Oral squamous cell carcinoma (OSCC) has increased morbidity, and its high metastatic potential affects patient survival. Bromodomain containing 4 (BRD4) is a chromatin protein that associates with ...acetylated histone lysines and facilitates transcription. BRD4 has been implicated in cell proliferation, metastasis, and prognosis in several types of cancer. However, the role of BRD4 in OSCC remains to be elucidated.
We investigated the role of BRD4 and its potential utility as a therapeutic target in OSCC.
JQ1, the BRD4 inhibitor, suppressed the cell proliferation, migration, and invasion in the OSCC cell lines and in vivo. JQ1 reduced the expression levels of 15 metastasis genes in OSCC, including matrix metallopeptidase 2 (MMP2). Our chromatin immunoprecipitation assay showed that JQ1 reduced the BRD4 binding to the histone H3 lysine 27 acetylation-enriched sites in the MMP2 locus. Analyses of biopsy specimens from OSCC patients revealed that the BRD4 and MMP2 expression levels were correlated in the cancerous regions, and both were highly expressed in lymph node metastasis cases, including delayed metastasis.
BRD4 contributes to metastasis in OSCC, through the epigenetic regulation of the MMP2 gene, and thus BRD4 may represent a therapeutic target and a novel prediction indicator for metastasis.
The peptides derived from ideal cancer-testis antigens, including LY6K, CDCA1, and IMP3 (identified using genome-wide cDNA microarray analyses), were used in immunotherapy for head and neck squamous ...cell cancer (HNSCC). In this trial, we analyzed the immune response to and safety and efficacy of vaccine therapy.
A total of 37 patients with advanced HNSCC were enrolled in this trial of peptide vaccine therapy, and the OS, PFS, and immunologic response were evaluated using enzyme-linked ImmunoSpot (ELISPOT) and pentamer assays. The peptides were subcutaneously administered weekly with IFA. The primary endpoints were evaluated on the basis of differences between HLA-A*2402-positive A24(+) patients treated with peptide vaccine therapy and -negative A24(-) patients treated without peptide vaccine therapy among those with advanced HNSCC.
Our cancer vaccine therapy was well tolerated. The OS of the A24(+) vaccinated group (n = 37) was statistically significantly longer than that of the A24(-) group (n = 18) and median survival time (MST) was 4.9 versus 3.5 months, respectively; P < 0.05. One of the patients exhibited a complete response. In the A24(+) vaccinated group, the ELISPOT assay identified LY6K-, CDCA1-, and IMP3-specific CTL responses in 85.7%, 64.3%, and 42.9% of the patients, respectively. The patients showing LY6K- and CDCA1-specific CTL responses demonstrated a longer OS than those without CTL induction. Moreover, the patients exhibiting CTL induction for multiple peptides demonstrated better clinical responses.
The immune response induced by this vaccine may improve the prognosis of patients with advanced HNSCC.
In promoting tumour malignancy IL-6 signalling is considered to have an important role. However, the biological roles of IL-6 on radiosensitivity in oral squamous cell carcinoma (OSCC) remain largely ...unclear. The objective of this study is to determine the effects and molecular mechanisms of IL-6 on radiosensitivity in OSCC.
Two OSCC cell lines, and OSCC tissue samples with radioresistant cells were used. We examined the effects of IL-6, or tocilizumab, a humanised anti-human IL-6 receptor antibody, or both on radiosensitivity and DNA damage after X-ray irradiation in vitro. In addition, we investigated the involvement of the Nrf2-antioxidant pathway in IL-6-mediated radioresistant mechanisms using OSCC cell lines and tissues.
Increased levels of IL-6 suppressed radiation-induced cell death, and the blockade of IL-6 signalling by tocilizumab sensitised tumour cells to radiation. The radioresistant effect of IL-6 was associated with decreased DNA damage after radiation. We also found that IL-6 promotes the activation of not only the downstream molecule STAT3 but also the Nrf2-antioxidant pathway, leading to a significant decrease in oxidative stress by upregulating Mn-SOD.
These results indicate that the blockade of IL-6 signalling combined with conventional radiotherapy could augment the treatment response and survival rate in patients with radioresistant OSCC.
Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy, ...which eliminates cancers effectively and safely, is the current clinical choice. Since aggressive tumors are substantially resistant to multidisciplinary therapies that target apoptosis, tumor-specific activation of another cell death modality is a promising avenue for meeting this goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can kill OS and OC by causing a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) based on its characteristic unipolar mitochondrial perinuclear accumulation. The APAM caused apoptotic and nonapoptotic cell death. The APAM increased mitochondrial ROS (mROS) and cell death, and the antioxidants such as
-acetylcysteine (NAC) prevented them. MPMC occurred following mitochondrial fragmentation, which coincided with nuclear damages. MPMC was accompanied by mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC, Ferrostatin-1, and Nocodazole. In contrast, the APAM induced minimal cell death, mROS generation, mLPO accumulation, and MPMC in fibroblasts. These results suggest that MPMC occurs in a tumor-specific manner via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC induction might serve as a promising target for exerting tumor-specific cytotoxicity.
Objectives
To evaluate the prognostic value of preoperative radiological findings for nodal recurrence in clinically node-negative (cN0) patients with oral tongue squamous cell carcinoma (SCC).
...Methods
The study population consisted of 52 patients with cT1-2N0 oral tongue SCC classified according to the 7th edition of the Union for International Cancer Control (UICC) staging system. The subjects had undergone preoperative radiological examinations, including magnetic resonance imaging (MRI) and
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F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography. All patients were treated with local resection and watchful waiting for neck management. Using an unpaired
t
test, Pearson’s chi-squared test, and the Kaplan–Meier method, the MRI-derived depth of invasion (DOI), the standardized uptake value (SUV) on FDG-PET, and the T stage according to the 7th and 8th UICC were assessed as prognostic factors.
Results
The MRI-derived DOI was recorded as ≤ 5 mm in 24 patients and > 5 mm in 28 patients. During the follow-up period, nine patients exhibited nodal recurrence, with the MRI-derived DOI being significantly higher in patients with positive than in those with negative (
p
= 0.011). The SUV was not significant. Five-year cumulative nodal recurrence probabilities were 4.5% for patients with an MRI-derived DOI ≤ 5 mm, while it was 32.1% for > 5 mm (
p
= 0.013). Although the T classifications were not significant, none of our patients whose T stage according to the 8th UICC was T1 suffered nodal recurrence.
Conclusions
MRI-derived DOI can predict nodal recurrence, while preoperative information may assist in treatment planning for oral tongue SCC.
The highly malignant phenotype of oral squamous cell carcinoma (OSCC), including the presence of nodal and distant metastasis, reduces patient survival. High-mobility group A protein 2 (HMGA2) is a ...non-histone chromatin factor that is involved in advanced malignant phenotypes and poor prognosis in several human cancers. However, its biological role in OSCC remains to be elucidated. The purpose of this study was to determine the clinical significance and role of HMGA2 in the malignant potential of OSCC. We first investigated the expression pattern of HMGA2 and its clinical relevance in 110 OSCC specimens using immunohistochemical staining. In addition, we examined the effects HMGA2 on the regulation of vascular endothelial growth factor (VEGF)-A, VEGF-C, and fibroblast growth factor (FGF)-2, which are related to angiogenesis, in vitro. High expression of HMGA2 was significantly correlated with distant metastasis and poor prognosis. Further, HMGA2 depletion in OSCC cells reduced the expression of angiogenesis genes. In OSCC tissues with high HMGA2 expression, angiogenesis genes were increased and a high proportion of blood vessels was observed. These findings suggest that HMGA2 plays a significant role in the regulation of angiogenesis and might be a potential biomarker to predict distant metastasis and prognosis in OSCC.
Radioresistance is a major obstacle to the successful treatment of oral squamous cell carcinoma (OSCC). To help overcome this issue, we have developed clinically relevant radioresistant (CRR) cell ...lines generated by irradiating parental cells over time, which are useful for OSCC research. In the present study, we conducted gene expression analysis using CRR cells and their parental lines to investigate the regulation of radioresistance in OSCC cells. Based on gene expression changes over time in CRR cells and parental lines subjected to irradiation, forkhead box M1 (FOXM1) was selected for further analysis in terms of its expression in OSCC cell lines, including CRR cell lines and clinical specimens. We suppressed or upregulated the expression of FOXM1 in OSCC cell lines, including CRR cell lines, and examined radiosensitivity, DNA damage, and cell viability under various conditions. The molecular network regulating radiotolerance was also investigated, especially the redox pathway, and the radiosensitizing effect of FOXM1 inhibitors was examined as a potential therapeutic application. We found that FOXM1 was not expressed in normal human keratinocytes but was expressed in several OSCC cell lines. The expression of FOXM1 was upregulated in CRR cells compared with that detected in the parental cell lines. In a xenograft model and clinical specimens, FOXM1 expression was upregulated in cells that survived irradiation. FOXM1-specific small interfering RNA (siRNA) treatment increased radiosensitivity, whereas FOXM1 overexpression decreased radiosensitivity, and DNA damage was altered significantly under both conditions, as well as the levels of redox-related molecules and reactive oxygen species production. Treatment with the FOXM1 inhibitor thiostrepton had a radiosensitizing effect and overcame radiotolerance in CRR cells. According to these results, the FOXM1-mediated regulation of reactive oxygen species could be a novel therapeutic target for the treatment of radioresistant OSCC; thus, treatment strategies targeting this axis might overcome radioresistance in this disease.
Occult neck metastasis is an important prognostic factor in patients with tongue squamous cell carcinoma (TSCC) who are deemed clinically negative for neck metastasis. The purpose of this study was ...to identify predictive factors for occult neck metastasis arising from TSCC and to determine patient prognosis. Ninety-seven patients with cT2N0 TSCC who underwent surgical resection of their primary lesion as initial therapy were enrolled in this retrospective study. Cutoff values for depth of invasion (≥3.3 mm) and the tumor budding score (≥4) were determined using receiver operator characteristic analyses. Univariate and multivariate analyses revealed that a tumor budding score ≥4 is a significant independent predictive factor for the occurrence of occult neck metastasis, which in turn is a significant independent prognostic factor. When evaluating tumor budding, we demonstrated greater interobserver and intraobserver agreement when using immunohistochemical staining for cytokeratin AE1/AE3 than with hematoxylin and eosin staining (HE). We conclude that the evaluation of tumor budding is effective for identifying populations at high risk of occult neck metastasis, which will enable the planning of appropriate therapeutic strategies for patients with cT2N0 TSCC. Furthermore, cytokeratin staining is recommended over HE staining for simpler and more accurate evaluation of tumor budding.
•TNM staging may be unreliable for tongue squamous cell carcinoma (TSCC).•We investigated whether tumor budding predicts occult neck metastasis in TSCC.•A tumor budding score ≥4 is a significant independent predictor of occult metastasis.•Occult neck metastasis was found to be a significant prognostic factor.•Evaluating tumor budding by cytokeratin staining is favored over hematoxylin/eosin.
This study aimed to assess the role of preoperative
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F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) for predicting late neck metastasis in clinically ...node-negative (cN0) early-stage oral squamous cell carcinoma (OSCC). We retrospectively investigated the standardized uptake value (SUV) parameters in patients with late neck metastasis based on the neck node level. The study population consisted of 16 patients with cT1N0 or cT2N0 oral SCC who were evaluated with dual-phase FDG-PET/CT and were treated with local resection of the primary tumor and watchful waiting for neck management. The SUV at each level was measured on the early and delayed images, and the laterality of the SUV was calculated. The laterality on the delayed images significantly differed between positive and negative pairs at the levels Ib (
p
= 0.002) and IIb (
p
= 0.013); a cut-off value of 1.4 yielded a true-positive rate of 50% and a false-positive rate of 6%. The laterality of FDG-uptake should be used to stratify the risk for nodal-level metastasis.
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