation of LNMAS orchestrates partial EMT and immune escape from macrophage phagocytosis to promote lymph node metastasis of cervical cancer , 2022, Oncogene.

[8]  D. Dimitrov,et al.  A highly-specific fully-human antibody and CAR-T cells targeting CD66e/CEACAM5 are cytotoxic for CD66e-expressing cancer cells in vitro and in vivo. , 2021, Cancer letters.

[9]  D. Zandberg,et al.  Immunotherapy in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck , 2021, Frontiers in Oncology.

[10]  Huijun Wei,et al.  Urolithin A Inhibits Epithelial–Mesenchymal Transition in Lung Cancer Cells via P53-Mdm2-Snail Pathway , 2021, OncoTargets and therapy.

[11]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[12]  Stephen N. Jones,et al.  Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis , 2021, Proceedings of the National Academy of Sciences.

[13]  Nadezhda T. Doncheva,et al.  The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets , 2020, Nucleic Acids Res..

[14]  R. Weber,et al.  Inclusion of extranodal extension in the lymph node classification of cutaneous squamous cell carcinoma of the head and neck , 2020, Cancer.

[15]  Shu-juan Xie,et al.  RNA sequencing: new technologies and applications in cancer research , 2020, Journal of Hematology & Oncology.

[16]  P. Nelson,et al.  Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5–SN38 Antibody–drug Conjugate in Neuroendocrine Prostate Cancer , 2020, Clinical Cancer Research.

[17]  Ji‐Hyun Lee,et al.  HPV/p16-positive oropharyngeal cancer treated with transoral robotic surgery: The roles of margins, extra-nodal extension and adjuvant treatment. , 2020, American journal of otolaryngology.

[18]  Keying Liu,et al.  F-box protein FBXO31 modulates apoptosis and epithelial-mesenchymal transition of cervical cancer via inactivation of the PI3K/AKT-mediated MDM2/p53 axis. , 2020, Life sciences.

[19]  Jingting Jiang,et al.  Circular RNA S-7 promotes ovarian cancer EMT via sponging miR-641 to up-regulate ZEB1 and MDM2 , 2020, Bioscience reports.

[20]  G. Hu,et al.  Gene sequencing and expression of Raf-1 in lymphatic metastasis of hypopharyngeal carcinoma. , 2020, Cancer biomarkers : section A of Disease markers.

[21]  R. Fisher,et al.  Head and Neck Squamous Cell Carcinoma , 2020, Definitions.

[22]  S. Karam,et al.  Radioimmunotherapy for the treatment of head and neck cancer. , 2019, The Lancet. Oncology.

[23]  Yun-Gui Yang,et al.  Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma , 2019, Cell Research.

[24]  V. Budach,et al.  Novel prognostic clinical factors and biomarkers for outcome prediction in head and neck cancer: a systematic review. , 2019, The Lancet. Oncology.

[25]  Xuhong Wang,et al.  BRAFV600E-induced KRT19 expression in thyroid cancer promotes lymph node metastasis via EMT , 2019, Oncology letters.

[26]  Othman Soufan,et al.  NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis , 2019, Nucleic Acids Res..

[27]  C. Blanpain,et al.  EMT Transition States during Tumor Progression and Metastasis. , 2019, Trends in cell biology.

[28]  D M Parkin,et al.  Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods , 2018, International journal of cancer.

[29]  Xuchen Cao,et al.  KRT19 and CEACAM5 mRNA-marked circulated tumor cells indicate unfavorable prognosis of breast cancer patients , 2018, Breast Cancer Research and Treatment.

[30]  L. Claesson‐Welsh,et al.  Cytokines regulating lymphangiogenesis. , 2018, Current opinion in immunology.

[31]  R. Satija,et al.  Single-cell RNA sequencing to explore immune cell heterogeneity , 2017, Nature Reviews Immunology.

[32]  Qiang He,et al.  Correlation between lymphatic endothelial markers and lymph node status or N-staging of colorectal cancer , 2017, World Journal of Surgical Oncology.

[33]  Shawn M. Gillespie,et al.  Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer , 2017, Cell.

[34]  Satoko Matsumura,et al.  Prognostic significance of surgical extranodal extension in head and neck squamous cell carcinoma patients , 2017, Japanese journal of clinical oncology.

[35]  J. Fuxe,et al.  Epithelial‐mesenchymal transition in cancer metastasis through the lymphatic system , 2017, Molecular oncology.

[36]  D. Gyorki,et al.  Prognostic markers in metastatic cutaneous squamous cell carcinoma of the head and neck , 2017, Head & neck.

[37]  Brian O'Sullivan,et al.  Head and neck cancers—major changes in the American Joint Committee on cancer eighth edition cancer staging manual , 2017, CA: a cancer journal for clinicians.

[38]  Stephen N. Jones,et al.  Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis. , 2016, Cell reports.

[39]  J. Carpten,et al.  Translating RNA sequencing into clinical diagnostics: opportunities and challenges , 2016, Nature Reviews Genetics.

[40]  A. Garden,et al.  Relation between the level of lymph node metastasis and survival in locally advanced head and neck squamous cell carcinoma , 2016, Cancer.

[41]  E. Mroz,et al.  Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas , 2015, PLoS medicine.

[42]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of head and neck squamous cell carcinomas , 2015, Nature.

[43]  C. Chung,et al.  Emerging biomarkers in head and neck cancer in the era of genomics , 2015, Nature Reviews Clinical Oncology.

[44]  Petar Stojanov,et al.  Integrative and Comparative Genomic Analysis of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas , 2014, Clinical Cancer Research.

[45]  Michael Detmar,et al.  Mechanisms of lymphatic metastasis. , 2014, The Journal of clinical investigation.

[46]  Samy Lamouille,et al.  Molecular mechanisms of epithelial–mesenchymal transition , 2014, Nature Reviews Molecular Cell Biology.

[47]  S. Stacker,et al.  Lymphangiogenesis and lymphatic vessel remodelling in cancer , 2014, Nature Reviews Cancer.

[48]  Jong Kuk Park,et al.  Mdm2 increases cellular invasiveness by binding to and stabilizing the Slug mRNA. , 2013, Cancer letters.

[49]  G. Berx,et al.  Regulatory networks defining EMT during cancer initiation and progression , 2013, Nature Reviews Cancer.

[50]  G. Wahl,et al.  MDM2, MDMX and p53 in oncogenesis and cancer therapy , 2013, Nature Reviews Cancer.

[51]  F. Janot,et al.  Sentinel node biopsy in early oral squamous cell carcinomas: A 10‐year experience , 2012, The Laryngoscope.

[52]  G. Meijer,et al.  Differential glycosylation of MUC1 and CEACAM5 between normal mucosa and tumour tissue of colon cancer patients , 2012, International journal of cancer.

[53]  Ker-Chau Li,et al.  p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug , 2009, Nature Cell Biology.

[54]  F. He,et al.  MDM2 Promoter SNP309 Is Associated with Risk of Occurrence and Advanced Lymph Node Metastasis of Nasopharyngeal Carcinoma in Chinese Population , 2007, Clinical Cancer Research.

[55]  C. Stanners,et al.  Recent advances in the tumour biology of the GPI-anchored carcinoembryonic antigen family members CEACAM5 and CEACAM6 , 2007, Current oncology.

[56]  D. Goldenberg,et al.  Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers , 2007, BMC Cancer.

[57]  D. Goldenberg,et al.  Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen). , 2005, Cancer research.

[58]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[59]  P. Chène.  Inhibiting the p53–MDM2 interaction: an important target for cancer therapy , 2003, Nature Reviews Cancer.

[60]  S. Taylor.  Head and neck cancer. , 1991, Cancer chemotherapy and biological response modifiers.

[61]  R. Spiro,et al.  Carcinoma of the hypopharynx. , 1976, American journal of surgery.