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1.
J Pak Med Assoc ; 74(4): 762-768, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38751274

ABSTRACT

Cancer of the oral cavity has numerous types and, among all, oral squamous cell carcinoma represents >90% of all cancers of the oral area. Oral squamous cell carcinoma arises from the squamous lining of the oral cavity. Across the globe, most commonly it develops in the regions of tongue followed by floor of the mouth, and lower lip. Neurogenic locus notch homolog protein 1 gene has its association with oral squamous cell carcinoma and is known to be associated with both oncogenic and tumour suppressor roles. The current narrative review comprised literature published from 2013 to 2023. It was searched on Google Scholar, PubMed and Google databases. Globally, neurogenic locus notch homolog protein 1 mutations are associated with the development of oral squamous cell carcinoma. Most of the mutations are linked to ligand bind epidermal growth factor-like repeat region of extracellular domain of neurogenic locus notch homolog protein 1. Once activated, the pathway is involved in tumour progression and metastasis. The Asians compared to Caucasians are more affected by neurogenic locus notch homolog protein 1 mutations.


Subject(s)
Carcinoma, Squamous Cell , Mouth Neoplasms , Mutation , Receptor, Notch1 , Humans , Receptor, Notch1/genetics , Mouth Neoplasms/genetics , Carcinoma, Squamous Cell/genetics
2.
Commun Biol ; 7(1): 567, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38745046

ABSTRACT

Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca2+ signaling. The exact mechanisms by which EP4 influences cell migration through Ca2+ signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca2+ levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.


Subject(s)
Carcinoma, Squamous Cell , Cell Movement , Mitochondria , Mouth Neoplasms , Receptors, Prostaglandin E, EP4 Subtype , Humans , Mouth Neoplasms/pathology , Mouth Neoplasms/metabolism , Mouth Neoplasms/genetics , Mitochondria/metabolism , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Receptors, Prostaglandin E, EP4 Subtype/genetics , Animals , Mice , Cell Line, Tumor , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/genetics , Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics , Calmodulin/metabolism , Calmodulin/genetics , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology
3.
Mol Cancer ; 23(1): 104, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38755637

ABSTRACT

BACKGROUND: The faithful maintenance of DNA methylation homeostasis indispensably requires DNA methyltransferase 1 (DNMT1) in cancer progression. We previously identified DNMT1 as a potential candidate target for oral squamous cell carcinoma (OSCC). However, how the DNMT1- associated global DNA methylation is exploited to regulate OSCC remains unclear. METHODS: The shRNA-specific DNMT1 knockdown was employed to target DNMT1 on oral cancer cells in vitro, as was the use of DNMT1 inhibitors. A xenografted OSCC mouse model was established to determine the effect on tumor suppression. High-throughput microarrays of DNA methylation, bulk and single-cell RNA sequencing analysis, multiplex immunohistochemistry, functional sphere formation and protein immunoblotting were utilized to explore the molecular mechanism involved. Analysis of human samples revealed associations between DNMT1 expression, global DNA methylation and collaborative molecular signaling with oral malignant transformation. RESULTS: We investigated DNMT1 expression boosted steadily during oral malignant transformation in human samples, and its inhibition considerably minimized the tumorigenicity in vitro and in a xenografted OSCC model. DNMT1 overexpression was accompanied by the accumulation of cancer-specific DNA hypomethylation during oral carcinogenesis; conversely, DNMT1 knockdown caused atypically extensive genome-wide DNA hypomethylation in cancer cells and xenografted tumors. This novel DNMT1-remodeled DNA hypomethylation pattern hampered the dual activation of PI3K-AKT and CDK2-Rb and inactivated GSK3ß collaboratively. When treating OSCC mice, targeting DNMT1 achieved greater anticancer efficacy than the PI3K inhibitor, and reduced the toxicity of blood glucose changes caused by the PI3K inhibitor or combination of PI3K and CDK inhibitors as well as adverse insulin feedback. CONCLUSIONS: Targeting DNMT1 remodels a novel global DNA hypomethylation pattern to facilitate anticancer efficacy and minimize potential toxic effects via balanced signaling synergia. Our study suggests DNMT1 is a crucial gatekeeper regarding OSCC destiny and treatment outcome.


Subject(s)
DNA (Cytosine-5-)-Methyltransferase 1 , DNA Methylation , Gene Expression Regulation, Neoplastic , Mouth Neoplasms , Humans , DNA (Cytosine-5-)-Methyltransferase 1/metabolism , DNA (Cytosine-5-)-Methyltransferase 1/genetics , DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors , Animals , Mouth Neoplasms/genetics , Mouth Neoplasms/pathology , Mouth Neoplasms/metabolism , Mice , Cell Line, Tumor , Xenograft Model Antitumor Assays , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Signal Transduction , Cell Proliferation
4.
BMC Cancer ; 24(1): 564, 2024 May 06.
Article in English | MEDLINE | ID: mdl-38711026

ABSTRACT

BACKGROUND: 5-Fluorouracil (5FU) is a primary chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC). However, the development of drug resistance has significantly limited its clinical application. Therefore, there is an urgent need to determine the mechanisms underlying drug resistance and identify effective targets. In recent years, the Wingless and Int-1 (WNT) signaling pathway has been increasingly studied in cancer drug resistance; however, the role of WNT3, a ligand of the canonical WNT signaling pathway, in OSCC 5FU-resistance is not clear. This study delved into this potential connection. METHODS: 5FU-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells underwent RNA sequencing analysis, which was then substantiated via Real-time quantitative PCR (RT-qPCR) and western blot tests. The influence of the WNT signaling on OSCC chemoresistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor methyl 3-benzoate (MSAB) was probed for its capacity to boost 5FU efficacy. RESULTS: In this study, the WNT/ß-catenin signaling pathway was notably activated in 5FU-resistant OSCC cell lines, which was confirmed through transcriptome sequencing analysis, RT-qPCR, and western blot verification. Additionally, the key ligand responsible for pathway activation, WNT3, was identified. By knocking down WNT3 in resistant cells or overexpressing WNT3 in parental cells, we found that WNT3 promoted 5FU-resistance in OSCC. In addition, the WNT inhibitor MSAB reversed 5FU-resistance in OSCC cells. CONCLUSIONS: These data underscored the activation of the WNT/ß-catenin signaling pathway in resistant cells and identified the promoting effect of WNT3 upregulation on 5FU-resistance in oral squamous carcinoma. This may provide a new therapeutic strategy for reversing 5FU-resistance in OSCC cells.


Subject(s)
Drug Resistance, Neoplasm , Fluorouracil , Mouth Neoplasms , Wnt Signaling Pathway , Wnt3 Protein , Humans , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Drug Resistance, Neoplasm/genetics , Mouth Neoplasms/drug therapy , Mouth Neoplasms/metabolism , Mouth Neoplasms/genetics , Mouth Neoplasms/pathology , Wnt Signaling Pathway/drug effects , Cell Line, Tumor , Wnt3 Protein/metabolism , Wnt3 Protein/genetics , beta Catenin/metabolism , beta Catenin/genetics , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Gene Expression Regulation, Neoplastic/drug effects , Antimetabolites, Antineoplastic/pharmacology , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/pathology
5.
Cell Mol Biol (Noisy-le-grand) ; 70(5): 145-149, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38814222

ABSTRACT

The purpose of this study was to investigate the expression of CD109 and its clinicopathological significance in oral squamous cell carcinoma. Data from TIMER2.0 and UALCAN were analyzed to assess CD109 mRNA levels in OSCC. The immunohistochemical method was used to investigate the expressions of CD109 in 20 normal oral mucosa and 75 OSCC and analyzed the relationship between the expression of CD109 and the clinical variables. The mRNA levels of CD109 in OSCC tissues were significantly higher than in adjacent normal tissues (p<0.05). Immunohistochemical analysis revealed that CD109 protein expression was increased in OSCC tissues compared to normal tissues, and this difference was statistically significant (P<0.05). The positive rate of CD109 expression was 94% (16/117) in the group with lymph node metastasis, while it was 55% (32/58) in the group without metastasis (P<0.05). Similarly, the positive rate of CD109 expression was 91% (22/23) in the low differentiation group and 59% (26/52) in the high differentiation group (P<0.05). CD109 expression is markedly higher in OSCC, contributes to the pathological grading of OSCC and predicts lymph node metastasis.


Subject(s)
Antigens, CD , Carcinoma, Squamous Cell , GPI-Linked Proteins , Lymphatic Metastasis , Mouth Neoplasms , Neoplasm Proteins , Humans , Mouth Neoplasms/pathology , Mouth Neoplasms/metabolism , Mouth Neoplasms/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/genetics , Female , Male , Antigens, CD/metabolism , Antigens, CD/genetics , Middle Aged , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/biosynthesis , Immunohistochemistry , Gene Expression Regulation, Neoplastic , Aged , RNA, Messenger/genetics , RNA, Messenger/metabolism , Adult , Mouth Mucosa/metabolism , Mouth Mucosa/pathology , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Clinical Relevance
6.
Cell Death Dis ; 15(5): 376, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811531

ABSTRACT

The tumor margin as the invasive front has been proven to be closely related to the progression and metastasis of oral squamous cell carcinoma (OSCC). However, how tumor cells in the marginal region obtain the extra energy needed for tumor progression is still unknown. Here, we used spatial metabolomics and the spatial transcriptome to identify enhanced energy metabolism in the tumor margin of OSCC and identified that the downregulation of Ras-related glycolysis inhibitor and calcium channel regulator (RRAD) in tumor cells mediated this process. The absence of RRAD enhanced the ingestion of glucose and malignant behaviors of tumor cells both in vivo and in vitro. Mechanically, the downregulation of RRAD promoted the internal flow of Ca2+ and elevated its concentration in the nucleus, which resulted in the activation of the CAMKIV-CREB1 axis to induce the transcription of the glucose transporter GLUT3. GLUT inhibitor-1, as an inhibitor of GLUT3, could suppress this vigorous energy metabolism and malignant behaviors caused by the downregulation of RRAD. Taken together, our study revealed that enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of OSCC and proved that GLUT3 is a potential target for future treatment of OSCC.


Subject(s)
Carcinoma, Squamous Cell , Disease Progression , Energy Metabolism , Mouth Neoplasms , Humans , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Mouth Neoplasms/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/genetics , Animals , Cell Line, Tumor , Mice , Mice, Nude , Gene Expression Regulation, Neoplastic , Glucose Transporter Type 3/metabolism , Glucose Transporter Type 3/genetics , Mice, Inbred BALB C , Glucose/metabolism , Calcium/metabolism , Glycolysis
7.
BMC Oral Health ; 24(1): 625, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38807101

ABSTRACT

BACKGROUND: Oral squamous cell cancer (OSCC) is a prevalent malignancy in oral cavity, accounting for nearly 90% of oral malignancies. It ranks sixth among the most common types of cancer worldwide and is responsible for approximately 145,000 deaths each year. It is widely accepted that noncoding RNAs participate cancer development in competitive regulatory interaction, knowing as competing endogenous RNA (ceRNA) network, whereby long non-coding RNA (lncRNA) function as decoys of microRNAs to regulate gene expression. LncRNA FOXD2-AS1 was reported to exert an oncogenic role in OSCC. Nevertheless, the ceRNA network mediated by FOXD2-AS1 was not investigated yet. This study aimed to explore the effect of FOXD2-AS1 on OSCC cell process and the underlying ceRNA mechanism. METHODS: FOXD2-AS1 expression in OSCC cells were determined via reverse transcription and quantitative polymerase chain reaction. Short hairpin RNA targeting FOXD2-AS1 was transfected into OSCC cells to silence FOXD2-AS1 expression. Then, loss-of-function experiments (n = 3 each assay) were performed to measure cell proliferation, apoptosis, migration, and invasion using colony formation, TdT-mediated dUTP Nick-End Labeling, wound healing and Transwell assays, respectively. RNA binding relation was verified by RNA immunoprecipitation and luciferase reporter assays. Rescue experiments were designed to validate whether FOXD2-AS1 affects cell behavior via the gene cellular retinoic acid binding protein 2 (CRABP2). Statistics were processed by GraphPad Prism 6.0 Software and SPSS software. RESULTS: FOXD2-AS1 was significantly upregulated in Cal27 and SCC9 cells (6.8 and 6.4 folds). In response to FOXD2-AS1 knockout, OSCC cell proliferation, migration and invasion were suppressed (approximately 50% decrease) while OSCC cell apoptosis was enhanced (more than two-fold increase). FOXD2-AS1 interacted with miR-378 g to alter CRABP2 expression. CRABP2 upregulation partly rescued (*p < 0.05, **p < 0.01, ***p < 0.001) the inhibitory impact of FOXD2-AS1 depletion on malignant characteristics of OSCC cells. CONCLUSION: FOXD2-AS1 enhances OSCC malignant cell behaviors by interacting with miR-378 g to regulate CRABP2 expression.


Subject(s)
Apoptosis , Carcinoma, Squamous Cell , Cell Movement , Cell Proliferation , MicroRNAs , Mouth Neoplasms , RNA, Long Noncoding , Humans , MicroRNAs/metabolism , MicroRNAs/genetics , Mouth Neoplasms/genetics , Mouth Neoplasms/pathology , Mouth Neoplasms/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Cell Proliferation/genetics , Apoptosis/genetics , Cell Line, Tumor , Cell Movement/genetics , Gene Expression Regulation, Neoplastic
8.
BMC Oral Health ; 24(1): 622, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38807156

ABSTRACT

BACKGROUND: C-X-C motif chemokine ligand (CXCL8), also known as interleukin-8, is a prototypical CXC family chemokine bearing a glutamic acid-leucine-arginine (ELR) motif that plays key roles in the onset and progression of a range of cancers in humans. Many prior studies have focused on exploring the relationship between CXCL8 gene polymorphisms and the risk of cancer. However, the statistical power of many of these reports was limited, yielding ambiguous or conflicting results in many cases. METHODS: Accordingly, the PubMed, Wanfang, Scopus and Web of Science databases were searched for articles published until July 20, 2023 using the keywords 'IL-8' or 'interleukin-8' or 'CXCL8', 'polymorphism' and 'cancer' or 'tumor'. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized to examine the association. The CXCL8 +781 polymorphism genotypes were assessed with a TaqMan assay. RESULTS: About 29 related publications was conducted in an effort to better understand the association between these polymorphisms and disease risk. The CXCL8 -353A/T polymorphism was associated with an increased overall cancer risk [A vs. T, odds ratio (OR) = 1.255, 95% confidence interval (CI) (1.079-1.459), Pheterogeneity = 0.449, P = 0.003]. The CXCL8 +781 T/C allele was similarly associated with a higher risk of cancer among Caucasians [TT vs. TC + CC, OR = 1.320, 95%CI (1.046-1.666), Pheterogeneity = 0.375, P = 0.019]. Furthermore, oral cancer patients carrying the CXCL8 +781 TT + TC genotypes exhibited pronounced increases in serum levels of CXCL8 as compared to the CC genotype (P < 0.01), and also shown similar trend as compared to genotype-matched normal controls (P < 0.01). Finally, several limitations, such as the potential for publication bias or heterogeneity among the included studies should be paid attention. CONCLUSION: Current study suggested that the CXCL8 -353 and +781 polymorphisms may be associated with a greater risk of cancer, which might impact cancer prevention, diagnosis, or treatment through the different expression of CXCL8. At the same time, the +781 polymorphism may further offer value as a biomarker that can aid in the early identification and prognostic evaluation of oral cancer.


Subject(s)
Genetic Predisposition to Disease , Interleukin-8 , Mouth Neoplasms , Humans , Interleukin-8/genetics , Mouth Neoplasms/genetics , Case-Control Studies , Genetic Predisposition to Disease/genetics , Polymorphism, Genetic , Polymorphism, Single Nucleotide , Risk Factors
9.
PLoS One ; 19(5): e0296565, 2024.
Article in English | MEDLINE | ID: mdl-38781195

ABSTRACT

Epigenetic silencing through methylation is one of the major mechanisms for downregulation of tumor suppressor miRNAs in various malignancies. The aim of this study was to identify novel tumor suppressor miRNAs which are silenced by DNA hypermethylation and investigate the role of at least one of these in oral squamous cell carcinoma (OSCC) pathogenesis. We treated cells from an OSCC cell line SCC131 with 5-Azacytidine, a DNA methyltransferase inhibitor, to reactivate tumor suppressor miRNA genes silenced/downregulated due to DNA methylation. At 5-day post-treatment, total RNA was isolated from the 5-Azacytidine and vehicle control-treated cells. The expression of 2,459 mature miRNAs was analysed between 5-Azacytidine and control-treated OSCC cells by the microRNA microarray analysis. Of the 50 miRNAs which were found to be upregulated following 5-Azacytidine treatment, we decided to work with miR-6741-3p in details for further analysis, as it showed a mean fold expression of >4.0. The results of qRT-PCR, Western blotting, and dual-luciferase reporter assay indicated that miR-6741-3p directly targets the oncogene SRSF3 at the translational level only. The tumor-suppressive role of miR-6741-3p was established by various in vitro assays and in vivo study in NU/J athymic nude mice. Our results revealed that miR-6741-3p plays a tumor-suppressive role in OSCC pathogenesis, in part, by directly regulating SRSF3. Based on our observations, we propose that miR-6741-3p may serve as a potential biological target in tumor diagnostics, prognostic evaluation, and treatment of OSCC and perhaps other malignancies.


Subject(s)
Carcinoma, Squamous Cell , Gene Expression Regulation, Neoplastic , MicroRNAs , Mouth Neoplasms , Serine-Arginine Splicing Factors , MicroRNAs/genetics , MicroRNAs/metabolism , Humans , Mouth Neoplasms/genetics , Mouth Neoplasms/pathology , Animals , Cell Line, Tumor , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Mice , Gene Expression Regulation, Neoplastic/drug effects , Serine-Arginine Splicing Factors/genetics , Serine-Arginine Splicing Factors/metabolism , DNA Methylation , Introns/genetics , Mice, Nude , Azacitidine/pharmacology , Oncogenes/genetics
10.
Anticancer Res ; 44(6): 2517-2531, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38821588

ABSTRACT

BACKGROUND/AIM: Despite advances in oral squamous cell carcinoma (OSCC) diagnosis and treatment, the five-year survival rate remains low, underscoring the need for improved biomarkers and therapeutic strategies. This study investigated the role of let-7d-5p microRNA (miRNA) and its target gene OLR1 in OSCC, focusing on their implications in tumor progression, metastasis and potential as therapeutic targets. MATERIALS AND METHODS: Employing next-generation sequencing and bioinformatic tools, we profiled differentially expressed miRNAs in metastatic OSCC cell lines, identifying let-7d-5p as a key down-regulated miRNA and OLR1 as a novel target of let-7d-5p. We validated this interaction using luciferase reporter assays and studied the biological effects of modulating let-7d-5p and OLR1 expression on OSCC cell proliferation, migration, invasion, and stemness. Additionally, we analyzed clinical data to establish the relevance of OLR1 expression in OSCC prognosis. RESULTS: Our findings revealed let-7d-5p as a potent suppressor of OSCC metastasis, primarily by targeting and down-regulating OLR1. OLR1-silencing reduced OSCC cell invasiveness, migration, and stemness, indicating its prominent role in tumor progression. Mechanistically, let-7d-5p modulates a signaling cascade involving FAK, SRC, PAXILLIN, and p53, influencing cellular apoptosis and chemoresistance. Clinically, elevated OLR1 expression significantly correlates with advanced OSCC stages and poorer survival rates, highlighting its potential as a prognostic marker and therapeutic target. CONCLUSION: Our study uncovers the significance of the let-7d-5p-OLR1 axis in OSCC pathogenesis, offering novel insights for future therapeutic interventions.


Subject(s)
Carcinoma, Squamous Cell , Cell Proliferation , Disease Progression , Focal Adhesion Kinase 1 , Gene Expression Regulation, Neoplastic , MicroRNAs , Mouth Neoplasms , Signal Transduction , Tumor Suppressor Protein p53 , Humans , Mouth Neoplasms/pathology , Mouth Neoplasms/genetics , Mouth Neoplasms/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Prognosis , Focal Adhesion Kinase 1/metabolism , Focal Adhesion Kinase 1/genetics , Signal Transduction/genetics , Cell Line, Tumor , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Cell Proliferation/genetics , Cell Movement/genetics
11.
Anticancer Res ; 44(6): 2369-2376, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38821622

ABSTRACT

BACKGROUND/AIM: This study aimed at the analogous detection of PIK3CA mutations, common in oral squamous cell carcinoma (OSCC), in matched tumor and saliva samples. PATIENTS AND METHODS: Tissue and saliva samples were obtained from 29 patients diagnosed with primary OSCC. Saliva samples were obtained preoperatively; tissue specimens were acquired during tumor resection. Tumor DNA was extracted from both tissue and saliva samples. All samples were controlled for DNA quantity and quality and genetic matching of sample pairs was confirmed using the iPlex Pro Exome QC Panel. Variant detection was performed using the MassARRAY® System, a mass-spectrometry based detection system. Mutational analysis in tissue tumor DNA was made using the multiplexed ClearSEEK™ PIK3CA v1.0 Panel covering 20 hotspot mutations in PIK3CA. In saliva samples, variants were analyzed using both the ClearSEEK™ and the UltraSEEK® Lung v1.1 Panel, with a higher limit of detection but covering less PIK3CA variants. RESULTS: Overall, a PIK3CA variant was found in seven of the 29 tumor tissue samples (24%) by ClearSEEK™; UltraSEEK® additionally confirmed the variant in four of these seven positive samples. Of the three variants not detected by UltraSEEK®, two were not included in the panel and one was included but not detected. Of the seven variants found in tissue, five could also be detected in the matching saliva samples (71%), either by utilizing ClearSEEK™ or UltraSEEK® Conclusion: The detection of PIK3CA hotspot mutations in OSCC and their simultaneous occurrence in saliva underline the potential benefit of liquid biopsies for non-invasive cancer detection and follow-up care of OSCC patients.


Subject(s)
Biomarkers, Tumor , Carcinoma, Squamous Cell , Class I Phosphatidylinositol 3-Kinases , Mouth Neoplasms , Mutation , Saliva , Humans , Class I Phosphatidylinositol 3-Kinases/genetics , Mouth Neoplasms/genetics , Mouth Neoplasms/diagnosis , Biomarkers, Tumor/genetics , Female , Male , Middle Aged , Aged , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/diagnosis , DNA Mutational Analysis/methods , Aged, 80 and over , Adult
12.
JCI Insight ; 9(10)2024 May 22.
Article in English | MEDLINE | ID: mdl-38775151

ABSTRACT

Because cancer cells have a genetically unstable nature, they give rise to genetically different variant subclones inside a single tumor. Understanding cancer heterogeneity and subclone characteristics is crucial for developing more efficacious therapies. Oral squamous cell carcinoma (OSCC) is characterized by high heterogeneity and plasticity. On the other hand, CX3C motif ligand 1 (CX3CL1) is a double-faced chemokine with anti- and pro-tumor functions. Our study reported that CX3CL1 functioned differently in tumors with different cancer phenotypes, both in vivo and in vitro. Mouse OSCC 1 (MOC1) and MOC2 cells responded similarly to CX3CL1 in vitro. However, in vivo, CX3CL1 increased keratinization in indolent MOC1 cancer, while CX3CL1 promoted cervical lymphatic metastasis in aggressive MOC2 cancer. These outcomes were due to double-faced CX3CL1 effects on different immune microenvironments indolent and aggressive cancer created. Furthermore, we established that CX3CL1 promoted cancer metastasis via the lymphatic pathway by stimulating lymphangiogenesis and transendothelial migration of lymph-circulating tumor cells. CX3CL1 enrichment in lymphatic metastasis tissues was observed in aggressive murine and human cell lines. OSCC patient samples with CX3CL1 enrichment exhibited a strong correlation with lower overall survival rates and higher recurrence and distant metastasis rates. In conclusion, CX3CL1 is a pivotal factor that stimulates the metastasis of aggressive cancer subclones within the heterogeneous tumors to metastasize, and our study demonstrates the prognostic value of CX3CL1 enrichment in long-term monitoring in OSCC.


Subject(s)
Carcinoma, Squamous Cell , Chemokine CX3CL1 , Lymphangiogenesis , Lymphatic Metastasis , Mouth Neoplasms , Chemokine CX3CL1/metabolism , Chemokine CX3CL1/genetics , Animals , Mouth Neoplasms/pathology , Mouth Neoplasms/genetics , Mouth Neoplasms/metabolism , Mice , Lymphangiogenesis/genetics , Humans , Cell Line, Tumor , Lymphatic Metastasis/pathology , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Female , Tumor Microenvironment/immunology , Male
13.
Cancer Med ; 13(11): e7309, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38819439

ABSTRACT

INTRODUCTION: Identification of molecular biomarkers in the saliva and serum of oral cavity cancer patients represents a first step in the development of essential and efficient clinical tools for early detection and post-treatment monitoring. We hypothesized that molecular analyses of paired saliva and serum samples from an individual would likely yield better results than analyses of either serum or saliva alone. MATERIALS AND METHODS: We performed whole-transcriptome and small non-coding RNA sequencing analyses on 32 samples of saliva and serum collected from the same patients with oral squamous cell carcinoma (OSCC) and healthy controls (HC). RESULTS: We identified 12 novel saliva and serum miRNAs and a panel of unique miRNA and mRNA signatures, significantly differentially expressed in OSCC patients relative to HC (log2 fold change: 2.6-26.8; DE: 0.02-0.000001). We utilized a combined panel of the 10 top-deregulated miRNAs and mRNAs and evaluated their putative diagnostic potential (>87% sensitivity; 100% specificity), recommending seven of them for further validation. We also identified unique saliva and serum miRNAs associated with OSCC and smoking history (OSCC smokers vs. never-smokers or HC: log2 fold change: 22-23; DE: 0.00003-0.000000001). Functional and pathway analyses indicated interactions between the discovered OSCC-related non-invasive miRNAs and mRNAs and their targets, through PI3K/AKT/mTOR signaling. CONCLUSION: Our data support our hypothesis that using paired saliva and serum from the same individuals and deep sequencing analyses can provide unique combined mRNA and miRNA signatures associated with canonical pathways that may have a diagnostic advantage relative to saliva or serum alone and may be useful for clinical testing. We believe this data will contribute to effective preventive care by post-treatment monitoring of patients, as well as suggesting potential targets for therapeutic approaches.


Subject(s)
Biomarkers, Tumor , MicroRNAs , Mouth Neoplasms , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Saliva , Signal Transduction , TOR Serine-Threonine Kinases , Humans , Mouth Neoplasms/genetics , Mouth Neoplasms/blood , Mouth Neoplasms/metabolism , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Female , Male , Biomarkers, Tumor/genetics , Saliva/metabolism , Saliva/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Middle Aged , MicroRNAs/genetics , MicroRNAs/blood , Transcriptome , Gene Expression Regulation, Neoplastic , Gene Expression Profiling , Aged , RNA, Small Untranslated/genetics , RNA, Small Untranslated/blood , Adult , Case-Control Studies , Sequence Analysis, RNA , RNA, Messenger/genetics , RNA, Messenger/metabolism , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/blood , Carcinoma, Squamous Cell/metabolism
14.
BMC Oral Health ; 24(1): 588, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38773401

ABSTRACT

BACKGROUND: White Sponge Nevus (WSN) is traditionally considered a benign genetic disorder affecting the oral mucosa, primarily caused by pathogenic mutations in keratin 4 (KRT4) or keratin 13 (KRT13). Despite its benign nature, recent evidence has begun to question the malignant potential of WSN. CASE PRESENTATION: We report a case involving a 70-year-old man who presented with a white lesion on the right floor of his mouth. Initial diagnostic evaluations confirmed the lesion as WSN. Over a one-year follow-up, the lesion underwent malignant transformation, evolving into local epithelial moderate-to-severe dysplasia. Exome sequencing identified a novel insertion mutation in exon 1 of the KRT4 gene, resulting in a deletion-insertion amino acid mutation involving glycine. Single-cell RNA sequencing further revealed altered epithelial proliferation and differentiation dynamics within the lesion. CONCLUSIONS: This case not only expands the known genetic spectrum of KRT4 mutations associated with WSN but also provides preliminary evidence suggesting the malignant potential of WSN. The novel pathogenic mutation in KRT4 is postulated to alter epithelial proliferation and differentiation, thereby raising concerns about the malignant transformation of WSN. Further studies are warranted to confirm these findings.


Subject(s)
Cell Transformation, Neoplastic , Keratin-4 , Leukokeratosis, Hereditary Mucosal , Humans , Male , Aged , Keratin-4/genetics , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Leukokeratosis, Hereditary Mucosal/genetics , Leukokeratosis, Hereditary Mucosal/pathology , Mutation , Mouth Neoplasms/genetics , Mouth Neoplasms/pathology , Mouth Mucosa/pathology
15.
Molecules ; 29(10)2024 May 20.
Article in English | MEDLINE | ID: mdl-38792263

ABSTRACT

Oral cancer (OC) is among the most common malignancies in the world. Despite advances in therapy, the worst-case scenario for OC remains metastasis, with a 50% survival rate. Therefore, it is critical to comprehend the pathophysiology of the condition and to create diagnostic and treatment plans for OC. The development of high-throughput genome sequencing has revealed that over 90% of the human genome encodes non-coding transcripts, or transcripts that do not code for any proteins. This paper describes the function of these different kinds of non-coding RNAs (ncRNAs) in OC as well as their intriguing therapeutic potential. The onset and development of OC, as well as treatment resistance, are linked to dysregulated ncRNA expression. These ncRNAs' potentially significant roles in diagnosis and prognosis have been suggested by their differing expression in blood or saliva. We have outlined every promising feature of ncRNAs in the treatment of OC in this study.


Subject(s)
Gene Expression Regulation, Neoplastic , Mouth Neoplasms , RNA, Untranslated , Humans , Mouth Neoplasms/genetics , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Mouth Neoplasms/therapy , RNA, Untranslated/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Prognosis
16.
Cancer Genet ; 284-285: 48-57, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38729078

ABSTRACT

Although lncRNAs are recognized to contribute to the development of oral squamous-cell carcinoma (OSCC), their exact function in invasion and cell migration is not clear. In this research, we explored the molecular and cellular mechanisms of FOXD2-AS1 in OSCC. Prognostic and bioinformatics analyses were used to test for the differential expression of FOXD2-AS1-PLOD1. Following FOXD2-AS1 suppression or overexpression, changes in cell viability were measured using the CCK-8 test; changes in cell migration and invasion abilities were measured using the migration and the Transwell assay. The expression of associated genes and proteins was found using Western blot and RT-qPCR. Analysis of luciferase reporter genes was done to look for regulatory connections between various molecules. The FOXD2-AS1-PLOD1 pair, which was highly expressed in OSCC, was analyzed and experimentally verified to be closely related to the prognosis of OSCC, and a nomogram model and correction curve were constructed. The inhibition of FOXD2-AS1 resulted in the reduction of cell activity, migration, invasion ability and changes in genes related to invasion and migration. In vivo validation showed that inhibition of FOXD2-AS1 expression slowed tumor growth, and related proteins changed accordingly. The experiments verified that FOXD2-AS1 negatively regulated miR-185-5 p and that miR-185-5 p negatively regulated PLOD1. In addition, it was found that the expression of PLOD1, p-Akt and p-mTOR proteins in OSCC cells was reduced by the inhibition of FOXD2-AS1, and FOXD2-AS1 and PLOD1 were closely related to the Akt/mTOR pathway. Increased expression of FOXD2-AS1 promotes OSCC growth, invasion and migration, which is important in part by targeting miR-185-5 p/PLOD1/Akt/mTOR pathway activity.


Subject(s)
Cell Movement , Cell Proliferation , MicroRNAs , Mouth Neoplasms , Neoplasm Invasiveness , Proto-Oncogene Proteins c-akt , RNA, Long Noncoding , TOR Serine-Threonine Kinases , Humans , MicroRNAs/genetics , RNA, Long Noncoding/genetics , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Cell Movement/genetics , Mouth Neoplasms/genetics , Mouth Neoplasms/pathology , Mouth Neoplasms/metabolism , Cell Proliferation/genetics , Mice , Animals , Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase/genetics , Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase/metabolism , Cell Line, Tumor , Signal Transduction/genetics , Gene Expression Regulation, Neoplastic , Female , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/metabolism , Male , Prognosis , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Mice, Nude
17.
Aging (Albany NY) ; 16(10): 9204-9215, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38795388

ABSTRACT

OBJECTIVE: This study aimed to investigate the impact of Dickkopf 2 (DKK2) on the progression of oral squamous cell carcinoma (OSCC) and explore its role in the PI3K/AKT signaling transduction pathway. MATERIALS AND METHODS: The study initially examined the expression of the DKK2 gene in OSCC tissues and normal tissues. Simultaneously, the expression of DKK2 in HOK cells and OSCC cells was verified, and changes in DKK2 expression under hypoxic conditions were detected. DKK2 overexpression and knockdown were performed in SCC-15 and CAL-27 cells. Subsequently, the effects of DKK2 on the proliferation, migration and invasion of OSCC were detected. Western blotting was employed to detect the expression of key proteins in the DKK2/PI3K/AKT signaling axis before and after transfection, and further explore the relevant molecular mechanisms. RESULTS: Compared to normal tissues, DKK2 expression was elevated in OSCC tissues. The expression of DKK2 in the SCC-15 and CAL-27 cell lines was higher than that in HOK cells, and hypoxic conditions could promote DKK2 expression. DKK2 overexpression promoted cell proliferation, migration, and invasion, while DKK2 knockdown inhibited these processes. DKK2 overexpression activated the PI3K/AKT pathway, while DKK2 knockdown suppressed this pathway. CONCLUSION: This study suggests that hypoxic conditions enhance the expression of DKK2 in OSCC. DKK2 regulates the proliferation, migration, and invasion of OSCC through the PI3K/AKT signaling pathway.


Subject(s)
Carcinoma, Squamous Cell , Cell Movement , Cell Proliferation , Intercellular Signaling Peptides and Proteins , Mouth Neoplasms , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Signal Transduction , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Mouth Neoplasms/pathology , Mouth Neoplasms/metabolism , Mouth Neoplasms/genetics , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Cell Movement/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/genetics , Disease Progression , Gene Expression Regulation, Neoplastic , Neoplasm Invasiveness
18.
Arch Oral Biol ; 164: 105977, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38696945

ABSTRACT

OBJECTIVE: The potentiation of glycolysis is a leading driver of squamous cell carcinoma. Targeted modulation of the glycolytic process might be a pivotal tool for treating squamous cell carcinoma. Tribble homolog 3 (TRIB3) expression is elevated in some squamous cell carcinomas and correlates with poor prognosis. We investigated whether increased TRIB3 expression contributes to the progression of oral squamous cell carcinoma (OSCC) by modulating glycolysis. METHODS: We analyzed the expression of TRIB3 in the TCGA database for clinical tissue samples, in vitro, and in vivo. Cell proliferation, migration, invasion, and apoptosis were observed by overexpressing or knocking down TRIB3. Crucially, the impact of TRIB3 on aerobic glycolysis in OSCC was also probed in our study, including glucose uptake, lactate content, ATP production, extracellular acidification rate, and oxygen consumption rate. Importantly, we examined the relationship between TRIB3 and the JNK/JUN pathway and whether it regulates glycolytic processes in OSCC cells through the JNK/JUN pathway. Finally, tumor growth in vivo was tested using Xenograft models to observe the effect of knockdown TRIB3. RESULTS: Our study identified TRIB3 as the most variable and prognostic in OSCC. A significant high expression of TRIB3 in OSCC cells was determined in vitro and promoted cell proliferation, migration, invasion, apoptosis, and aerobic glycolysis. Knockdown of TRIB3 produced opposite effects. In addition, these effects are regulated by the JNK/JUN pathway. The use of JNK inhibitor inhibited the pro-growth and glycolytic effects of TRIB3 on OSCC cells. Finally, we further determined that TRIB3 knockdown would effectively suppress tumor growth in vivo. CONCLUSION: This study reveals that TRIB3 promotes OSCC growth by regulating JNK/JUN pathway-mediated aerobic glycolysis, and TRIB3 may be a potential target for treating OSCC.


Subject(s)
Apoptosis , Carcinoma, Squamous Cell , Cell Proliferation , Glycolysis , Mouth Neoplasms , Protein Serine-Threonine Kinases , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Mouth Neoplasms/genetics , Humans , Animals , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/genetics , Mice , Cell Line, Tumor , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Cell Movement , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Prognosis , MAP Kinase Signaling System , Blotting, Western , Mice, Nude , Repressor Proteins
19.
J Transl Med ; 22(1): 477, 2024 May 19.
Article in English | MEDLINE | ID: mdl-38764038

ABSTRACT

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a malignant tumor with a poor prognosis. Traditional treatments have limited effectiveness. Regulation of the immune response represents a promising new approach for OSCC treatment. B cells are among the most abundant immune cells in OSCC. However, the role of B cells in OSCC treatment has not been fully elucidated. METHODS: Single-cell RNA sequencing analysis of 13 tissues and 8 adjacent normal tissues from OSCC patients was performed to explore differences in B-cell gene expression between OSCC tissues and normal tissues. We further investigated the relationship between differentially expressed genes and the immune response to OSCC. We utilized tissue microarray data for 146 OSCC clinical samples and RNA sequencing data of 359 OSCC samples from The Cancer Genome Atlas (TCGA) to investigate the role of T-cell leukemia 1 A (TCL1A) in OSCC prognosis. Multiplex immunohistochemistry (mIHC) was employed to investigate the spatial distribution of TCL1A in OSCC tissues. We then investigated the effect of TCL1A on B-cell proliferation and trogocytosis. Finally, lentiviral transduction was performed to induce TCL1A overexpression in B lymphoblastoid cell lines (BLCLs) to verify the function of TCL1A. RESULTS: Our findings revealed that TCL1A was predominantly expressed in B cells and was associated with a better prognosis in OSCC patients. Additionally, we found that TCL1A-expressing B cells are located at the periphery of lymphatic follicles and are associated with tertiary lymphoid structures (TLS) formation in OSCC. Mechanistically, upregulation of TCL1A promoted the trogocytosis of B cells on dendritic cells by mediating the upregulation of CR2, thereby improving antigen-presenting ability. Moreover, the upregulation of TCL1A expression promoted the proliferation of B cells. CONCLUSION: This study revealed the role of B-cell TCL1A expression in TLS formation and its effect on OSCC prognosis. These findings highlight TCL1A as a novel target for OSCC immunotherapy.


Subject(s)
B-Lymphocytes , Carcinoma, Squamous Cell , Gene Expression Regulation, Neoplastic , Mouth Neoplasms , Proto-Oncogene Proteins , Tertiary Lymphoid Structures , Humans , Prognosis , Mouth Neoplasms/pathology , Mouth Neoplasms/genetics , Mouth Neoplasms/metabolism , Mouth Neoplasms/immunology , Tertiary Lymphoid Structures/pathology , Tertiary Lymphoid Structures/immunology , Tertiary Lymphoid Structures/metabolism , B-Lymphocytes/metabolism , B-Lymphocytes/immunology , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/metabolism , Female , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Male , Middle Aged , Cell Line, Tumor , Cell Proliferation
20.
Cell Cycle ; 23(5): 588-601, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38743408

ABSTRACT

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, with a poor prognosis, yet the underlying mechanism needs further exploration. Non-SMC condensin I complex subunit D2 (NCAPD2) is a widely expressed protein in OSCC, but its role in tumor development is unclear. This study aimed to explore NCAPD2 expression and its biological function in OSCC. NCAPD2 expression in OSCC cell lines and tissue specimens was analyzed using quantitative polymerase chain reaction, western blotting, and immunohistochemistry. Cancer cell growth was evaluated using cell proliferation, 5-Ethynyl-2'-deoxyuridine (EdU) staining, and colony formation assays. Cell migration was evaluated using wound healing and Transwell assays. Apoptosis was detected using flow cytometry. The influence of NCAPD2 on tumor growth in vivo was evaluated in a mouse xenograft model. NCAPD2 expression was significantly higher in OSCC than that in normal oral tissue. In vitro, the knockdown of NCAPD2 inhibited OSCC cell proliferation and promoted apoptosis. NCAPD2 depletion also significantly inhibited the migration of OSCC cells. Moreover, NCAPD2 overexpression induced inverse effects on OSCC cell phenotypes. In vivo, we demonstrated that downregulating NCAPD2 could inhibit the tumorigenicity of OSCC cells. Mechanically, OSCC regulation by NCAPD2 involved the Wnt/ß-catenin signaling pathway. These results suggest NCAPD2 as a novel oncogene with an important role in OSCC development and a candidate therapeutic target for OSCC.


Subject(s)
Apoptosis , Carcinoma, Squamous Cell , Cell Movement , Cell Proliferation , Mouth Neoplasms , Wnt Signaling Pathway , Humans , Mouth Neoplasms/pathology , Mouth Neoplasms/metabolism , Mouth Neoplasms/genetics , Animals , Wnt Signaling Pathway/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell Movement/genetics , Apoptosis/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/genetics , Mice , Mice, Nude , Disease Progression , Female , Male , Gene Expression Regulation, Neoplastic , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Mice, Inbred BALB C , beta Catenin/metabolism
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