Progression Of Oral Squamous Cell Carcinoma Research Articles

Dysregulation of a novel m6A regulator YWHAG is correlated with metastasis and poor prognosis in oral squamous cell carcinoma – A cross-sectional study

ObjectiveThis study aimed to investigate the role of a novel m6A and cell cycle regulator YWHAG in oral squamous cell carcinoma (OSCC) by analyzing its expression and functional implications. DesignTumor samples (n = 51) and adjacent non-tumor samples (n = 38) were collected from patients with OSCC, and cell lines were processed. YWHAG mRNA expression was assessed using quantitative reverse transcription PCR (RT-qPCR) analysis. Various tools, such as UALCAN, Protein-Atlas analysis, TIMER 2.0, and other in silico tools, were used to explore clinicopathological correlations, protein expression, immune cell infiltration, and functional associations of YWHAG. ResultsYWHAG mRNA and protein expression were significantly upregulated in OSCC tumor tissues and OSCC cell lines compared to non-tumor tissues and normal cells (p < 0.001). High YWHAG expression significantly correlated with advanced tumor stage, higher grade, lymph node metastasis, and poor prognosis (p < 0.05). Functional analysis revealed that YWHAG is associated with pathways involved in aggressive cancer progression. YWHAG expression positively correlated with its target gene CTTN expression, which was also upregulated in OSCC and associated with poor prognosis (p < 0.05). ConclusionsStudy findings indicate that YWHAG may contribute to the progression of OSCC and could be a potential therapeutic target or prognostic biomarker. Further investigation is necessary to understand the underlying mechanisms and assess the clinical implications of YWHAG dysregulation in OSCC.

Multi-regional genomic and transcriptomic characterization of a melanoma-associated oral cavity cancer provide evidence for CASP8 alteration-mediated field cancerization

BackgroundPrecancerous and malignant tumours arise within the oral cavity from a predisposed “field” of epithelial cells upon exposure to carcinogenic stimulus. This phenomenon is known as “Field Cancerization”. The molecular genomic and transcriptomic alterations that lead to field cancerization and tumour progression is unknown in Indian Oral squamous cell carcinoma (OSCC) patients.MethodsWe have performed whole exome sequencing, copy-number variation array and whole transcriptome sequencing from five tumours and dysplastic lesions (sampled from distinct anatomical subsites - one each from buccal anterior and posterior alveolus, dorsum of tongue–mucosal melanoma, lip and left buccal mucosa) and blood from a rare OSCC patient with field cancerization.ResultsA missense CASP8 gene mutation (p.S375F) was observed to be the initiating event in oral tumour field development. APOBEC mutation signatures, arm-level copy number alterations, depletion of CD8 + T cells and activated NK cells and enrichment of pro-inflammatory mast cells were features of early-originating tumours. Pharmacological inhibition of CASP8 protein in a CASP8-wild type OSCC cell line showed enhanced levels of cellular migration and viability.ConclusionCASP8 alterations are the earliest driving events in oral field carcinogenesis, whereas additional somatic mutational, copy number and transcriptomic alterations ultimately lead to OSCC tumour formation and progression.

Role of Antioxidant Enzymes in Pathogenesis of Oral Squamous Cell Carcinoma: a Systematic Review and Meta-analysis.

To investigate the antioxidant enzyme status in biological samples of patients with oral squamous cell carcinoma (OSCC) and compare them with biological samples of healthy people through a systematic review and meta-analysis. Antioxidant enzymes of catalase (CAT), sodium dismutase (SOD) and glutathione peroxide (GPx) were included in the analysis. A literature search was conducted of the PubMed, Science Direct, Scopus, Web of Science and Wiley Online Library databases for studies published between January 1999 and December 2022. A total of 831 articles were selected, of which 131 were found to be relevant. Finally, the full texts of 12 studies were screened and included. Studies that evaluated other antioxidant enzymes were excluded. Standardised mean difference (SMD) was derived to conduct a meta-analysis using comprehensive meta-analysis v3 (Biostat, Englewood, NJ, USA). A random effects model with 95% confidence interval (CI) was used to estimate the effect size. P < 0.05 was considered significant. CAT levels were measured in eight studies (n &#61; 567) and the mean values for the OSCC and control groups were 4.81 ± 2.57 and 10.02 ± 1.81, respectively (SMD 3.18, 95% CI 1.01 to 1.42; P &#61; 0.001). SOD level was evaluated in 11 studies (n &#61; 762) and the values for the OSCC and control groups were 3.78 ± 1.45 and 7.34 ± 1.79, respectively (SMD 3.66, 95% CI 1.51 to 1.94; P &#61; 0.001). GPx level was evaluated in 10 studies (n &#61; 697) and the values for the OSCC and control groups were 13.33 ± 1.42 and 16.54 ± 2.9, respectively (SMD 1.91, 95% CI 1.34 to 1.77; P &#61; 0.001). The heterogeneity between the studies was severe (I2 ≥ 90%). The risk of bias between studies was low to moderate. Analysis revealed that the levels of antioxidant enzymes decreased in biological samples of patients with OSSC as compared to healthy controls. Understanding the pathological progress of OSCC by analysing the level of antioxidant enzymes is beneficial in formulating a personalised, targeted pro-oxidant therapy for cancer treatment.

STAT3 interactome predicts presence of proteins that regulate immune system in oral squamous cell carcinoma

ObjectivesSignal transducer and activator of transcription 3 (STAT3) is one of the key proliferation mechanism–related proteins that helps in oral squamous cell carcinoma (OSCC) progression. Immune evasion by STAT3 is mediated by the JAK2/STAT3/PDL1 signaling axis. Based on previous findings, we hypothesized that STAT3-binding partners participate in the inhibition of anti-tumor activity in OSCC. MethodsA 3D cancer-immune co-culture model was constructed using oral cancer cell lines SCC4, SCC9, SCC25, and CAL27 and normal oral cell line OKF6. The cells were co-cultured with natural killer (NK-92) and Jurkat cells. The target protein STAT3 was chosen based on SWATH data, and co-immunoprecipitation (Co-IP)-based proteomics was conducted. The Co-IP LC-MS/MS output was analysed to determine the protein interaction network, gene ontology, pathway analysis, and protein cluster annotation. ResultsSTAT3 in oral cancer cell lines interacts with the epidermal growth factor receptor (EGFR) and other proteins that participate in proliferation and immune mechanisms. Proteome analysis showed that some STAT3-binding proteins found in this study are known immune system regulators. ConclusionOverall, STAT3 interactive proteins regulate the immune system in oral squamous cell carcinoma cells.

LncRNAPVT1 is Associated with Cancer-Associated Fibroblasts Proliferation Through Regulating TGF-βin Oral Squamous Cell Carcinoma

ABSTRACT Introduction Human oral squamous cell carcinoma (OSCC) is the most common type of oral cancer and has a poor survival rate. Cell-cell communication between OSCC cells and cancer-associated fibroblasts (CAFs) plays important roles in OSCC progression. We previously demonstrated that CAFs promote OSCC cell migration and invasion. However, how OSCC cells influence CAFs proliferation is unknown. Methods Knockdown of PVT1 was confirmed using lentivirus infection technique. CAFs in tissues were identified by staining the cells with α-SMA using immunohistochemical technique. CCK-8 assay was used to evaluate cell proliferation. The mRNA level of a gene was measured by qRT-PCR. Secreted TGF-β were detected using ELISA assay. Results We found that knockdown of the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was associated with a low density of CAFs in xenograft tumors in mice; further analysis revealed that PVT1 in OSCC cells induced CAF proliferation through transforming growth factor (TGF)-β. Discussion Our results demonstrate that lncRNA PVT1 in tumor cells participates in CAF development in OSCC by regulating TGF-β. This study revealed a new mechanism by which PVT1 regulates OSCC progression and PVT1 is a potential therapeutic target in OSCC

CONSORT article: Single-cell sequencing analysis revealed CMKLR1+ macrophage as a subpopulation of macrophage with tumor-suppressive characteristics in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is an aggressive oral malignancy. Metastasis and postoperative recurrence are major causes of a high mortality of OSCC. The landscape of immune cells in OSCC remained to be comprehensively explored. Tumor tissues of OSCC patients were collected from the Gene Expression Omnibus database, based on which single-cell sequencing analysis was performed to identify subtypes of macrophages and to annotate the subpopulations according to the expression levels of cell marker genes. Functional enrichment analysis was performed to explore the biological processes involved in each cell subcluster. Gene regulatory networks driven by SPECIFIC transcription factors (TFs) were developed applying single-cell regulatory network inference and clustering (SCENIC) analysis. Binding strength between receptors and ligands between different cells was analyzed using cell communication analysis. A single-cell landscape in OSCC was successfully developed and a total of 11 cell clusters were identified. Specifically, CD163 + macrophages were a crucial type of macrophage with 4 cell subpopulations, namely, SAT1 + macrophages, IDO1 + macrophages, TRIM29 + macrophages, and CMKLR1 + macrophages. IDO1 + macrophages and CMKLR1 + macrophages mainly had the characteristics of M1-type macrophages. CMKLR1 + macrophages fulfilled the function of M1-type macrophages to inhibit OSCC progression. IDO1 + macrophages and CMKLR1 + macrophages were both involved in the activation response of T cells. CMLKR1 + macrophages had a stronger activating effect on T cells. CMKLR1 + macrophages directly regulated the proliferation of epithelial cells and inhibited the progression of OSCC. CMKLR1 + macrophages in OSCC were identified as a crucial cell subpopulation of macrophages in inhibiting tumor progression. Adjusting the infiltration abundance and cell activity of CMKLR1 + macrophages may be a novel therapeutic direction to improve OSCC prognosis.

Noncanonical formation of SNX5 gene-derived circular RNA regulates cancer growth

Oral squamous cell carcinoma (OSCC) is a prevalent cancer worldwide, exhibiting unique regional prevalence. Despite advancements in diagnostics and therapy, the 5-year survival rate for patients has seen limited improvement. A deeper understanding of OSCC pathogenesis, especially its molecular underpinnings, is essential for improving detection, prevention, and treatment. In this context, noncoding RNAs, such as circular RNAs (circRNAs), have gained recognition as crucial regulators and potential biomarkers in OSCC progression. Our study highlights the discovery of previously uncharacterized circRNAs, including a SNX5 gene-derived circRNA, circSNX5, through deep sequencing of OSCC patient tissue transcriptomes. We established circSNX5’s tumor-specific expression and its strong correlation with patient survival using structure-specific and quantitative PCR analyses. In vitro and in vivo experiments underscored circSNX5 RNA’s regulatory role in cancer growth and metastasis. Further, our omics profiling and functional assays revealed that ADAM10 is a critical effector in circSNX5-mediated cancer progression, with circSNX5 maintaining ADAM10 expression by sponging miR-323. This novel circRNA-miRNA-mRNA regulatory axis significantly contributes to oral cancer progression and malignancy. Moreover, we discovered that circSNX5 RNA is produced via noncanonical sequential back-splicing of pre-mRNA, a process negatively regulated by the RNA-binding protein STAU1. This finding adds a new dimension to our understanding of exonic circRNA biogenesis in the eukaryotic transcriptome. Collectively, our findings offer a detailed mechanistic dissection and functional interpretation of a novel circRNA, shedding light on the role of the noncoding transcriptome in cancer biology and potentially paving the way for innovative therapeutic strategies.

Biomarkers Identification in the Microenvironment of Oral Squamous Cell Carcinoma: A Systematic Review of Proteomic Studies.

An important determinant for oral squamous cell carcinoma (OSCC) onset and outcome is the composition of the tumor microenvironment (TME). Thus, the study of the interactions occurring among cancer cells, immune cells, and cancer-associated fibroblasts within the TME could facilitate the understanding of the mechanisms underlying OSCC development and progression, as well as of its sensitivity or resistance to the therapy. In this context, it must be highlighted that the characterization of TME proteins is enabled by proteomic methodologies, particularly mass spectrometry (MS). Aiming to identify TME protein markers employable for diagnosing and prognosticating OSCC, we have retrieved a total of 119 articles spanning 2001 to 2023, of which 17 have passed the selection process, satisfying all its criteria. We have found a total of 570 proteins detected by MS-based proteomics in the TME of OSCC; among them, 542 are identified by a single study, while 28 are cited by two or more studies. These 28 proteins participate in extracellular matrix remodeling and/or energy metabolism. Here, we propose them as markers that could be used to characterize the TME of OSCC for diagnostic/prognostic purposes. Noteworthy, most of the 28 individuated proteins share one feature: being modulated by the hypoxia that is present in the proliferating OSCC mass.

Unravelling the Significance of NLRP3 and IL-β1 in Oral Squamous Cell Carcinoma and Potentially Malignant Oral Disorders: A Diagnostic and Prognostic Exploration.

Nucleotide-binding domain-like receptor protein 3 (NLRP3), an inflammasome, is reported to be dysregulated or aberrantly expressed in chronic inflammation, leading to a myriad of inflammatory disorders, autoimmune diseases, and cancer. This study aimed to explore the expression and role of NLRP3 protein and the secreted cytokine IL-β1 in oral squamous cell carcinoma (OSCC) and potentially malignant oral disorders (PMOD). Tissue NLRP3 expression was quantified using sandwich ELISA in 30 cases each of OSCC, PMOD, and normal oral mucosa. Serum IL-β1 level was also measured by ELISA to determine their correlation. In surgically treated OSCC cases, pathological parameters such as tumor size, depth of invasion (DOI), pTNM stage, and perineural & lymphovascular invasion were assessed and correlated with NLRP3 & IL-β1 levels to investigate their roles in tumor progression, invasion, and metastasis. Tissue NLRP3 expression was markedly elevated in OSCC, with significant IL-β1 levels observed in the serum of both OSCC and PMOD cases. Both markers showed a pronounced increase with the severity of dysplasia, indicating a strong association (p = 0.003%). The expression levels of tissue NLRP3 and serum IL-β1 were positively correlated with DOI and tumor size. Furthermore, their elevated levels, alongside higher histological grades, indicate roles in the dedifferentiation and progression of tumor cells. The findings indicated that increased expression of NLRP3 and IL-β1 in PMOD correlates with higher transformation rates, along with tumor progression and dedifferentiation in OSCC. Consequently, these markers hold promise as valuable targets for prognostic assessment, diagnostics, and therapeutic strategies in OSCC.

PRELP inhibits the progression of oral squamous cell carcinoma via inactivation of the NF-κB pathway

ObjectivesThe aim of this study was to investigate the role and molecular mechanism of proline/arginine-rich end leucine-rich repeat protein (PRELP), a secreted protein in extracellular matrix, in oral squamous cell carcinoma (OSCC) progression. DesignPRELP expression in OSCC was analyzed in the Gene Set Enrichment (GSE) 138206, GSE37991, and GSE23558 datasets as well as cell lines. Also, PRELP expression and its relationship with prognosis and immune infiltration in head and neck squamous cell carcinoma (HNSCC) were confirmed by bioinformatics analysis. The proliferation, apoptosis, invasion, epithelial-to-mesenchymal transition (EMT) and NF-κB activation were detected after alteration of PRELP expression in OSCC cells using CCK-8, EdU, flow cytometry, Transwell, real-time PCR, immunofluorescence and Western blot. Additionally, an NF-κB inhibitor PDTC was used to confirm the regulation mechanism of PRELP. ResultsThe expression of PRELP in OSCC tissues, cells and in HNSCC samples was low. HNSCC patients with higher PRELP expression was associated with longer overall survival. A positive correlation between PRELP expression and immune cell infiltration was found in HNSCC. Upregulation of PRELP inhibited, whereas PRELP silencing promoted, the proliferation, invasion and EMT of OSCC cells. Also, overexpression of PRELP promoted cell apoptosis. Mechanistically, PRELP suppressed p65 phosphorylation and nuclear translocation. And PDTC treatment partially reversed the influences of PRELP knockdown on the malignant behaviors in OSCC cells. ConclusionPRELP suppressed OSCC progression via inactivation of the NF-κB pathway. Targeting PRELP may be a potential approach for OSCC treatment.

Pituitary tumor‑transforming gene 1 regulates the senescence and apoptosis of oral squamous cell carcinoma in a p21‑dependent DNA damage response manner.

Pituitary tumor‑transforming gene 1 (PTTG1), also known as securin, is a proto‑oncogene involved in the development of various cancers by promoting cell proliferation and mobility. However, its underlying biological mechanisms in oral squamous cell carcinoma (OSCC) progression remain unclear. in the present study, it was sought to elucidate the role of PTTG1 as an oncogene in OSCC progression and was attempted to unravel the underlying mechanism and impact of PTTG1 expression on cell cycle, cell death, and cellular senescence. The effect of double strand break on PTTG1 expression was investigated in OSCC growth. To identify the role of PTTG1 in OSCC growth, the cell viability and senescence was analyzed by EdU and senescence‑associated beta‑galactosidase (SA‑β‑gal) assay, respectively. To verify the DNA damage‑induced senescence of PTTG1, the chromosomal damage in OSCC was analyzed in vitro. Finally, the effect of PTTG1 on tumor growth and gene expression related to cell viability and DNA damaged‑induced senescence was investigated in vivo. PTTG1 expression was compared between OSCC and healthy patient samples (n=32) using reverse transcription‑quantitative PCR and immunohistochemistry; and it was found that PTTG1 expression was upregulated in OSCC. Small interfering RNA‑mediated knockdown of PTTG1 in two OSCC cell lines revealed that PTTG1 downregulation significantly inhibited cell proliferation and arrested the cell cycle pathway as evidenced by changes in checkpoint genes (such as cyclin D1, E and B1). PTTG1 knockdown also increased apoptosis, as evidenced by the upregulation of apoptotic genes [such as cleaved (c‑) Caspase‑7 and c‑poly (ADP‑ribose) polymerase]. Moreover, PTTG1 downregulation promoted cellular senescence, as shown by western blotting and SA‑β‑gal staining. Finally, senescence‑induced DNA damage was observed in OSCC cells, which accelerates genomic instability, through chromosomal damage analysis. Taken together, the present findings suggested that PTTG1 acts as a proto‑oncogene; regulates cell proliferation, cell cycle, cellular senescence and DNA damage in OSCC; and may serve as a novel diagnostic biomarker and potential therapeutic target for OSCC.

Exploring the prognostic landscape of oral squamous cell carcinoma through mitochondrial damage-related genes

Oral squamous cell carcinoma (OSCC), the most prevalent form of oral cancer, poses significant challenges to the medical community due to its high recurrence rate and low survival rate. Mitochondrial Damage-Related Genes (MDGs) have been closely associated with the occurrence, metastasis, and progression of OSCC. Consequently, we constructed a prognostic model for OSCC based on MDGs and identified potential mitochondrial damage-related biomarkers. Gene expression profiles and relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Differential analysis was conducted to identify MDGs associated with OSCC. COX analysis was employed to screen seven prognosis-related MDGs and build a prognostic prediction model for OSCC. Cases were categorized into low-risk or high-risk groups based on the optimal risk score threshold. Kaplan-Meier (KM) analysis revealed significant survival differences (P < 0.05). Additionally, the area under the ROC curve (AUC) for patient survival at 1 year, 3 years, and 5 years were 0.687, 0.704, and 0.70, respectively, indicating a high long-term predictive accuracy of the prognostic model. To enhance predictive accuracy, age, gender, risk score, and TN staging were incorporated into a nomogram and verified using calibration curves. Risk scoring based on MDGs was identified as a potential independent prognostic biomarker. Furthermore, BID and SLC25A20 were identified as two potential independent mitochondrial damage-related prognostic biomarkers, offering new therapeutic targets for OSCC.

DAZAP1 Phase Separation Regulates Mitochondrial Metabolism to Facilitate Invasion and Metastasis of Oral Squamous Cell Carcinoma.

Tumor invasion and metastasis are the underlying causes of the high mortality rate of oral squamous cell carcinoma (OSCC). Energy metabolism reprogramming has been identified as a crucial process mediating tumor metastasis, thus indicating an urgent need for in-depth investigation of the specific mechanisms of tumor energy metabolism. Here, we identified an RNA-binding protein, DAZ associated protein 1 (DAZAP1), as a tumor-promoting factor with an important role in OSCC progression. DAZAP1 was significantly upregulated in OSCC, which enhanced the migration and invasion of OSCC cells and induced the epithelial-mesenchymal transition (EMT). RNA-seq analysis and experimental validation demonstrated that DAZAP1 regulates mitochondrial energy metabolism in OSCC. Mechanistically, DAZAP1 underwent liquid-liquid phase separation (LLPS) to accumulate in the nucleus where it enhanced cytochrome-c oxidase 16 (COX16) expression by regulating pre-mRNA alternative splicing, thereby promoting OSCC invasion and mitochondrial respiration. In mouse OSCC models, loss of DAZAP1 suppressed EMT, downregulated COX16, and reduced tumor growth and metastasis. In OSCC patient samples, expression of DAZAP1 positively correlated with COX16, and high expression of both proteins was associated with poor patient prognosis. Together, these findings revealed a mechanism by which DAZAP1 supports mitochondrial metabolism and tumor development of OSCC, suggesting the potential of therapeutic strategies targeting DAZAP1 to block OSCC invasion and metastasis.

Circ_0002722-induced regulation of YAP promotes platinum resistance in oral squamous cell carcinoma: Implications for verteporfin therapy

Oral squamous cell carcinoma (OSCC) poses a significant public health burden due to its high prevalence and poor prognosis. Platinum resistance is one of the major challenges in OSCC treatment. Yes-associated protein (YAP) has been identified as a pivotal player in OSCC tumorigenesis and progression. Circular RNA (circRNA) has been implicated in chemoresistance in various cancers by regulation the function of microRNA. Nevertheless, the specific mechanisms linking circRNA to YAP expression in OSCC remain poorly understood. In this study, we detected the YAP and circRNA hsa_circ_0002722 (circ_0002722) expression by western blot (WB) and quantitative polymerase chain reaction (qPCR). We found that YAP and circ_0002722 were up-regulated in platinum resistance in OSCC tissues. Furthermore, transfection of circ_0002722 siRNA into platinum-resistant cells revealed that circ_0002722 acted as a regulator of miR-1305, which influenced YAP expression and thereby affected platinum sensitivity. In vivo experiments corroborated the synergistic effects of cisplatin and verteporfin (a YAP inhibitor) in combating platinum resistance. Targeting YAP emerges as a promising therapeutic strategy for addressing platinum resistance in OSCC, with circ_0002722 serving as a potential therapy target and valuable diagnostic marker. These findings shed light on the underlying mechanisms of platinum resistance, paving the way for the development of effective treatment approaches.

DEAD/H-box helicase 11 is transcriptionally activated by Yin Yang-1 and accelerates oral squamous cell carcinoma progression.

Oral squamous cell carcinoma (OSCC) is the most common oral malignancy. DEAD/H-box helicase 11 (DDX11), a DNA helicase, has been implicated in the progression of several cancers. Yet, the precise function of DDX11 in OSCC is poorly understood. The DDX11 expression in OSCC cells and normal oral keratinocytes was evaluated in the Gene Expression Omnibus database (GSE146483 and GSE31853). SCC-4 and CAL-27 cells expressing doxycycline-inducible DDX11 or DDX11 shRNA were generated by lentiviral infection. The role of DDX11 in OSCC cells was determined by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, colony formation assay, flow cytometry assay, TUNEL staining, and western blot. The effects of DDX11 on tumor growth were explored in a xenograft nude mouse model. The relationship between DDX11 and transcription factor Yin Yang-1 (YY1) was researched using the dual luciferase report assay and chromatin immunoprecipitation assay. DDX11 expression was significantly upregulated in OSCC cells. Knockdown of DDX11 inhibited cell proliferation, induced cell cycle arrest, and suppressed PI3K-AKT pathway, while DDX11 overexpression showed opposite effects. The number of apoptotic cells was increased in DDX11 silenced cells. DDX11 upregulation or knockdown accelerated or suppressed tumor growth in vivo, respectively. Moreover, the YY1 bound and activated the DDX11 promoter, resulting in increasing DDX11 expression. Forced expression DDX11 reversed the anticancer effects of YY1 silencing on OSCC cells. DDX11 has tumor-promoting function in OSCC and is transcriptionally regulated by YY1, indicating that DDX11 may serve as a potential target for the OSCC treatment.

Effects of Angiogenic Factors on the Epithelial-to-Mesenchymal Transition and Their Impact on the Onset and Progression of Oral Squamous Cell Carcinoma: An Overview.

High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development of new blood and lymphatic vessels that nourish the growing OPMDs or OSCCs and provide the latter with metastatic routes. Notably, VEGF, FGF-2, and ANG-2 are also linked to the epithelial-to-mesenchymal transition (EMT), a trans-differentiation process that respectively promotes or exasperates the invasiveness of normal and neoplastic oral epithelial cells. Here, we have summarized published work regarding the impact that the interplay among VEGF, FGF-2, ANG-2, vessel generation, and EMT has on oral carcinogenesis. Results from the reviewed studies indicate that VEGF, FGF-2, and ANG-2 spark either protein kinase B (AKT) or mitogen-activated protein kinases (MAPK), two signaling pathways that can promote both EMT and new vessels' formation in OPMDs and OSCCs. Since EMT and vessel generation are key to the onset and progression of OSCC, as well as to its radio- and chemo-resistance, these data encourage including AKT or MAPK inhibitors and/or antiangiogenic drugs in the treatment of this malignancy.

Differential effects of areca nut, tobacco, and lime on oral squamous cell carcinoma progression

Differential effects of areca nut, tobacco, and lime on oral squamous cell carcinoma progression

Knockdown of Stanniocalcin-1 inhibits growth and glycolysis in oral squamous cell carcinoma cells.

Oral squamous cell carcinoma (OSCC) is the most common malignancy among head and neck squamous cell carcinomas. Targeted therapy plays a crucial role in the treatment of OSCC. However, new and more targets are still needed to develop. Stanniocalcin-1 (STC-1) is a glycoprotein hormone that affects the progression of cancers. However, the potential role of STC-1 in OSCC progression remains to be explored. Here, we aimed to elucidate the role of STC-1 in OSCC. We revealed that STC-1 was highly expressed in OSCC tissues and is correlated with poor patient prognosis. Knockdown of STC-1 significantly suppressed the growth of OSCC cells and restrained glycolysis by reducing glucose consumption, ATP production, and lactate levels. Mechanistically, STC-1 ablation inhibited the PI3K/Akt pathway, reducing the phosphorylation levels of PI3K and Akt. In conclusion, STC-1 depletion restrained OSCC cell growth and glycolysis via PI3K/Akt pathway and has the potential to serve as a therapeutic target for OSCC.

MiRNA genetic variations associated with the predisposition of oral squamous cell carcinoma in central Indian population

The disease burden of Oral Squamous Cell Carcinoma (OSCC) is rising day-by-day and is expected to rise 62 % through 2035. The chewing of tobacco, areca nut, and betel leaf, poor oral hygiene, and chronic infection are common risk factors of OSCC, but genetic and epigenetic factors also contribute equally. MicroRNAs (miRNAs) are comprised of small, non-coding endogenous RNA that regulate a plethora of biological activities by targeting messenger RNA through degradation or inhibition. Single Nucleotide Polymorphisms (SNPs) in miRNA genes can regulate the development and progression of OSCC. The present study aimed to determine the association between SNPs in miRNA genes (miRSNPs) with the risk of OSCC. A case-control study involving 225 histo-pathologically confirmed OSCC cases and 225 healthy controls was conducted, where 25 miRSNPs were analyzed by iPLEX MassArray analysis. A SNP rs12220909 in MIR4293 showed a highly protective effect (CC vs GG, OR = 0.0431, 95%CI = 0.005–0.323, p = 3e-6). Whereas three SNPs, namely, rs4705342 in MIR143 (CC vs TT, OR = 2.25, 95%CI = 2.00–2.53, p = 0.0008), rs531564 in MIR124 (CC vs GG, OR = 24.18, 95%CI = 3.22–181.37, p = 3e-6), and rs3746444 in MIR499 (AA vs GG, OR = 2.01, 95%CI = 1.32–3.05, p = 0.001) were significantly associated with a higher risk of OSCC. Additionally, NanoString-based nCounter miRNA expression profiling revealed that miR-499a (Log2FC = −1.07), and miR-143 (Log2FC = −1.56) were aberrantly expressed in OSCC tissue. Taken together, the above miSNPs may contribute to the high incidence of OSCC in central India. However, further studies with large cohorts and ethnic stratification are required to validate our findings.

Hypomethylation-associated Sox11 upregulation promotes oncogenesis via the PI3K/AKT pathway in OLP-associated OSCC.

Oral lichen planus (OLP) is a particularly prevalent oral disorder with the potential to progress to oral squamous cell carcinoma (OSCC). SRY-box transcription factor 11 (Sox11) has been reported to serve as a prognostic marker for various cancers. However, the role and mechanism of Sox11 in OLP-related OSCC are unknown. Our results indicated that Sox11 was highly expressed, and that Sox11 promoter methylation was significantly reduced in OLP-associated OSCC tissues. High Sox11 expression and Sox11 promoter hypomethylation indicate a poor patient prognosis. According to invivo and invitro experiments, the knockdown of Sox11 inhibited proliferation, invasion, and migration while driving its apoptotic death in OSSC cells; Sox11 overexpression exerted the opposite effect as Sox11 knockdown. Mechanistically, knockdown of Sox11 inhibited PI3K/AKT and glycolysis pathway, and overexpression of Sox11 enhanced the PI3K/AKT and glycolysis pathways in OSCC cells. In addition, we demonstrated that Sox11 overexpression accelerated the progression of OSCC, at least in part by promoting PI3K/AKT pathway activation. In conclusion, our data indicated that the DNA hypomethylation-associated upregulation of Sox11 could promote oncogenic transformation via the PI3K/AKT pathway in OLP-associated OSCC. Therefore, Sox11 might be a reliable biomarker for predicting the progression of precancerous oral tissues.