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Project description:Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) during target therapy. Yet the mechanism that caused cetuximab resistance, especially the miRNA regulation therein remains unclear. With growing evidence suggests that miRNAs may function within the cell nucleus and act as “nuclear activating miRNAs” for targeting the promoter region or enhancers related to target genes. They are believed to regulate diseases development including tumorigenesis. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, qRT-PCR and FISH results provide compelling evidence of miR-451a nuclear enrichment with cetuximab treatment. ChIRP-seq, microarray, bioinformatic analysis and dual luciferase reporter assay results show that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It is also demonstrated that activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Analyses of HNSCC samples through logistic regression indicated the significance of miR-451a and KDM7A in cetuximab resistance. These discoveries hold promise for the potential utilization of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear activating miRNAs.
2024-01-01 | GSE245153 | GEO
Project description:Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) during target therapy. Yet the mechanism that caused cetuximab resistance, especially the miRNA regulation therein remains unclear. With growing evidence suggests that miRNAs may function within the cell nucleus and act as “nuclear activating miRNAs” for targeting the promoter region or enhancers related to target genes. They are believed to regulate diseases development including tumorigenesis. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, qRT-PCR and FISH results provide compelling evidence of miR-451a nuclear enrichment with cetuximab treatment. ChIRP-seq, microarray, bioinformatic analysis and dual luciferase reporter assay results show that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It is also demonstrated that activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Analyses of HNSCC samples through logistic regression indicated the significance of miR-451a and KDM7A in cetuximab resistance. These discoveries hold promise for the potential utilization of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear activating miRNAs.
2024-01-01 | GSE244948 | GEO
Project description:Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma
| PRJNA1027272 | ENA
Project description:Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma [miRNA-Seq]
| PRJNA1026481 | ENA
Project description:Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma [ChIRP-seq]
| PRJNA1027257 | ENA
Project description:To filter the up-regulated gene induced by miR-451a overexpression and in cetuximab resistant HNSCC cell. We employed whole genome microarray. The HNSCC cell CAL27 was used as a control sample. CAL27_CTX, the cetuximab resistant CAL27 was compared with CAL27. The miR-451a overexpressed CAL27_451a sample was compared with the CAL27_NC sample. CAL27_CTX and CAL27_451A samples were collected after 48h of cetuximab treatment. The microarray results were taken together with ChIRP-seq analysis and bioinformatics analysis for miR-451a binding and enhancer analysis to eventually find the nuclear acticating target of miR-451a
2024-01-01 | GSE245159 | GEO
Project description:MicroRNAs (miRs) participate in tumor growth and dissemination by regulating expression of various target genes. MiR-223-3p is suspected of being involved in head and neck squamous cell carcinoma (HNSCC) growth although its precise role has not been elucidated. In this study, we showed that miR-223-3p is present in biopsies of HNSCC patients and that its presence is correlated with high neutrophil infiltrate. We found that overexpression of miR-223-3p slightly increased proliferation of the CAL27 squamous carcinoma cell line both in vitro and in vivo. Moreover, miR-223-3p induced CAL27 apoptosis in an orthotopic xenograft mouse model, counteracting the proliferative effect and resulting in no impact on overall tumor growth. We analyzed the effect of miR-223-3p overexpression on signaling pathways and showed that it induced pERK2, pAKT and AKT, consistent with an increase in cell proliferation. In addition, we found that miR-223-3p reduced the STAT3 level correlating with increased cell apoptosis and inhibited vasculature formation. In HNSCC tissues, miR-223-3p expression was inversely correlated to CD31, highlighting the relationship between miR-223 and vessel formation. Finally, we studied the effect of miR-223-3p on response to selected anticancer agents and showed that cells expressing miR-223-3p are more resistant to drugs, notably cetuximab. In conclusion, our study is the first to show the antiangiogenic properties of miR-223-3p in HNSCC patients and to question whether expression levels of miR-223-3p can be evaluated as an indicator of eligibility for non-treatment of HNSCC patients with cetuximab.
| S-EPMC5593634 | biostudies-literature
Project description:To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)-targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging.EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using (64)Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with (90)Y-DOTA-cetuximab.EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher (64)Cu-DOTA-cetuximab accumulation than the SCC1 tumors. Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to (90)Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody.Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles.
| S-EPMC2848903 | biostudies-other
Project description:Objective: In patients with head and neck squamous cell carcinoma (HNSCC), cetuximab [a monoclonal antibody targeting epidermal growth factor receptor (EGFR)] has been shown to improve overall survival when combined with radiotherapy in the locally advanced setting or with chemotherapy in first-line recurrent and/or metastatic (R/M) setting, respectively. While biomarkers of resistance to cetuximab have been identified in metastatic colorectal cancer, no biomarkers of efficacy have been identified in HNSCC. Here, we aimed to identify biomarkers of cetuximab sensitivity/resistance in HNSCC. Methods: HNSCC patients treated with cetuximab at the Curie Institute, for whom complete clinicopathological data and formalin-fixed paraffin-embedded (FFPE) tumor tissue collected before cetuximab treatment were available, were included. Immunohistochemistry analyses of PTEN and EGFR were performed to assess protein expression levels. PIK3CA and H/N/KRAS mutations were analyzed using high-resolution melting (HRM) and Sanger sequencing. We evaluated the predictive value of these alterations in terms of progression-free survival (PFS). Results: Hot spot activating PIK3CA and KRAS/HRAS mutations were associated with poor PFS among HNSCC patients treated with cetuximab in the first-line R/M setting, but not among HNSCC patients treated with cetuximab in combination with radiotherapy. Loss of PTEN protein expression had a negative predictive value among HNSCC patients treated with cetuximab and radiotherapy. High EGFR expression did not predict cetuximab sensitivity in our patient population. Conclusions: Hot spot activating PIK3CA and RAS mutations predicted cetuximab resistance among HNSCC patients in the first-line R/M setting, whereas loss of PTEN protein expression predicted resistance to cetuximab when combined to radiotherapy.
| S-EPMC7142836 | biostudies-literature
Project description:BACKGROUND:Mechanisms of resistance to immune-modulating cancer treatments are poorly understood. Using a novel cohort of patients with head and neck squamous cell carcinoma (HNSCC), we investigated mechanisms of immune escape from epidermal growth factor receptor-specific monoclonal antibody (mAb) therapy. METHODS:HNSCC tumors (n = 20) from a prospective trial of neoadjuvant cetuximab monotherapy underwent whole-exome sequencing. Expression of killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen-C (HLA-C) and the effect of KIR blockade were assessed in HNSCC cell lines. RESULTS:Nonresponders to cetuximab had an increased rate of mutations in HLA-C compared to responders and HNSCC tumors (n = 528) in The Cancer Genome Atlas (P < 0.00001). In vitro, cetuximab-activated natural killer (NK) cells induced upregulation of HLA-C on HNSCC cells (P < 0.01) via interferon gamma. Treatment of NK cells with the anti-KIR mAb lirilumab increased killing of HNSCC cells (P < 0.001). CONCLUSIONS:Alterations in HLA-C may provide a mechanism of immune evasion through disruption of NK activation.
| S-EPMC6625877 | biostudies-literature