Molecular Insights into Oral Malignancy

Deshmukh, Anuja; Rao, Karthik Nagaraja; Arora, Ripu Daman; Nagarkar, Nitin M.; Singh, Ambesh; Shetty, Om Shree

doi:10.1007/s13193-021-01431-4

Cited by 11 publications

(16 citation statements)

References 95 publications

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“…HNSCC accounts for approximately 90% of malignancies in the head and neck region, and despite the advances in diagnosis, imaging, treatment modalities, and cancer genetics, its five-year overall survival has not substantially improved over the last few decades [ 36 ]. New therapeutic strategies that enable less-invasive treatment of HNSCC are required, and to make it a reality, it is necessary to understand the molecular background of HNSCC.…”

Section: Discussionmentioning

confidence: 99%

Establishment of anti-DKK3 peptide for the cancer control in head and neck squamous cell carcinoma (HNSCC)

et al. 2022

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Background Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of the head and neck. We identified cancer-specific genes in HNSCC and focused on DKK3 expression. DKK3 gene codes two isoforms of proteins (secreted and non-secreted) with two distinct cysteine rich domains (CRDs). It is reported that DKK3 functions as a negative regulator of oncogenic Wnt signaling and, is therefore, considered to be a tumor suppressor gene. However, our series of studies have demonstrated that DKK3 expression is specifically high in HNSCC tissues and cells, and that DKK3 might determine the malignant potentials of HNSCC cells via the activation of Akt. Further analyses strongly suggested that both secreted DKK3 and non-secreted DKK3 could activate Akt signaling in discrete ways, and consequently exert tumor promoting effects. We hypothesized that DKK3 might be a specific druggable target, and it is necessary to establish a DKK3 inhibitor that can inhibit both secreted and non-secreted isoforms of DKK3. Methods Using inverse polymerase chain reaction, we generated mutant expression plasmids that express DKK3 without CRD1, CRD2, or both CRD1 and CRD2 (DKK3ΔC1, DKK3ΔC2, and DKK3ΔC1ΔC2, respectively). These plasmids were then transfected into HNSCC-derived cells to determine the domain responsible for DKK3-mediated Akt activation. We designed antisense peptides using the MIMETEC program, targeting DKK3-specific amino acid sequences within CRD1 and CRD2. The structural models for peptides and DKK3 were generated using Raptor X, and then a docking simulation was performed using CluPro2. Afterward, the best set of the peptides was applied into HNSCC-derived cells, and the effects on Akt phosphorylation, cellular proliferation, invasion, and migration were assessed. We also investigated the therapeutic effects of the peptides in the xenograft models. Results Transfection of mutant expression plasmids and subsequent functional analyses revealed that it is necessary to delete both CRD1 and CRD2 to inhibit Akt activation and inhibition of proliferation, migration, and invasion. The inhibitory peptides for CRD1 and CRD2 of DKK3 significantly reduced the phosphorylation of Akt, and consequently suppressed cellular proliferation, migration, invasion and in vivo tumor growth at very low doses. Conclusions This inhibitory peptide represents a promising new therapeutic strategy for HNSCC treatment.

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Section: Discussionmentioning

confidence: 99%

Establishment of anti-DKK3 peptide for the cancer control in head and neck squamous cell carcinoma (HNSCC)

et al. 2022

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“…CDKN2A prevents the progression of the cell cycle by inhibiting the activity of cyclin-dependent kinases [ 40 ]. CDKN2A is an additional tumor suppressor gene that is frequently mutated in OSCC, promoting uncontrolled cell proliferation [ 14 , 37 ], particularly in non-smoking patients [ 36 ]. It is believed to promote malignant transformation and disease progression [ 41 ], which is supported by the observation that infection with high-risk HPV strains induces overexpression of p16 in oral premalignant lesions and carcinomas [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…In accordance with other malignancies, OSCC is characterized by the pathological dysregulation of the cell cycle [ 13 ]. Although its genetic landscape can be diverse, several genes stand out, demonstrating unique mutational patterns, while others are reported to exhibit characteristically abnormal expression levels within the tumor’s microenvironment [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Review of Disease-Specific microRNAs by Strategically Bridging Genetics and Epigenetics in Oral Squamous Cell Carcinoma

Gintoni

Vassiliou

Yapijakis

2023

Genes

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Oral squamous cell carcinoma (OSCC) is one of the most prevalent human malignancies and a global health concern with a poor prognosis despite some therapeutic advances, highlighting the need for a better understanding of its molecular etiology. The genomic landscape of OSCC is well-established and recent research has focused on miRNAs, which regulate gene expression and may be useful non-invasive biomarkers or therapeutic targets. A plethora of findings regarding miRNA expression have been generated, posing challenges for the interpretation and identification of disease-specific molecules. Hence, we opted to identify the most important regulatory miRNAs by bridging genetics and epigenetics, focusing on the key genes implicated in OSCC development. Based on published reports, we have developed custom panels of fifteen major oncogenes and five major tumor suppressor genes. Following a miRNA/target gene interaction analysis and a comprehensive study of the literature, we selected the miRNA molecules which target the majority of these panels that have been reported to be downregulated or upregulated in OSCC, respectively. As a result, miR-34a-5p, miR-155-5p, miR-124-3p, miR-1-3p, and miR-16-5p appeared to be the most OSCC-specific. Their expression patterns, verified targets, and the signaling pathways affected by their dysregulation in OSCC are thoroughly discussed.

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“…With the increasing incidence of head and neck cancer, the healthcare system lacks early diagnosis. The most common causes of carcinoma have been established and studied, including but not limited to tobacco use, alcohol abuse, nutritional deficiency, poor oral hygiene, and viral infection ( Deshmukh et al, 2022 ). These primary and secondary etiologies can both be prevented and treated as patients seek medical attention; however, the focus of interest is the diagnostic approach.…”

Section: Introductionmentioning

confidence: 99%

Salivary miRNAs as auxiliary liquid biopsy biomarkers for diagnosis in patients with oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis

Nguyen,

Nonaka

2024

Front. Genet.

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Objective: The healthcare system needs a novel approach to improve and diagnose early oropharyngeal squamous cell carcinoma against its low survival rate. We conduct a systematic review and a comprehensive meta-analysis for the diagnostic role of blood and salivary microRNAs (miRNAs).Methods: An unbiased and thorough literature search in PubMed yielded appropriate data from qualified articles regarding different miRNA biomarkers, method of extraction, research location, and year of publication. Stata was used to calculate the sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve.Results: We included 9 studies with 399 qualified oropharyngeal squamous cell carcinoma patients, which yielded a high diagnostic accuracy of blood miRNAs in combination with salivary miRNAs with a sensitivity of 0.70 (p < 0.001), specificity of 0.75 (p = 0.26), diagnostic odds ratio of 7, and an area under the curve of 0.78.Conclusion: Combined blood- and saliva-derived miRNAs demonstrated a high diagnostic accuracy in detecting oropharyngeal squamous cell carcinoma.Systematic review registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024509424.

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Molecular Insights into Oral Malignancy

Cited by 11 publications

References 95 publications

Establishment of anti-DKK3 peptide for the cancer control in head and neck squamous cell carcinoma (HNSCC)

Establishment of anti-DKK3 peptide for the cancer control in head and neck squamous cell carcinoma (HNSCC)

Review of Disease-Specific microRNAs by Strategically Bridging Genetics and Epigenetics in Oral Squamous Cell Carcinoma

Salivary miRNAs as auxiliary liquid biopsy biomarkers for diagnosis in patients with oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis

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