Microsatellite alterations in phenotypically normal esophageal squamous epithelium and metaplasia-dysplasia-adenocarcinoma sequence

AIM: To investigate the microsatellite alterations in phenotypically normal esophageal squamous epithelium and metaplasia-dysplasia-adenocarcinoma sequence. METHODS: Forty-one specimens were obtained from esophageal cancer (EC) patients. Histopathological assessment identified 23 squamous cell carcinomas (SCC) and 18 adenocarcinomas (ADC), including only 8 ADC with Barrett esophageal columnar epithelium (metaplasia) and dysplasia adjacent to ADC. Paraffin-embedded normal squamous epithelium, Barrett esophageal columnar epithelium (metaplasia), dysplasia and esophageal tumor tissues were dissected from the surrounding tissues under microscopic guidance. DNA was extracted using proteinase K digestion buffer, and DNA was diluted at 1:100, 1:1000, 1:5000, 1:10 000 and 1:50 000, respectively. Seven microsatellite markers (D2S123, D3S1616, D3S1300, D5S346, D17S787, D18S58 and BATRII loci) were used in this study. Un-dilution and dilution polymerase chainreactions (PCR) were performed, and microsatellite analysis was carried out. RESULTS: No statistically significant difference was found in microsatellite instability (MSI) and loss of heterozygosity (LOH) of un-diluted DNA between SCC and ADC. The levels of MSI and LOH were high in the metaplasia-dysplasia-adenocarcinoma sequence of diluted DNA. The more the diluted DNA was, the higher the rates of MSI and LOH were at the above 7 loci, especially at D3S1616, D5S346, D2S123, D3S1300 and D18S58 loci. CONCLUSION: The sequence of metaplasia-dysplasia-adenocarcinoma is associated with microsatellite alterations, including MSI and LOH. The MSI and LOH may be the early genetic events during esophageal carcinogenesis, and genetic alterations at the D3S1616, D5S346 and D3S123 loci may play a role in the progress of microsatellite alterations.

A squamous metaplasia in a gastric ulcer scar of the antrum

An 81-year-old man presented with epigastric pain and weight loss for one month. He had a past history of pulmonary tuberculosis, 10 years ago. We performed a gastroscopy, which showed a linear depressed whitish gastric ulcer scar (0.8 cm in length) in the posterior wall of the prepyloric antrum. The result of biopsy was reported as squamous epithelium. Immunohistochemical staining using an antibody to high molecular weight cytokeratin (HMC) revealed positive staining in the squamous epithelium. Two years later, the lesion was followed up. The lesion remained at same site endoscopically, but no squamous epithelium could be seen microscopically.

Pleomorphic Adenoma with Exuberant Squamous Metaplasia and Keratin Cysts Mimicking Squamous Cell Carcinoma in Minor Salivary Gland

Salivary gland tumors, the second most common neoplasm of the mouth after squamous cell carcinoma, account for a significant proportion of tumors of the oral and perioral regions. An unusual case of adenoma presented as a solitary intraoral palatine mass in a 32-year-old woman is reported here. The tumor was interpreted as an unusual pleomorphic adenoma because of the presence of exuberant squamous metaplasia, clinically mimicking squamous cell carcinoma. Moreover, the presence of cystic structures filled with keratinized material was also salient feature. Pleomorphic adenomas may occasionally display focal squamous metaplastic changes;when extensive, it presents the potential for misinterpretation of the histology as indicative of well-differentiated squamous cell carcinoma.

Spatial transcriptomics reveals that metabolic characteristics define the tumor immunosuppression microenvironment via iCAF transformation in oral squamous cell carcinoma

Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism,and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-βexpression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.

WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling

Wnt signaling are critical pathway involved in organ development, tumorigenesis, and cancer progression. WNT7A, a member of the Wnt family, remains poorly understood in terms of its role and the underlying molecular mechanisms it entails in head and neck squamous cell carcinoma (HNSCC). According to the Cancer Genome Atlas (TCGA), transcriptome sequencing data of HNSCC, the expression level of WNT7A in tumors was found to be higher than in adjacent normal tissues, which was validated using Real-time RT-PCR and immunohistochemistry. Unexpectedly, overexpression of WNT7A did not activate the canonical Wnt-β-catenin pathway in HNSCC. Instead, our findings suggested that WNT7A potentially activated the FZD7/JAK1/STAT3 signaling pathway, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis. Furthermore, in a patient-derived xenograft (PDX) tumor model, high expression of WNT7A and phosphorylated STAT3 was observed, which positively correlated with tumor progression.These findings underscore the significance of WNT7A in HNSCC progression and propose the targeting of key molecules within the FZD7/JAK1/STAT3 pathway as a promising strategy for precise treatment of HNSCC.

FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression.Aberrant glycosylation has been intricately linked with immune escape and tumor growth.SEMA7A is a highly glycosylated protein with five glycosylated sites.The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear.Here,we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma,and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides(Asn 105,157,258,330,and 602)via a direct protein‒protein interaction.A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane.Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8,whereas TGF-β1 promotes abnormal glycosylation of SEMA7A via induction of epithelial–mesenchymal transition.Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8^(+)T cells along a trajectory toward an exhausted state,thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death.Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy.Finally,we also define RBM4,a splice regulator,as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing.These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

Prognostic significance of SOX2 for chemotherapeutic patients with oral squamous cell carcinoma

Oral squamous cell carcinoma(OSCC)is the most common oral cancers worldwide,accounting for over 90%of all oral malignancies[1].Despite encouraging improvements in therapeutic approaches,including surgical resection,chemotherapy,and radiotherapy,the five-year overall survival rate of OSCC has not been improved significantly over the past decades,mainly due to the high ratio of tumor recurrence and metastasis.

Retraction: KIF18A is a potential prognostic factor and promotes tumor progression in oral tongue squamous cell carcinoma

Following the publication of this paper,a concerned reader alerted the Editors to the similarities between the data presented in this article and data published in prior works by different authors from different research institutions.Specifically,the colony formation data in Fig.4B,the Western Blot data in Fig.4C,and the tumor data in Figs.5A and 5B appear strikingly similar to data previously published.

Identifying Comprehensive Genomic Alterations and Potential Neoantigens for Cervical Cancer Immunotherapy in a Cohort of Chinese Squamous Cell Carcinoma of the Cervix

Objective Genomic alterations and potential neoantigens for cervical cancer immunotherapy were identified in a cohort of Chinese patients with cervical squamous cell carcinoma(CSCC).Methods Whole-exome sequencing was used to identify genomic alterations and potential neoantigens for CSCC immunotherapy.RNA Sequencing was performed to analyze neoantigen expression.Results Systematic bioinformatics analysis showed that C>T/G>A transitions/transversions were dominant in CSCCs.Missense mutations were the most frequent types of somatic mutation in the coding sequence regions.Mutational signature analysis detected signature 2,signature 6,and signature 7 in CSCC samples.PIK3CA,FBXW7,and BICRA were identified as potential driver genes,with BICRA as a newly reported gene.Genomic variation profiling identified 4,960 potential neoantigens,of which 114 were listed in two neoantigen-related databases.Conclusion The present findings contribute to our understanding of the genomic characteristics of CSCC and provide a foundation for the development of new biotechnology methods for individualized immunotherapy in CSCC.

Latest insights into the global epidemiological features,screening,early diagnosis and prognosis prediction of esophageal squamous cell carcinoma

As a highly invasive carcinoma,esophageal cancer(EC)was the eighth most prevalent malignancy and the sixth leading cause of cancer-related death worldwide in 2020.Esophageal squamous cell carcinoma(ESCC)is the major histological subtype of EC,and its incidence and mortality rates are decreasing globally.Due to the lack of specific early symptoms,ESCC patients are usually diagnosed with advanced-stage disease with a poor prognosis,and the incidence and mortality rates are still high in many countries,especially in China.Therefore,enormous challenges still exist in the management of ESCC,and novel strategies are urgently needed to further decrease the incidence and mortality rates of ESCC.Although the key molecular mechanisms underlying ESCC pathogenesis have not been fully elucidated,certain promising biomarkers are being investigated to facilitate clinical decision-making.With the advent and advancement of highthroughput technologies,such as genomics,proteomics and metabolomics,valuable biomarkers with high sensitivity,specificity and stability could be identified for ESCC.Herein,we aimed to determine the epidemiological features of ESCC in different regions of the world,especially in China,and focused on novel molecular biomarkers associated with ESCC screening,early diagnosis and prognosis prediction.

The activation of adenosine monophosphate–activated protein kinase inhibits the migration of tongue squamous cell carcinoma cells by targeting Claudin-1 via epithelial–mesenchymal transition

Background:The role of Claudin-1 in tongue squamous cell carcinoma(TSCC)metastasis needs further clarification,particularly its impact on cell migration.Herein,our study aims to investigate the role of Claudin-1 in TSCC cell migration and its underlying mechanisms.Methods:36 TSCC tissue samples underwent immunohistochemical staining for Claudin-1.Western blotting and immunofluorescence analyses were conducted to evaluate Claudin-1 expression and distribution in TSCC cells.Claudin-1 knockdown cell lines were established using short hairpin RNA transfection.Migration effects were assessed through wound healing assays.Furthermore,the expression of EMTassociated molecules was measured via western blotting.Results:Claudin-1 expression decreased as TSCC malignancy increased.Adenosine monophosphate–activated protein kinase(AMPK)activation led to increased Claudin-1 expression and membrane translocation,inhibiting TSCC cell migration and epithelial–mesenchymal transition(EMT).Conversely,Claudin-1 knockdown reversed these inhibitory effects on migration and EMT caused by AMPK activation.Conclusions:Our results indicated that AMPK activation suppresses TSCC cell migration by targeting Claudin-1 and EMT pathways.

Plasma DNA methylation detection for early screening,diagnosis,and monitoring of esophageal adenocarcinoma and squamous cell carcinoma

BACKGROUND The early diagnosis rate of esophageal cancer(EC),one of the most prevalent digestive tract cancers worldwide,remains low.AIM To investigate the utility of plasma SHOX2,SEPTIN9,EPO,and RNF180 methylation in the clinical diagnosis and monitoring of EC.Plasma samples were collected from 210 patients at Hubei Cancer Hospital,and TaqMan polymerase chain reaction was employed to detect plasma SHOX2,SEPTIN9,RNF180,and EPO methylation.The area under the curve was used to estimate their diagnostic value for EC.Cox and logistic regression analyses were used to estimate the independent screening risk factors for patients with EC.RESULTS The sensitivity and specificity of combined assessment of plasma SHOX2,SEPTIN9,RNF180,and EPO methylation for adenocarcinoma,squamous cell carcinoma(SCC),and EC detection were 66.67%and 86.27%,77.40%and 85.29%,and 76.19%and 86.27%,respectively;the area under the curve values for diagnosing adenocarcinoma,SCC,and EC were 0.737[95%confidence interval(CI):0.584–0.89],0.824(95%CI:0.775–0.891),and 0.864(95%CI:0.809–0.92),respectively.CONCLUSION According to our findings,plasma SHOX2,SEPTIN9,RNF180,and EPO methylation exhibits appreciated sensitivity for diagnosing EC.The precise measurement of plasma SHOX2,SEPTIN9,RNF180,and EPO methylation can improve EC diagnosis and therapy efficacy monitoring.

MicroRNAs:A novel signature in the metastasis of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma(ESCC)is a malignant epithelial tumor,characterized by squamous cell differentiation,it is the sixth leading cause of cancer-related deaths globally.The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered,coupled with higher risk of metastasis,which is an exceedingly malignant charac-teristic of cancer,frequently leading to a high mortality rate.Unfortunately,there is currently no specific and effective marker to predict and treat metastasis in ESCC.MicroRNAs(miRNAs)are a class of small non-coding RNA molecules,approximately 22 nucleotides in length.miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence,progression,and prognosis of cancer.Here,we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis,and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors.This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis,with the ultimate aim of reducing the mortality rate among patients with ESCC.

Current Research Status of MicroRNAs in Squamous Cell Carcinoma of the Tongue

Tongue squamous cell carcinoma (TSCC) is the most invasive type of oral malignant tumor, posing a serious threat to human life and health. Its pathogenesis is complex and has a high degree of malignancy. Recurrence and metastasis often lead to poor prognosis. MicroRNAs are a type of single stranded small molecule RNA with only 18 - 25 nucleotides, which can regulate the expression of various genes and participate in the occurrence and development of tumors. Studies have found that microRNA expression profiling can serve as a reliable and stable biological indicator for early diagnosis and prognosis of tumors. This article provides a review of the research status of MicroRNAs in squamous cell carcinoma of the tongue.

Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a deadly malignancy with limited treatment options.Deubiquitinases(DUBs)have been confirmed to play a crucial role in the development of malignant tumors.JOSD2 is a DUB involved in con-trolling protein deubiquitination and influencing critical cellular processes in cancer.AIM To investigate the impact of JOSD2 on the progression of ESCC.METHODS Bioinformatic analyses were employed to explore the expression,prognosis,and enriched pathways associated with JOSD2 in ESCC.Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines(KYSE30 and RESULTS )Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues,which was associated with poor prognosis.Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells.JOSD2 knockdown inhibited ESCC cell activity,including proliferation and colony-forming ability.Moreover,JOSD2 knockdown decreased the drug resistance and migration of ESCC cells,while JOSD2 overexpression enhanced these phenotypes.In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC.Mechanistically,JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways.Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2,which identified the four primary proteins that bind to JOSD2,namely USP47,IGKV2D-29,HSP90AB1,and PRMT5.CONCLUSION JOSD2 plays a crucial role in enhancing the proliferation,migration,and drug resistance of ESCC,suggesting that JOSD2 is a potential therapeutic target in ESCC.

Squamous Cell Carcinoma of the Middle Ear: Case Report and Literature Review

Malignant tumors originating from the middle ear are rare. The literature identifies chronic inflammation and Human Papillomavirus (HPV) infection as the most common risk factors. A CT scan to assess bony invasion and an MRI to evaluate soft tissue involvement, depth of invasion, and perineural invasion, followed by a biopsy, are indispensable for diagnosis and treatment. There is no standard treatment for squamous cell carcinoma of the middle ear, however, most reported cases are treated with surgical resection followed by postoperative radiotherapy. Given the challenges of achieving complete surgical excision, radiotherapy plays a crucial role in controlling middle ear cancers, as demonstrated in our case. We present a case of squamous cell carcinoma of the middle ear in a 63-year-old female with a history of chronic suppurative otitis media. The patient underwent a right subtotal petrosectomy without lymph node dissection followed by concurrent chemoradiotherapy. At the one-year follow visit, no recurrence or metastasis was detected.

Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

Fibroblast activation protein (FAP) as a prognostic biomarker in multiple tumors and its therapeutic potential in head and neck squamous cell carcinoma

Background:Fibroblast activation protein(FAP),a cell surface serine protease,plays roles in tumor invasion and immune regulation.However,there is currently no pan-cancer analysis of FAP.Objective:We aimed to assess the pan-cancer expression profile of FAP,its molecular function,and its potential role in head and neck squamous cell carcinoma(HNSC).Methods:We analyzed gene expression,survival status,immune infiltration,and molecular functional pathways of FAP in The Cancer Genome Atlas(TCGA)and Genotype Tissue Expression(GTEx)tumors.Furthermore,to elucidate the role of FAP in HNSC,we performed proliferation,migration,and invasion assays post-FAP overexpression or knock-down.Results:FAP expression was elevated in nine tumor types and was associated with poor survival in eight of them.In the context of immune infiltration,FAP expression negatively correlated with CD8+T-cell infiltration infive tumor types and positively with regulatory T-cell infiltration in four tumor types.Our enrichment analysis highlighted FAP’s involvement in the PI3K-Akt signaling pathway.In HNSC cells,FAP overexpression activated the PI3K-Akt pathway,promoting tumor proliferation,migration,and invasion.Conversely,FAP knockdown showed inhibitory effects.Conclusion:Our study unveils the association of FAP with poor tumor prognosis across multiple cancers and highlights its potential as a therapeutic target in HNSC.

Artificial intelligence enhances the management of esophageal squamous cell carcinoma in the precision oncology era

Esophageal squamous cell carcinoma(ESCC)is the most common histological type of esophageal cancer with a poor prognosis.Early diagnosis and prognosis assessment are crucial for improving the survival rate of ESCC patients.With the advancement of artificial intelligence(AI)technology and the proliferation of medical digital information,AI has demonstrated promising sensitivity and accuracy in assisting precise detection,treatment decision-making,and prognosis assessment of ESCC.It has become a unique opportunity to enhance comprehen-sive clinical management of ESCC in the era of precision oncology.This review examines how AI is applied to the diagnosis,treatment,and prognosis assessment of ESCC in the era of precision oncology,and analyzes the challenges and potential opportunities that AI faces in clinical translation.Through insights into future prospects,it is hoped that this review will contribute to the real-world application of AI in future clinical settings,ultimately alleviating the disease burden caused by ESCC.

Impact of baseline steroids on the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell carcinoma

BACKGROUND Immunochemotherapy involving the combination of programmed cell death 1/programmed cell death ligand 1 inhibitors with chemotherapy has advanced the treatment of locally advanced esophageal squamous cell carcinoma(ESCC).The use of corticosteroids as pretreatment might reduce immunotherapy efficacy.AIM To investigate the impact of baseline corticosteroid use on neoadjuvant immunochemotherapy(nIC)outcomes in locally advanced ESCC patients.METHODS Patients with locally advanced ESCC who received nIC at Sun Yat-sen University Cancer Center and the Third Affiliated Hospital of Sun Yat-sen University were included.Patients were divided into dexamethasone and antihistamine groups on the basis of the administered pretreatment.Antiallergic efficacy and safety were evaluated,as well as its impact on short-term efficacy[complete pathological response(pCR),major pathological response(MPR)]and long-term efficacy[overall survival(OS),progression-free survival(PFS)]of nIC.RESULTS From September 2019 to September 2023,142 patients were analyzed.No severe treatment-related adverse events or deaths were observed.Allergy occurrence was greater in the antihistamine group(P=0.014).Short-term efficacy was not significantly different:The pCR rates were 29.9%and 40.0%,and the MPR rates were 57.9%and 65.7%in the dexamethasone and antihistamine groups,respectively.The long-term efficacy was not significantly different:The 2 years OS rates were 95.2%and 93.5%,and the 2 years PFS rates were 90.3%and 87.8%.Subgroup analysis revealed no difference in OS between the 20 mg dexamethasone group and the<20 mg dexamethasone group,but PFS was significantly greater in the 20 mg dexamethasone group(93.9%vs 56.4%,P=0.001).CONCLUSION Dexamethasone or antihistamines can be used before nIC in locally advanced ESCC without affecting short-or long-term efficacy.Administering 20 mg dexamethasone before nIC may improve PFS in ESCC.