Human papillomavirus-stratified analysis of the prognostic role of miR-21 in oral cavity and oropharyngeal squamous cell carcinoma (original) (raw)
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British journal of cancer, 2012
Background:Although the role of human papilloma virus (HPV) in cervical squamous cell carcinoma (CSCC) is well established, the role in head and neck SCC (HNSCC) is less clear. MicroRNAs (miRNAs) have a role in the cancer development, and HPV status may affect the miRNA expression pattern in HNSCC. To explore the influence of HPV in HNSCC, we made a comparative miRNA profile of HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC against CSCC.Methods:Fresh frozen and laser microdissected-paraffin-embedded samples obtained from patients with HPV+/HPV- HNSCC, CSCC and controls were used for microarray analysis. Differentially expressed miRNAs in the HPV+ and HPV- HNSCC samples were compared with the differentially expressed miRNAs in the CSCC samples.Results:Human papilloma virus positive (+) HNSCC had a distinct miRNA profile compared with HPV- HNSCC. Significantly more similarity was seen between HPV+ HNSCC and CSCC than HPV- and CSCC. A set of HPV core miRNAs were identified. Of these...
Oncology Reports, 2014
MicroRNAs (miRs) are small non-coding RNAs that regulate the translation of many genes in normal and cancer cells where they are frequently dysregulated promoting tumor progression. Several studies have illustrated the potential of manipulating miR expression in cancer research and therapy. The aim of the present study was to investigate expression patterns of a panel of miRs in head and neck squamous cell carcinoma (HNSCC) shown to be relevant in other carcinomas and to elucidate their role if dysregulated. We performed analysis of miR-21, -200c, -138-1, -138-2, -25 and -34 expression by qRT-PCR in 6 HNSCC cell lines and computerized search for genetic targets of dysregulated miRNA-21 (miR-21). Lipofection of mock and anti-miR-21 and determination of expression efficiencies and final programmed cell death 4 (PDCD4) expression were carried out by luciferase assay and western blotting. MTT assay was used to measure cell proliferation and flow cytometry was performed for cell cycle analysis. Expression of miR-21 was most prominently upregulated in the HNSCC cell lines, particularly in UM-SCC11B (6.45±0.25-fold, P<0.05) and UM-SCC9 (4.35±0.22-fold, P<0.05) as compared to primary epidermal keratinocytes used as control. The expression levels of the other miRs showed no difference except for miR-34 and -138-1 each in one cell line. Subsequent transfection of precursor miR-21 stimulated proliferation while anti-miR-21 inhibited proliferation of both cell lines. PDCD4 was identified with software designed for this purpose as potential target gene of miR-21. Subsequently, its role in HNSCC lines was experimentally confirmed by regulation of PDCD4 transfecting miR-21 mimics and anti-miR-21. Finally, we showed that PDCD4 is negatively regulated by miR-21 at the post-transcriptional level via binding to the 3'-untranslated region of PDCD4 mRNA. A role of upregu-lated miR-21 and reduced PDCD4 stimulating the proliferation was demonstrated in HNSCC lines and, in turn, transfection of anti-miR-21 upregulating PDCD4 reduced the cellular division rate. We explored miR-21 and PDCD4 expression as markers of progression and prognosis and for a potential translational value in the development of agents slowing growth of HNSCC and other carcinomas useful in palliative therapy or as a component of multi-modality treatments.
Diagnostics
Introduction: MicroRNAs (miRs) are a group of endogenous, non-coding, 18-24 nucleotide length single-strand RNAs that mediate gene expression at the post-transcriptional level through mRNA degradation or translational repression. They are involved in regulating diverse cellular biological processes such as cell cycle, differentiation, and apoptosis. The deregulation of miRs affects normal biological processes, leading to malignancies, including oral squamous cell carcinoma (OSCC). This study evaluates the expression level of miR-21-5p and miR-429 genes in biopsy samples from patients with OSCC and performs a comparison with controls. Materials and Methods: In this study, tissue samples were obtained from 40 individuals (20 OSCC patients and 20 healthy controls) to determine miR-21-5p and miR-429 expression using the ΔCT method and analyzed by the Mann–Whitney test. Results: The mean age of subjects in the control and patient groups was 47.15 and 53.8 years, respectively. According t...
Journal of Clinical Medicine, 2019
Head and neck squamous cell carcinoma (HNSCC) is a group of malignancies with serious impact on patient quality of life due to a reduced rate of response to chemotherapy or radiation therapy. MiR-21 has been identified as one of the most common proto-oncogenes. It is hypothesized that upregulated miR-21 could serve as a potential biomarker for human cancer diagnosis. Considering the target genes identified for miR-21 in HNSCC, this transcript is an important player in several cellular processes that control carcinogenesis. The abnormal expression of miR-21 in this group of pathologies has been assessed in several publications, but given the heterogeneity of the published results, a meta-analysis and proper bioinformatics analysis of expression databases are needed to correctly establish the prognostic potential of this molecule. The present meta-analysis comprises the published survival data on HNSCC patients, reported as HR and 95% CI, in association with the expression levels of miR-21. Our investigation revealed that miR-21 could be used successfully as a prognostic biomarker in HNSCC patients, confirming its oncogenic potential. Specifically, the upregulation of miR-21 in these patients predicts a worse outcome in terms of survival rate.
Molecular Cancer, 2010
Background: The tumor suppressor Programmed Cell Death 4 (PDCD4) has been found to be under-expressed in several cancers and associated with disease progression and metastasis. There are no current studies characterizing PDCD4 expression and its clinical relevance in Oral Squamous Cell Carcinoma (OSCC). Since nodal metastasis is a major prognostic factor in OSCC, we focused on determining whether PDCD4 under-expression was associated with patient nodal status and had functional relevance in OSCC invasion. We also examined PDCD4 regulation by microRNA 21 (miR-21) in OSCC. Results: PDCD4 mRNA expression levels were assessed in 50 OSCCs and 25 normal oral tissues. PDCD4 was underexpressed in 43/50 (86%) OSCCs, with significantly reduced mRNA levels in patients with nodal metastasis (p = 0.0027), and marginally associated with T3-T4 tumor stage (p = 0.054). PDCD4 protein expression was assessed, by immunohistochemistry (IHC), in 28/50 OSCCs and adjacent normal tissues; PDCD4 protein was absent/underexpressed in 25/28 (89%) OSCCs, and marginally associated with nodal metastasis (p = 0.059). A matrigel invasion assay showed that PDCD4 expression suppressed invasion, and siRNA-mediated PDCD4 loss was associated with increased invasive potential of oral carcinoma cells. Furthermore, we showed that miR-21 levels were increased in PDCD4-negative tumors, and that PDCD4 expression may be down-regulated in OSCC by direct binding of miR-21 to the 3′UTR PDCD4 mRNA.
The American Journal of Pathology, 2009
Small noncoding microRNAs (miRNAs) have been shown to be abnormally expressed in every tumor type examined. The importance of miRNAs as potential cancer prognostic indicators is underscored by their involvement in the regulation of basic cellular processes such as cell proliferation, differentiation, and apoptosis. In this study, miRNA expression profiles of head and neck squamous cell carcinoma (HNSCC) tumor and adjacent normal tissue were examined by microarray analysis and validated by quantitative TaqMan real-time polymerase chain reaction. Using TaqMan real-time polymerase chain reaction we measured the quantitative associations between a subset of miRNAs identified on microarrays in primary tumors at diagnosis and cancer survival in a cohort of 104 HNSCC patients undergoing treatment with curative intent. The majority of miRNAs exhibiting altered expression in primary human HNSCC tumors show lower expression levels relative to normal adjacent tissue. In contrast, hsa-miR-21 is frequently overexpressed in human HNSCC tumors. Using univariate and multivariable statistical models we show that low levels of hsa-miR205 are significantly associated with loco-regional recurrence independent of disease severity at diagnosis and treatment. In addition , combined low levels of hsa-miR-205 and hsa-let-7d expression in HNSCC tumors are significantly associated with poor head and neck can-cer survival Our results show that miRNA expression levels can be used as prognostic markers of head and neck cancer.
miRNAs in head and neck cancer revisited
Cellular Oncology, 2013
Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer mortality in the world and the 5th most commonly occurring cancer. Tobacco smoking, alcohol consumption and human papilloma virus (HPV) infections have been associated with the occurrence of HNSCC. Despite advances that have been made in HNSCC treatment, smoking-associated HNSCC patients still exhibit a poor 5 year survival rate (30-50 %) and a concomitant poor quality of life. The major clinical challenge to date lies in the early detection of dysplastic lesions,which can progress to malignancy. In addition, there are currently no tools available to monitor HNSCC patients for early stages of local recurrences or distant metastases. In the recent past, micro-RNAs (miRNA) have been assessed for their role in cancer initiation and progression, including HNSCC. It is now well-established that deregulation of these single stranded, small non-coding, 19-25 nt RNAs can e.g. enhance the expression of oncogenes or subdue the expression of tumor suppressor genes. The aims of this review are threefold: first to retrieve from the literature miRNAs that have specifically been associated with HNSCC, second to group these miRNAs into those regulating tumor initiation, progression and metastasis, and third to discern miRNAs related to smoking-associated HNSCC versus HPV-associated HNSCC development. Conclusions This review gives an overview on the miRNAs regulating the development of head and neck cancers. The ultimate establishment of miRNA expression profiles that are HNSCC specific, and miRNAs that orchestrate altered gene and protein expression levels in HNSCC, could pave the way for a better understanding of the mechanism underlying its pathogenesis and the development of novel, targeted therapies. Keywords Head and neck squamous cell carcinoma (HNSCC). microRNA (miRNA). Human papilloma virus (HPV). 1 miRNA characteristics MicroRNAs (miRNAs) are non-coding regulatory RNA molecules of 19-25 nucleotides (nt) in length that have in recent years been encountered in all metazoans tested [1, 2]. Although, they account for a relatively small fraction of the expressed genome, the genes encoding miRNAs are located throughout the human genome in introns and exons of both coding and non-coding genes. miRNAs play a major role in maintaining tissue homeostasis by regulating many processes such as cellular proliferation, differentiation, migration, apoptosis, survival and morphogenesis [2-5]. It is estimated that the human genome may harbor up to 1,000 miRNAs [5-7]. Although miRNAs are not directly involved in encoding proteins, they are believed to control the expression of more than one third of all protein coding genes present within the
PLoS ONE, 2014
MicroRNAs (miRNAs) have a major impact on regulatory networks in human carcinogenesis. In this study, we sought to investigate the prognostic significance of miRNAs in patients with oral cavity squamous cell carcinoma (OSCC). In a discovery phase, RNA was extracted from 58 OSCC tumor samples and paired normal tissues. MiRNAs expression was evaluated with TaqMan Array Card and TaqMan MicroRNA assays. The prognostic significance of the miRNA signature identified in the discovery phase was validated by qRT-PCR in a replication set consisting of 141 formalin-fixed, paraffinembedded (FFPE) samples. We identified a miRNA regulatory network centered on the three hub genes (SP1, MYC, and TP53) that predicted distinct clinical endpoints. Three miRNAs (miR-218, miR-125b, and let-7g) and their downstream response genes had a concordant prognostic significance on disease-free survival and disease-specific survival rates. In addition, patients with a reduced expression of miR-218, miR-125b, and let-7g have a higher risk of poor outcomes in presence of specific risk factors (p-stage III-IV, pT3-4, or pN+). Our findings indicate that specific miRNAs have prognostic significance in OSCC patients and may improve prognostic stratification over traditional risk factors. (TCY) . These authors contributed equally to this work.
Gene Reports, 2020
Cervical cancer (CC) is the fourth most prevalent cancer worldwide. The deprivation of screenin gprogram implementation and inefficient conventional treatments of CC had led to diagnosis of disease in advanced stages and poor prognosis due to gradual increase in resistance to chemotherapy. Therefore, identification of CC molecular targets had become a primary task in order to improve detection, prognosis and development of cervical cancer targeted therapy. MicroRNAs (miRNA) have been validated as key players in cell physiology and alterations in miRNA expression were associated with cancer progression and therapy response. This study was designed to determine the expression of three microRNA molecules involved in human papilloma virus (HPV) induced cervical disease progression in Iraqi women for early detection of preneoplastic and neoplastic cervical lesions. A total of fifty cervical swab samples were collected from women who presented with cervical abnormalities and thirty samples from volunteers healthy women as a control group. Levels of miRNA expression were measured by two steps reverse transcription polymerase chain reaction (RT-PCR) technique. Results showed a significant increase in the expression levels of miRNA-21 and miRNA-20 (P = 0.0001 and 0.048, respectively) in HPV positive patients in comparison with HPV negative and healthy controls. Whereas, miRNA-143 showed a dichotomous expression pattern as being transiently upregulated (P = 0.0001) in preneoplastic lesions (CIN-II and CIN-III) and down regulated at cervical carcinoma. These data suggest that overexpression of cellular miRNA-21,-20 and-143 may be related to infection with high risk HPV and could be a biomarker and a useful therapeutic target.
2021
ObjectiveThis study aimed to clarify whether circulating miR-21 represents a predictive biomarker in patients with head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy, and to investigate the effect of miR-21 inhibitor for chemoradiation in human SCC cells.MethodsPlasma samples were obtained from 22 patients with HNSCC and 25 non-cancer volunteers. Plasma miR-21 expression was measured using real-time quantitative reverse transcription polymerase chain reaction. The effects of miR-21 inhibitor in human SCC cells were investigated by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blot analysis.ResultsPlasma miR-21 expression was higher in HNSCC patients than in control patients (p< 0.001). Seven patients with recurrence showed significantly higher plasma miR-21 than the 15 patients without recurrence. Moreover, miR-21 inhibition significantly enhanced cisplatin- or radiation-induced apoptosis. ...