Development Of Squamous Cell Carcinoma Research Articles

Circ_0058063 Contributed to Oral Squamous Cell Carcinoma Development by Sponging miR-145 and Regulating PI3K/AKT Pathway.

Circular RNAs (circRNAs) are key regulators of oral squamous cell carcinoma (OSCC) progression. In this study, we aimed to clarify the regulatory roles of circ_0058063 and its effect on tumorigenesis in OSCC. Quantitative real-time polymerase chain reaction was conducted to determine the expression levels of microRNA (miR)-145-5p and circ_0058063 in OSCC. Cell viability, adhesion, migration, and epithelial-mesenchymal transition (EMT) of OSCC cells were assessed using cell counting kit-8, cell adhesion, and transwell assays. Western blotting was performed to determine the phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) phosphorylation levels. Xenograft tumor models were constructed to evaluate the tumorigenicity of OSCC cells in vivo. In addition, the interaction between circ_0058063 and miR-145-5p was validated via luciferase reporter and RNA immunoprecipitation assays. Expression levels of circ_0058063 were elevated, whereas those of miR-145-5p were decreased in OSCC. Upregulation of circ_0058063 levels enhanced the viability, adhesion, migration, and EMT of OSCC cells in vitro and promoted tumorigenicity in vivo. Moreover, circ_0058063 promoted OSCC growth by upregulating the PI3K and AKT phosphorylation levels. miR-145-5p overexpression considerably inhibited the PI3K/AKT pathway and decreased OSCC cell viability, adhesion, migration, and EMT. Mechanistically, circ_0058063 sponged miR-145-5p and activated the PI3K/AKT pathway in OSCC cells. Our results revealed that circ_0058063 functions as an oncogene via regulation of the PI3K/AKT pathway by targeting miR-145-5p in OSCC, suggesting its potential for OSCC diagnosis and treatment.

LINC00173 blocks GATA6-mediated transcription of COL5A1 to affect malignant development of oral squamous cell carcinoma.

Aberrant expression of collagen type V alpha 1 chain (COL5A1) has been linked to several forms of human cancers. In this work, we focused on the interaction of the LINC00173/GATA binding protein 6 (GATA6)/COL5A1 axis in the malignant property of oral squamous cell carcinoma (OSCC) cells. We analyzed six publicly accessible datasets GSE160042, GSE74530, GSE138206, GSE23558, GSE31853 and GSE146483 to identify aberrantly expressed genes in OSCC. The expression of COL5A1 in OSCC tissues and cell lines was examined by reverse transcription-quantitative polymerase chain reaction and/or immunohistochemistry. The regulatory mechanism responsible for COL5A1 transcription was predicted via bioinformatics systems, and the interactions of LINC00173, GATA6, and COL5A1 were identified by immunoprecipitation and luciferase assays. Overexpression or downregulation of COL5A1, GATA6, and LINC00173 were induced in OSCC cell lines to determine their roles in the malignant phenotype of the OSCC cells in vitro and in vivo. COL5A1 showed elevated expression in OSCC tissues and cells. The COLA51 knockdown suppressed proliferation, migration and invasiveness, apoptosis resistance, and pro-angiogenic ability of OSCC cells, and it suppressed the growth and dissemination of xenograft tumors in vivo. GATA6 bound to COL5A1 promoter to activate its transcription, whereas LINC00173 bound to GATA6 to block this transcriptional activation. Overexpression of GATA6 or COL5A1 promoted the malignant phenotype of the OSCC cells, which were blocked upon LINC00173 upregulation. This work demonstrates that LINC00173 blocks GATA6-mediated transcription of COL5A1 to affect malignant development of OSCC.

Prevention and Treatment of HPV-Induced Skin Tumors.

Non-melanoma skin cancer (NMSC) is the most common cancer in humans with increasing incidence. Meanwhile, a growing body of evidence has provided a link between skin infections with HPV of the genus beta (betaHPV) and the development of cutaneous squamous cell carcinomas (cSCCs). Based on this association, the development of vaccines against betaHPV has become an important research topic. This review summarizes the current advances in prophylactic and therapeutic betaHPV vaccines, including progresses made in preclinical testing and clinical trials.

Methylation of the tumor associated genes in head and neck squamous cell carcinoma

Introduction. Head and neck cancer is a heterogenous group of malignant tumors of different etiologies, molecular mechanisms of which are still insufficiently studied.Aim. Investigation of DNA methylation status of some tumor associated genes (RASSF1A, RASSF2, RASSF5, CDO1, MEST and WIF1) in patients with head and neck squamous cell carcinoma.Materials and methods. The DNA methylation level of normal and tumor tissues was analyzed using bisulfite conversion and methylation-sensitive high-resolution melting in 25 patients (21 men and 4 women) diagnosed with neck squamous cell carcinoma.Results. There were significant differences in levels of DNA methylation between tumor and normal tissues in the CDO1 and WIF1 genes in all groups and subgroups of patients (larynx and other cancers, squamous cell carcinoma keratinizing and non-keratinizing, primary and recurrent tumor, smokers and non-smokers). The methylation level in the CDO1 gene in tumor tissue was significantly increased in the T4 and T3 stage subgroups compared to T2.Conclusion. The increased level of methylation of the CDO1 and WIF1 genes, as well as changes in their expression are among the molecular mechanisms involved in the neck squamous cell carcinoma development. They can be considered as prognostic and diagnostic markers for this pathology.

Long intergenic non-protein coding RNA 00858 participates in the occurrence and development of esophageal squamous cell carcinoma through the activation of the FTO-m6A-MYC axis by recruiting ZNF184

ObjectivesWe aimed at probing impact of LINC00858 on esophageal squamous cell carcinoma (ESCC) progression via ZNF184-FTO-m6A-MYC axis. MethodsExpression of related genes (LINC00858, ZNF184, FTO, and MYC) was detected in ESCC tissues or cells and their relationships were assessed. After expression alterations in ESCC cells, cell proliferation, invasion, migration, and apoptosis were detected. Tumor formation in nude mice was conducted. ResultsLINC00858, ZNF184, FTO, and MYC were overexpressed in ESCC tissues and cells. LINC00858 enhanced ZNF184 expression to upregulate FTO, which augmented MYC expression. LINC00858 knockdown diminished ESCC cell proliferative, migratory, and invasive properties while elevating apoptosis, which was negated by FTO overexpression. FTO knockdown exerted similar functions of LINC00858 knockdown on ESCC cell movements, which was annulled by MYC upregulation. Silencing LINC00858 repressed tumor growth and related gene expression in nude mice. ConclusionsLINC00858 modulated MYC m6A modification via FTO by recruiting ZNF184, thus facilitating ESCC progression.

Semi-quantitative assessment of environmental tobacco smoke exposure and its association with the development of oral squamous cell carcinoma: A pilot study.

Two known major risk factors for oral squamous cell carcinoma are smoking and alcohol consumption. Environmental tobacco smoke (also known as secondhand smoke) has been proven to be associated with the occurrence of lung and breast carcinoma. This study aimed to assess exposure to environmental tobacco smoke and its association with the development of oral squamous cell carcinomas. Using a standardized questionnaire, 165 cases and 167 controls were asked about their demographic data and risk behaviors, including environmental tobacco smoke exposure. An environmental tobacco smoke score (ETS-score) was developed to semi-quantitatively record the previous exposure to ETS. Statistical analyses were performed with χ2 test or Fishers exact test, and with ANOVA or Welch's t-test as appropriate. An analysis was done using multiple logistic regression. Cases had a significantly increased previous exposure to environmental tobacco smoke compared to the controls (ETS-score: 36.69 ± 26.34 vs 13.92 ± 12.44; p<0.0001). Comparing only the groups without additional active risk factors, exposure to environmental tobacco smoke was associated with a more than threefold higher likelihood of oral squamous cell carcinoma (OR=3.47; 95% CI: 1.31-10.55). Statistically significant differences in ETS-score were found for different tumor locations (p=0.0012) and different histopathological gradings (p=0.0399). A multiple logistic regression analysis confirmed exposure to environmental tobacco smoke as an independent risk factor for the development of oral squamous cell carcinomas (p<0.0001). Environmental tobacco smoke is an important but yet underestimated risk factor for the development of oral squamous cell carcinomas. Further studies are needed to confirm the results, including the usefulness of the developed environmental tobacco smoke score for exposure.

Identification and verification of eight cancer-associated fibroblasts related genes as a prognostic signature for head and neck squamous cell carcinoma

Cancer-associated fibroblasts (CAFs) can exert their immunosuppressive effects by secreting various effectors that are involved in the regulation of tumor-infiltrating immune cells as well as other immune components in the tumor immune microenvironment (TIME), thereby promoting tumorigenesis, progression, metastasis, and drug resistance. Although a large number of studies suggest that CAFs play a key regulatory role in the development of head and neck squamous cell carcinoma (HNSCC), there are limited studies on the relevance of CAFs to the prognosis of HNSCC. In this study, we identified a prognostic signature containing eight CAF-related genes for HNSCC by univariate Cox analysis, lasso regression, stepwise regression, and multivariate Cox analysis. Our validation in primary cultures of CAFs from human HNSCC and four human HNSCC cell lines confirmed that these eight genes are indeed characteristic markers of CAFs. Immune cell infiltration differences analysis between high-risk and low-risk groups according to the eight CAF-related genes signature hinted at CAFs regulatory roles in the TIME, further revealing its potential role on prognosis. The signature of the eight CAF-related genes was validated in different independent validation cohorts and all showed that it was a valid marker for prognosis. The significantly higher overall survival (OS) in the low-risk group compared to the high-risk group was confirmed by Kaplan-Meier (K-M) analysis, suggesting that the signature of CAF-related genes can be used as a non-invasive predictive tool for HNSCC prognosis. The low-risk group had significantly higher levels of tumor-killing immune cell infiltration, as confirmed by CIBERSORT analysis, such as CD8+ T cells, follicular helper T cells, and Dendritic cells (DCs) in the low-risk group. In contrast, the level of infiltration of pro-tumor cells such as M0 macrophages and activated Mast cells (MCs) was lower. It is crucial to delve into the complex mechanisms between CAFs and immune cells to find potential regulatory targets and may provide new evidence for subsequently targeted immunotherapy. These results suggest that the signature of the eight CAF-related genes is a powerful indicator for the assessment of the TIME of HNSCC. It may provide a new and reliable potential indicator for clinicians to predict the prognosis of HNSCC, which may be used to guide treatment and clinical decision-making in HNSCC patients. Meanwhile, CAF-related genes are expected to become tumor biomarkers and effective targets for HNSCC.

Germline mutations in patients with oral mucosal leukoplakia and squamous cell carcinoma: a prospective observational study

Background. The number of studies devoted to the molecular genetics of oral mucosal leukoplakia and squamous cell carcinoma is small, while the obtained results are usually preliminary in nature. We can assume the existence of region-specific pathogenic genetic variants involved in the development of oral mucosal leukoplakia and squamous cell carcinoma. With the knowledge of such variants, it would become possible to develop PCR (polymerase chain reaction) and NGS (next-generation sequencing) test systems for the detection of clinically significant germline mutations.Objectives — to identify pathogenic germline genetic variants in patients with oral mucosal leukoplakia accompanied by grade 1 epithelial dysplasia, as well as oral mucosal squamous cell carcinoma, using new-generation sequencing.Methods. Study design: prospective, observational, cross-sectional, without a control group. The sample included patients (48 persons) of either sex (18 years of age or older) with the following proven and morphologically confirmed diagnoses: oral mucosal leukoplakia accompanied by grade 1 squamous intraepithelial neoplasia of epithelium (24 people) and oral mucosal squamous cell carcinoma (24 people), who sought medical care at the Vitebsk Regional Clinical Dental Center and Vitebsk Regional Clinical Oncological Center in 2019–2020. The identified pathogenic and presumably pathogenic genetic variants involved in the development of these diseases were quantitatively assessed. The study was conducted at the Shareable Core Facilities GENOME of the Institute of Genetics and Cytology of the National Academy of Sciences of Belarus. In order to isolate deoxyribonucleic acid (DNA) from blood samples, a QIAamp DNA FFPE Tissue Kit (Qiagen, Germany) was used. The preparation of DNA libraries and sequencing were carried out by means of an Illumina NextSeq 550 sequencing system (Illumina, Inc., USA) using an Illumina Nextera DNA Exome kit (USA). Bioinformatic analysis was conducted using Illumina BaseSpace specialized software (USA) and Galaxy Project (Galaxy Community, an international non-profit project) in accordance with current guidelines. The obtained data were statistically processed employing specialized software packages Statistica 12 (StatSoft, Inc., USA) and MedCalc 18.9.1 (MedCalc Software, Ltd, Belgium).Results. Next-generation whole-exome sequencing of deoxyribonucleic acid samples isolated from the blood of patients with oral mucosal leukoplakia and squamous cell carcinoma has been conducted in the Republic of Belarus for the first time. The total number of unique germline genetic variants in the exome of both groups of patients was shown to be very high, yet most of them were not pathogenic. In the examined patients, the majority of germline mutations were found to be localized only in 19 exome genes: MAP2K3, DNAH5, HSPG2, OBSCN, SYNE1, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-A, HLA-B, PKD1L2, TTN, AHNAK2, PDE4DIP, MUC3A, MUC4, MUC12, MUC16, and MUC17. In both clinical groups, the greatest number of genetic variants (&gt; 40% of the total number) was detected in MUC3A, MUC4, MUC12, and MUC16, responsible for the synthesis of the glycoprotein mucin family.Conclusion. Oral mucosal leukoplakia and squamous cell carcinoma can arise from the pathogenic variants of MUC3A, MUC4, MUC12, and MUC16.

Fibrosis as a Risk Factor for Cutaneous Squamous Cell Carcinoma in Recessive Dystrophic Epidermolysis Bullosa: A Systematic Review.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe subtype of epidermolysis bullosa caused by changes in collagen VII with a high risk of early development of cutaneous squamous cell carcinoma (cSCC). This review aimed to discuss the relationship between the recurrent healing process, the appearance of fibrosis, and malignant epithelial transformation in RDEB. We searched PubMed, the Regional Portal of the Virtual Health Library, and Embase for articles on the relationship between blistering, recurrent scarring, and fibrosis in the context of cSCC and RDEB. That alterations of collagen VII result in blister formation, scar deficiency associated with inflammation, and increased expression of transforming growth factor β. These events promote the differentiation of myofibroblasts and the expression of profibrotic proteins, leading to structural changes and the establishment of a microenvironment favorable to carcinogenesis. Patients with RDEB and areas of recurrent scarring and fibrosis may be more prone to the development of cSCC.

Differential Expression Profile of Salivary oncomiRNAs among Smokeless Tobacco Users.

The aim of this study was to evaluate the expression of selected salivary oncomiRNAs among smokeless tobacco users and nonsmokers. Twenty-five subjects with chronic smokeless tobacco habit (> 1 year) and 25 nonsmokers were selected for this study. MicroRNA was extracted from saliva samples using the miRNeasy Kit (Qiagen, Hilden, Germany). The forward primers used in the reactions include hsa-miR-21-5p, hsa-miR-146a-3p, hsa-miR-155-3p, and hsa-miR-199a-3p. Relative expression of miRNAs was calculated using the 2-ΔΔCt method. Fold change is calculated by raising 2 to the power of the negative ΔΔCT value. Statistical analysis was carried out using GraphPad Prism 5 software. A p-value less than 0.05 was considered statistically significant. The four tested miRNAs were found overexpressed in saliva of subjects with smokeless tobacco habit when compared with saliva from nontobacco users. miR-21 expression was 3.74 ± 2.26 folds higher among subjects with smokeless tobacco habit compared to nontobacco users (p < 0.01). The expression for miR-146a (5.56 ± 8.3 folds; p < 0.05), miR-155 (8.06 ± 23.4 folds; p < 0.0001) and miR-199a (14.39 ± 30.3 folds; p < 0.05) was significantly higher among subjects with smokeless tobacco habit. Smokeless tobacco leads to salivary overexpression of the miRs 21, 146a, 155, and 199a. Monitoring the levels of these four oncomiRs may provide insight about the future development of oral squamous cell carcinoma, especially in patients with smokeless tobacco habits.

Actinic keratosis as a predictor of primary multiple synchronous squamous cell skin cancer: a clinical case

We present a clinical case of a primary multiple synchronous highly differentiated keratinizing squamous cell skin cancer in an 84-year old patient with multiple actinic keratosis and actinic cheilitis. The clinical case is unique for the simultaneous development of primary multiple squamous cell carcinoma of the tip of the nose and the vermilion zone of the lower lip in a patient with a past occupational and solar burden, a light phenotype, and signs of chronic photo injury the skin. Clinical, dermatoscopic and sonographic signs of keratotic actinic keratosis were identified in the patient and confirmed by pathomorphological examination. The risk factors for malignant transformation of actinic keratosis were found, such as multiple efflorescences and a long disease history. The malignant transformation of the actinic areas manifested as rapidly progressive ulceration zones more than 1 cm in diameter, pronounced hyperkeratosis, inflammation and infiltration of the underlying tissues, increased bleeding and pain. It is to be underlined that definitive and differential diagnosis requires pathomorphological assessment of the skin biopsy sample. This clinical case indicates that patients with multiple foci of actinic keratosis should be under a lifelong follow-up by dermatovenereologists, with mandatory treatment and prevention measure.

Tumorigenic activation around HPV integrated sites in head and neck squamous cell carcinoma.

Human papillomavirus (HPV) is causally involved in the development of head and neck squamous cell carcinoma (HNSCC). The integration of HPV drives tumorigenesis through expression of oncogenic viral genes as well as genomic alterations in surrounding regions. To elucidate involvement of epigenetic dysregulation in tumorigenesis, we here performed integrated analyses of the epigenome, transcriptome and interactome using ChIP-seq, RNA-seq and Hi-C and 4C-seq for HPV(+) HNSCCs. We analyzed clinical HNSCC using The Cancer Genome Atlas data and found that genes neighboring HPV integration sites were significantly upregulated and were correlated with oncogenic phenotypes in HPV(+) HNSCCs. While we found four HPV integration sites in HPV(+) HNSCC cell line UPCI-SCC-090 through target enrichment sequencing, 4C-seq revealed 0.5 to 40 Mb of HPV-interacting regions (HPVIRs) where host genomic regions interacted with integrated HPV genomes. While 9% of the HPVIRs were amplified and activated epigenetically forming super-enhancers, the remaining non-amplified regions were found to show a significant increase in H3K27ac levels and an upregulation of genes associated with GO terms, for example, Signaling by WNT and Cell Cycle. Among those genes, ITPR3 was significantly upregulated, involving UPCI-SCC-090-specific super-enhancer formation around the ITPR3 promoter and in the 80-kb-downstream region. The knockdown of ITPR3 by siRNA or CRISPR deletions of the distant enhancer region led to a significant suppression of cell proliferation. The epigenetic activation of HPVIRs was also confirmed in other cell lines, UM-SCC-47 and UM-SCC-104. These data indicate that epigenetic activation in HPVIRs contributes, at least partially, to genesis of HPV(+) HNSCC.

Skin Cancer Development Is Strongly Associated with Actinic Keratosis in Solid Organ Transplant Recipients: A Danish Cohort Study

Background and Objectives: Solid organ transplant recipients (SOTRs) are at increased risk of skin cancer and suffer from greater disease-specific morbidity and mortality. To risk stratify the expanding SOTR population for more targeted skin cancer screening, a detailed understanding of risk factors is needed. Using combined clinical and pathological data to capture prevalence of actinic keratosis (AK) and skin cancer, this study aimed to identify risk factors of skin cancer development in a Danish SOTR cohort. Methods: The trial comprised a retrospective cohort study of patients attending organ transplant clinics at the dermatological departments of Bispebjerg and Gentofte Hospitals in Copenhagen, Denmark, between 2009 and 2021. In addition to pathology records, AK prevalence was determined by review of electronic medical records (EMRs) of SOTR visits which specifically included descriptions of clinical AK. Prevalence of skin cancer, here defined as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) (invasive or in situ), or melanoma (invasive or in situ), was determined by EMR and pathology code review. Additional data extracted from EMRs included age, sex, Fitzpatrick skin type, transplantation date and type, and immunosuppressive therapy. The effect of risk factors on skin cancer was calculated by Cox proportional hazards regression. Results: A total of 822 SOTRs were included with a mean follow-up duration of 10.8 years (SD 2.4 years). A skin dysplasia diagnosis was identified in 30% (n = 250) of the population, consisting of either AK (22%; n = 177), skin cancer (23%; n = 186) or both (14%; n = 113). An AK diagnosis predicted both SCC (odds ratio [OR]: 31.5 [95% CI: 9.8–100.6], p < 0.0001) and BCC development (OR: 2.3 [95% CI: 1.6–3.3], p < 0.0001), with AKs diagnosed an average 3.1 years before the first SCC (p < 0.0001). Correspondingly, while the risk of SCC in SOTRs without AK was 1.4% 25 years after transplantation, SOTRs with AKs had a 23% SCC risk only 10 years posttransplant. Other identified risk factors included Fitzpatrick skin type I (BCC: OR: 2.4 [95% CI: 1.2–5.0], p = 0.018; SCC: 3.2 [95% CI: 1.2–8.2], p = 0.016) and transplantation duration >15 years (BCC: OR: 1.8 [95% CI: 1.2–2.7], p = 0.007). No significant association between skin cancer development and sex or immunosuppressive regimen was shown. Conclusion: Keratinocyte carcinoma is strongly associated with an AK diagnosis in SOTRS and should prompt intensified skin cancer screening in affected individuals.

PAK4 kinase as a potential therapeutic target of the transcription factor p63-meditated squamous cell carcinomas of the pancreas.

This study was undertaken to better understand the pathogenesis of squamous cell carcinoma (SCC) of the pancreas and to determine if inhibiting the p21-activated kinase 4 (PAK4) activity could be used for treating pancreatic SCCs. Here are the context of the research and preliminary results: Although significant research has been done on adenocarcinoma of the pancreas, the current understanding of pancreatic SCCs remains limited, and there is no known cure for it. We established a mouse model of pancreatic SCCs by over-expressing the transcription factor p63 in the pancreatic ductal epithelial-specific manner. Our working hypothesis was that dysregulation of p63-mediate transcriptional networks can lead to the development of pancreatic SCCs. As the stability of p63 is regulated at the protein level by phosphorylation, we searched for kinase that stabilizes p63 and identified PAK4 kinase. Although previous studies have shown that PAK4 is frequently overexpressed in ductal adenocarcinoma of the pancreas, the involvement of PAK4 in the pathogenesis of pancreatic SCCs remained unclear. We have demonstrated that suppression of the PAK4 kinase activity by a small molecule inhibitor reduced p63 levels in cellular models of pancreatic SCCs, leading to the complete suppression of their proliferation in vitro. These results indicate that PAK4 kinase can serve as a novel therapeutic target for some pancreatic SCCs and that PAK4-mediated stabilization/upregulation of the transcription factor p63 can be the key molecular event underlying the pathogenesis of pancreatic SCCs. We will use our mouse models in future studies to determine if administration of the PAK4 inhibitor in vivo can be used as an effective therapy for the treatment and prevention of the development of this most dangerous cancer subtype in human cancers.

High-risk HPV-related squamous cell carcinoma in the temporal bone: a rare but noteworthy subtype.

High-risk human papillomavirus (HPV) is a risk factor for the development of several head and neck squamous cell carcinomas (SCCs). However, there have been few reports of high-risk HPV infection in temporal bone squamous cell carcinomas (TBSCCs), and thus the prevalence and clinicopathologic significance of high-risk HPV in TBSCCs are still unclear. We retrospectively collected 131 TBSCCs and analyzed them for transcriptionally active high-risk HPV infection using messenger RNA in situ hybridization; we also assessed the utility of p16-immunohistochemistry (IHC) and Rb-IHC to predict HPV infection. Eighteen (13.7%) of the 131 TBSCCs were positive for p16-IHC, and five of them were positive for high-risk HPV infection (the estimated high-risk HPV positivity rate was 3.8% [5/131]). Interestingly, all five HPV-positive patients were male and had TBSCC on the right side. In the p16-IHC+/HPV+ cases (n = 5), the Rb-IHC showed a partial loss pattern (n = 4) or complete loss pattern (n = 1). In contrast, all p16-IHC-negative cases (n = 113) showed an Rb-IHC preserved pattern. The positive predictive value (PPV) of p16-IHC positivity for high-risk HPV infection was low at 27.8%, while the combination of p16-IHC+/Rb-IHC partial loss pattern showed excellent reliability with a PPV of 100%. The prognostic significance of high-risk HPV infection remained unclear. High-risk HPV-related TBSCC is an extremely rare but noteworthy subtype.

Evaluating the Histologic Grade of Digital Squamous Cell Carcinomas in Dogs and Copy Number Variation of KIT Ligand—A Correlation Study

Dark-haired dogs are predisposed to the development of digital squamous cell carcinoma (DSCC). This may potentially suggest an underlying genetic predisposition not yet completely elucidated. Some authors have suggested a potential correlation between the number of copies KIT Ligand (KITLG) and the predisposition of dogs to DSCC, containing a higher number of copies in those affected by the neoplasm. In this study, the aim was to evaluate a potential correlation between the number of copies of the KITLG and the histological grade of malignancy in dogs with DSCC. For this, 72 paraffin-embedded DSCCs with paired whole blood samples of 70 different dogs were included and grouped according to their haircoat color as follow: Group 0/unknown haircoat color (n = 11); Group 1.a/black non-Schnauzers (n = 15); group 1.b/black Schnauzers (n = 33); group 1.c/black and tan dogs (n = 7); group 2/tan animals (n = 4). The DSCCs were histologically graded. Additionally, KITLG Copy Number Variation (CNV) was determined by ddPCR. A significant correlation was observed between KITLG copy number and the histological grade and score value. This finding may suggest a possible factor for the development of canine DSCC, thus potentially having an impact on personalized veterinary oncological strategies and breeding programs.

FUT8-AS1/miR-944/Fused in Sarcoma/Transcription Factor 4 Feedback Loop Participates in the Development of Oral Squamous Cell Carcinoma through Activation of Wnt/β-Catenin Signaling Pathway

As a common type of head and neck squamous cell carcinoma, oral squamous cell carcinoma (OSCC) is a lethal and deforming disease. Long noncoding RNAs have emerged as critical modulators in different malignancies. However, the role of fucosyltransferase 8 antisense RNA 1 (FUT8-AS1) in OSCC still remains elusive. In this study, quantitative RT-PCR and Western blot were used for the measurement of RNAs and proteins. Mechanism assays explored the putative correlation among genes. Invitro assays evaluated the changes in OSCC cell malignant phenotype, whereas invivo assays highlighted the influence of FUT8-AS1 on tumor growth. FUT8-AS1, aberrantly up-regulated in OSCC tissues and cells, could exacerbate OSCC cell malignant behaviors. The cancerogenic property of FUT8-AS1 in OSCC was further confirmed via animal experiments. Furthermore, FUT8-AS1 enhanced the expression of transcription factor 4 (TCF4) via sponging miR-944 and recruiting fused in sarcoma (FUS), thus affecting OSCC cell biological behaviors via modulation on Wnt/β-catenin signaling activity. In addition, TCF4 was validated as the transcriptional activator of FUT8-AS1. To conclude, TCF4-mediated FUT8-AS1 could exacerbate OSCC cell malignant behaviors and facilitate tumor growth via modulation on miR-944/FUS/TCF4.

The Roles of Exosomes in the Diagnose, Development and Therapeutic Resistance of Oral Squamous Cell Carcinoma.

Oral cancer is one of the most common cancers worldwide, of which more than half of patients are diagnosed at a locally advanced stage with poor prognosis due to recurrence, metastasis and resistant to treatment. Thus, it is imperative to further explore the potential mechanism of development and drug resistance of oral cancer. Exosomes are small endosome-derived lipid nanoparticles that are released by cells. Since the cargoes of exosomes were inherited from their donor cells, the cargo profiles of exosomes can well recapitulate that of their donor cells. This is the theoretical basis of exosome-based liquid biopsy, providing a tool for early diagnosis of oral cancer. As an important intracellular bioactive cargo delivery vector, exosomes play a critical role in the development of oral cancer by transferring their cargoes to receipt cells. More importantly, recent studies have revealed that exosomes could induce therapy-resistance in oral cancer through multiple ways, including exosome-mediated drug efflux. In this review, we summarize and compare the role of exosomes in the diagnosis, development and therapy-resistant of oral cancer. We also highlight the clinical application of exosomes, and discuss the advantages and challenges of exosomes serving as predictive biomarker, therapy target and therapy vector in oral cancer.

Porphyromonas gingivalis predicts local recurrence after endoscopic submucosal dissection of early esophageal squamous cell carcinoma or precancerous lesion

BackgroundPorphyromonas gingivalis plays an oncogenic role in development and progression of esophageal squamous cell carcinoma (ESCC). However, the impact of P. gingivalis on local recurrence of early ESCC or precancerous lesion after ESD treatment remains unknown. The present study aimed to evaluate the impact of P. gingivalis on local recurrence after ESD treatment of early ESCC or high-grade dysplasia (HGD).MethodsThe amount of P. gingivalis was assessed by immunohistochemistry in 205 patients with early ESCC or HGD. Univariate and multivariate Cox regression analyses were performed to determine the effect of P. gingivalis on local recurrence. Propensity score matching analysis was performed to reduce the imbalance of baseline characteristics. A nomogram integrating significant prognostic factors was built for local recurrence prediction.ResultsThe amount of P. gingivalis increased significantly in neoplasms that invaded up to muscularis mucosa and submucosa compared with lesions confined to epithelium or lamina propria. Overabundance of P. gingivalis was positively associated with invasion depth, post-ESD stricture and local recurrence. Univariate and multivariate Cox regression analyses revealed that P. gingivalis, longitudinal length of lesion and lymphovascular invasion were independent predictors for post-ESD recurrence. A nomogram comprising P. gingivalis, lymphovascular involvement, and lesion length performed well for prediction of post-ESD local recurrence with the concordance indices of 0.72 (95%CI, 0.62 to 0.80), 0.72 (95%CI, 0.63 to 0.80), and 0.74 (95%CI, 0.65 to 0.83) in the validation cohort, the entire cohort, and the subcohort after PSM, respectively.ConclusionP. gingivalis overabundance is a risk factor and a potential predictor for local recurrence of early ESCC or HGD after ESD treatment. Thus, clearance of P. gingivalis represents an attractive strategy for prognosis improvement and for prevention of ESCC.

Tissue mechanics modulate PCNP expression in oral squamous cell carcinomas with different differentiation.

PEST-containing nuclear protein (PCNP), a novel zinc finger protein, participates in cell cycle regulation. Previous studies have confirmed that PCNP plays a role in mediating cellular development and invasion in a variety of cancer types. However, the relationship between PCNP expression and the occurrence and development of oral squamous cell carcinoma (OSCC) requires further exploration. In this study, we used biological atomic force microscopy to examine the histomorphological and mechanical properties of OSCC to explore the relationship between PCNP expression and differentiation of OSCC. Seventy-seven OSCC samples with varying degrees of differentiation were selected for hematoxylin and eosin staining, immunohistochemistry, and cellular mechanical measurement. The expression of PCNP and the mechanical properties such as stiffness and roughness of the tissue interface in OSCC samples were investigated. The Kaplan-Meier survival curve was utilized to assess the relationship of PCNP expression with patient survival. The level of PCNP was significantly higher in well-differentiated OSCC than in moderately and poorly differentiated OSCC (P < 0.001). High expression of PCNP was specifically associated with higher tumor differentiation, lack of lymph node metastasis, and lower tumor node metastasis stage (all P < 0.05). Patients with high PCNP expression had a higher survival rate than those with low PCNP expression. The average variation of stiffness within a single tissue ranged from 347 kPa to 539 kPa. The mean surface roughness of highly, moderately, and poorly differentiated OSCC and paraneoplastic tissues were 795.53 ± 47.2 nm, 598.37 ± 45.76 nm, 410.16 ± 38.44 nm, and 1010.94 ± 119.07 nm, respectively. Pearson correlation coefficient demonstrated a positive correlation between PCNP expression and tissue stiffness of OSCC (R = 0.86, P < 0.001). The expression of PCNP was positively correlated with patient survival, tumor differentiation, and mechanical properties of tissue interfaces. PCNP is a potential biomarker for the early diagnosis and staging of OSCC. Furthermore, determination of the mechanical properties of the tissue interface could provide further useful information required for the detection and differentiation of OSCC.