Differential expression of a novel serine protease homologue in squamous cell carcinoma of the head and neck

Abstract Background Radiotherapy (RT) with concomitant chemotherapy (CTRT) is the standard treatment for advanced head and neck squamous cell carcinoma (HNSCC). Despite advancements in treatment, a significant proportion of patients develop local recurrence and/or metastasis indicating resistance to treatment. Early identification of radio-resistant tumors using predictive and prognostic biomarkers is an important goal. We used a quantitative serum proteomics platform to evaluate the differential expression of proteins in HNSCC patients treated with CTRT. Methods Fifty patients with biopsy-proven, HPV-negative, squamous cell carcinoma of the oropharynx and larynx, undergoing curative CTRT were included in this prospective, IRB-approved study. Serum samples were collected before the start of RT (PreRT), 48 hours after RT (48hrsRT), and 1week after RT (1WeekRT). Patients were classified as “good responders” or “poor responders” based on their clinical outcome at follow-up. Relative quantitation of serum was carried out by iTRAQ to identify differentially expressed proteins. A total of 180–200 proteins were identified, of which twenty proteins showed more than 1.5 fold differential expression. PreRT protein expression levels were compared across good and poor responders to identify proteins with prognostic potential. Differential expression of proteins during RT was analyzed to identify proteins with predictive potential. Finally, twelve proteins were validated using targeted mass spectrometry in ten good and poor responders. Results A 1.5–2.5 fold pre-treatment upregulation of clusterin, gelsolin, extracellular matrix proteins, and proteins of the IGF pathway was observed in poor responders. A 2.0–5.0 fold upregulation of S100 proteins, clusterin, gelsolin, extracellular matrix proteins, IGF1, IGF2, and IGFBP3 was observed in poor responders within 48 hours to 1 week of starting RT. Conclusions The present results are the first report for a panel of twelve potential proteins that would help in early risk stratification and therapeutic prognosis of HNSCC treated with radiotherapy. The significant upregulation of clusterin and gelsolin at PreRT and within 48 hours to 1 week of starting RT, indicates their ability to act as prognostic and predictive markers, respectively. The panel of twelve proteins may facilitate the early identification of patients who are most likely to develop resistance to radiotherapy.

Download Full-text

Differential expression of MUC1 and carbohydrate antigens in primary and secondary head and neck squamous cell carcinoma

Head & Neck ◽

10.1002/hed.20756 ◽

2008 ◽

Vol 30 (5) ◽

pp. 647-657 ◽

Cited By ~ 14

Author(s):

María V. Croce ◽

Martín E. Rabassa ◽

Adrián Pereyra ◽

Amada Segal-Eiras

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Differential Expression ◽

Squamous Cell ◽

Neck Squamous Cell Carcinoma ◽

Carbohydrate Antigens

Download Full-text

Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis

Cancers ◽

10.3390/cancers13174395 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4395

Author(s):

Elaine Zayas Marcelino da Silva ◽

Thais Fernanda de Campos Fraga-Silva ◽

Yao Yuan ◽

Márcia Gaião Alves ◽

Gabriel Azevedo Publio ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Serine Protease ◽

Squamous Cell ◽

Therapeutic Targets ◽

Epithelial Stem Cells ◽

Proteolytic Activation ◽

Proteolytic Pathway

Head and neck squamous cell carcinoma remains challenging to treat with no improvement in survival rates over the past 50 years. Thus, there is an urgent need to discover more reliable therapeutic targets and biomarkers for HNSCC. Matriptase, a type-II transmembrane serine protease, induces malignant transformation in epithelial stem cells through proteolytic activation of pro-HGF and PAR-2, triggering PI3K-AKT-mTOR and NFKB signaling. The serine protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI) inhibits the matriptase-driven proteolytic pathway, directly blocking kallikreins in epithelial differentiation. Hence, we hypothesized LEKTI could inhibit matriptase-dependent squamous cell carcinogenesis, thus implicating kallikreins in this process. Double-transgenic mice with simultaneous expression of matriptase and LEKTI under the keratin-5 promoter showed a prominent rescue of K5-Matriptase+/0 premalignant phenotype. Notably, in DMBA-induced SCC, heterotopic co-expression of LEKTI and matriptase delayed matriptase-driven tumor incidence and progression. Co-expression of LEKTI reverted altered Kallikrein-5 expression observed in the skin of K5-Matriptase+/0 mice, indicating that matriptase-dependent proteolytic pathway inhibition by LEKTI occurs through kallikreins. Moreover, we showed that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. Collectively, our data identify a third signaling pathway for matriptase-dependent carcinogenesis in vivo. These findings are critical for the identification of more reliable biomarkers and effective therapeutic targets in Head and Neck cancer.

Download Full-text

Identification of Prognosis Associated microRNAs in HNSCC Subtypes Based on TCGA Dataset

Medicina ◽

10.3390/medicina56100535 ◽

2020 ◽

Vol 56 (10) ◽

pp. 535

Author(s):

Cintia M. Chamorro Petronacci ◽

Abel García García ◽

Elena Padín Iruegas ◽

Berta Rivas Mundiña ◽

Alejandro I. Lorenzo Pouso ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Differential Expression ◽

Signaling Pathway ◽

Squamous Cell ◽

Expression Patterns ◽

Differential Expression Analysis ◽

Neck Squamous Cell Carcinoma ◽

Altered Expression

Background and Objectives: Head and Neck Squamous Cell Carcinoma (HNSCC) includes cancers from the oral cavity, larynx, and oropharynx and is the sixth-most common cancer worldwide. MicroRNAs are small non-coding RNAs for which altered expression has been demonstrated in pathological processes, such as cancer. The objective of our study was to evaluate the different expression profile in HNSCC subtypes and the prognostic value that one or several miRNAs may have. Materials and Methods: Data from The Cancer Genome Atlas Program-Head and Neck Squamous Cell Carcinoma (TCGA-HNSCC) patients were collected. Differential expression analysis was conducted by edge R-powered TCGAbiolinks R package specific function. Enrichment analysis was developed with Diana Tool miRPath 3.0. Kaplan-Meier survival estimators were used, followed by log-rank tests to compute significance. Results: A total of 127 miRNAs were identified with differential expression level in HNSCC; 48 of them were site-specific and, surprisingly, only miR-383 showed a similar deregulation in all locations studied (tonsil, mouth, floor of mouth, cheek mucosa, lip, tongue, and base of tongue). The most probable affected pathways based on miRNAs interaction levels were protein processing in endoplasmic reticulum, proteoglycans in cancer (p < 0.01), Hippo signaling pathway (p < 0.01), and Transforming growth factor-beta (TGF-beta) signaling pathway (p < 0.01). The survival analysis highlighted 38 differentially expressed miRNAs as prognostic biomarkers. The miRNAs with a greater association between poor prognosis and altered expression (p < 0.001) were miR-137, miR-125b-2, miR-26c, and miR-1304. Conclusions: In this study we have determined miR-137, miR-125b-2, miR-26c, and miR-1304 as novel powerful prognosis biomarkers. Furthermore, we have depicted the miRNAs expression patterns in tumor patients compared with normal subjects using the TCGA-HNSCC cohort.

Download Full-text