Progression Of Squamous Cell Carcinoma Research Articles

FAM65A promotes the progression and growth of lung squamous cell carcinoma in vivo and vitro

BackgroundsCurrently, family with sequence similarity 65 member A (FAM65A) is reported as a pivotal regulator in various cancers. However, the effect of FAM65A in lung squamous cell carcinoma (LSCC) is still unclear, the prime objective of this research is to explore the role of FAM65A in LSCC.MethodsGene expression data and correlated clinical information were downloaded from the public database and the expression of FAM65A was detected. The expression of FAM65A was also detected in our collected clinical samples and LSCC cell lines. Survival package of R language was used to determine the survival significance of FAM65A. Proteins expression level was determined via western blot assay. Cell function experiments and in vivo experiments were performed to explore the effect of FAM65A on LSCC cell biological behaviors.ResultsFAM65A expression was significantly increased in LSCC clinical samples and cell lines. High FAM65A expression predicted poor prognosis in LSCC patients. After silencing FAM65A, the ability of LSCC cell proliferation, invasion and migration was decreased, and LSCC cell cycle was blocked. Moreover, in vivo experiments revealed that silencing FAM65A could inhibit LSCC cell proliferation.ConclusionsHigh FAM65A expression could enhance proliferative, invasive and migratory abilities of LSCC. FAM65A might be a novel biomarker of LSCC.

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

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

Prevention of supercritical carbon dioxide fluid extract from Chrysanthemum indicum Linnén on cutaneous squamous cell carcinomas progression following UV irradiation in mice.

Chrysanthemum indicum Linnén (C. indicum), a medicinal and food herb with various bioactive components, may be of beneficial use in cosmetics and the treatment of skin-related diseases. However, to date, few studies have been reported on its potential preventive and therapeutic effects on skin cancer. Therefore, the present study aimed to investigate the effect and potential mechanism of action of supercritical carbon dioxide extract from C. indicum (CISCFE) on UV-induced skin cancer in a mouse model. Kunming mice were allocated randomly to five treatment groups: Sham, model, low concentration CISCFE, high concentration CISCFE and positive control nicotinamide groups. The dorsal skin of mice was irradiated with UV light for 31 weeks. Histopathological changes, ELISA assays, immunohistochemical analysis and western blotting were performed to investigate the potential therapeutic effects of CISCFE. The results showed that CISCFE alleviated skin oxidative and inflammatory damage in a UV-induced mouse model of skin cancer. Moreover, CISCFE suppressed abnormal activation of proto-oncogene c-Myc and the overexpression of Ki-67 and VEGF, and increased expression of the anti-oncogene PTEN, thereby reducing abnormal proliferation of the epidermis and blood vessels. Additionally, CISCFE increased the protein expression levels of NAD-dependent protein deacetylase sirtuin-1 (SIRT1), Kelch-like ECH associated protein 1 (Keap1) and inhibited the expression of nuclear factor 2 erythroid 2-related factor 2 (Nrf2), phosphorylated (p)-p62 (Ser 349), p-p65 and acetyl-p65 proteins in a UV-induced skin cancer mouse model. In summary, CISCFE exhibited potent anti-skin cancer activity, which may be attributed its potential effects on the p62/Keap1-Nrf2 and SIRT1/NF-κB pathways.

HMGA1 promotes the progression of esophageal squamous cell carcinoma by elevating TKT-mediated upregulation of pentose phosphate pathway

Esophageal squamous cell carcinoma (ESCC) possesses a poor prognosis and treatment outcome. Dysregulated metabolism contributes to unrestricted growth of multiple cancers. However, abnormal metabolism, such as highly activated pentose phosphate pathway (PPP) in the progression of ESCC remains largely unknown. Herein, we report that high-mobility group AT-hook 1 (HMGA1), a structural transcriptional factor involved in chromatin remodeling, promoted the development of ESCC by upregulating the PPP. We found that HMGA1 was highly expressed in ESCC. Elevated HMGA1 promoted the malignant phenotype of ESCC cells. Conditional knockout of HMGA1 markedly reduced 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumorigenesis in mice. Through the metabolomic analysis and the validation assay, we found that HMGA1 upregulated the non-oxidative PPP. With the transcriptome sequencing, we identified that HMGA1 upregulated the expression of transketolase (TKT), which catalyzes the reversible reaction in non-oxidative PPP to exchange metabolites with glycolytic pathway. HMGA1 knockdown suppressed the PPP by downregulating TKT, resulting in the reduction of nucleotides in ESCC cells. Overexpression of HMGA1 upregulated PPP and promoted the survival of ESCC cells by activating TKT. We further characterized that HMGA1 promoted the transcription of TKT by interacting with and enhancing the binding of transcription factor SP1 to the promoter of TKT. Therapeutics targeting TKT with an inhibitor, oxythiamine, reduced HMGA1-induced ESCC cell proliferation and tumor growth. Together, in this study, we identified a new role of HMGA1 in ESCCs by upregulating TKT-mediated activation of PPP. Our results provided a new insight into the role of HMGA1/TKT/PPP in ESCC tumorigenesis and targeted therapy.

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

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

Osteoblasts are induced into cancer-associated osteoblasts to promote tumor progression in head and neck squamous cell carcinoma

Bone invasion by head and neck squamous cell carcinoma (HNSCC) significantly impacts tumor staging, treatment choice, prognosis, and quality of life. While HNSCC is known to cause osteolytic bone invasion, we found that specific HNSCC subtypes can induce osteogenic bone destruction at the tumor-bone interface. This destruction mode significantly correlated with reduced patient survival rates and increased neck lymph node metastasis. Further in vivo and in vitro experiments indicated that HNSCC cells triggered abnormal phenotypic changes in osteoblasts to remodel the tumor-bone microenvironment, facilitating tumor lymphatic metastasis. Through transcriptome analysis, we identified three genes—osteopontin (SPP1), chemokine (C-X-C motif) ligand 1 (CXCL1), and matrix metalloprotein (MMP)9 (MMP9) linked to a poorer prognosis. We discovered osteoblasts with abnormal phenotypes at the tumor-bone interface exhibiting high SPP1, MMP9, and CXCL1 expressions. Based on these characteristics, we identified this osteoblast subpopulation as “cancer-associated osteoblasts (CAOs).” HNSCC cells activated the TNF-α/NF-κB signaling pathway in osteoblasts, transforming them into “CAOs.” These CAOs significantly contributed to the progression of tumor-induced bone invasion, facilitating cancer growth and metastasis. We first provided clinical data and in vivo and in vitro evidence that HNSCC cells can promote tumor progression by manipulating osteoblasts into “CAOs” in the bone invasion.

Synaptotagmin 13 Could Drive the Progression of Esophageal Squamous Cell Carcinoma Through Upregulating ACRV1.

SYT13 is one of the atypical members of the synaptotagmin (SYT) family whose function has attracted considerable attention in recent years. Although SYT13 has been studied in several types of human cancers, such as lung cancer, its role in esophageal squamous cell carcinoma (ESCC) is still unclear. It was demonstrated that SYT13 is significantly upregulated in ESCC tissues compared with normal ones and correlated with higher degree of malignancy. Knockdown of SYT13 could inhibit ESCC cell proliferation and migration, while promoting cell apoptosis. Meanwhile, ESCC cells with relatively lower SYT13 expression grew slower invivo and finally formed smaller xenografts. Furthermore, acrosomal vesicular protein 1 was identified as a potential downstream target of SYT13, which regulates cell phenotypes of ESCC cells in cooperation with SYT13. All the in vitro and invivo results in this study identified that SYT13 silencing could be an effective strategy to inhibit the development of ESCC, which could be considered as a promising therapeutic target in the treatment of ESCC.

P4HA3 promotes head and neck squamous cell carcinoma progression via the WNT/β-catenin signaling pathway

Here, we explored the role of Prolyl 4-Hydroxylase Subunit Alpha 3 (P4HA3), the most recently identified member of the prolyl-4-hydroxylase (P4H) family, in head and neck squamous cell carcinoma (HNSCC) progression. P4HA3 is upregulated during cancer progression; however, its specific role in HNSCC progression remains elusive. Thus, this study aimed to elucidate the regulatory function of P4HA3 in HNSCC development and progression and to describe the underlying mechanisms. Initially, we analyzed the correlation between the expression of P4HA3 and the WNT pathway genes and clinicopathologic features in HNSCC based on microarray data from The Cancer Genome Atlas (TCGA). Next, we used Gene Oncology (GO) functional data to describe several potentially associated pathways in HNSCC. Then, we knocked down P4HA3 in SCC15 and SCC25 cells, two classic HNSCC cell lines, and assessed the resulting changes using RT-qPCR. Furthermore, we used Western blot to evaluate the regulatory role of P4HA3 in the epithelial-to-mesenchymal transition (EMT) and the WNT/β-catenin signaling pathway. To explore the effect of P4HA3 knockdown on tumor progression, in vivo experiments were conducted using a murine model. Immunohistochemistry assays were then employed to identify proteins associated with EMT and the WNT/β-catenin signaling pathway in tumor tissues. Upregulated P4HA3 in HNSCC patient tumor tissues was positively correlated with poor prognosis. Notably, P4HA3 knockdown significantly inhibited the proliferative and invasive abilities of HNSCC. The levels of genes and proteins associated with EMT and the WNT/β-catenin signaling pathway were also markedly reduced by P4HA3 knockdown. Importantly, the in vivo experiments demonstrated that P4HA3 can promote subcutaneous tumorigenesis in nude mice and knockdown of P4HA3 induce a significant ihibitation of EMT and WNT/β-catenin pathway detected by immunohistochemistry assay in tumor tissues. In summary, we demonstrated that P4HA3 is a promising diagnostic and therapeutic biomarker for HNSCC. As an oncogene, P4HA3 increases HNSCC proliferation by inducing the EMT and activating the WNT/β-catenin signaling pathway.

Metabolism score and machine learning models for the prediction of esophageal squamous cell carcinoma progression.

The incomplete prediction of prognosis in esophageal squamous cell carcinoma (ESCC) patients is attributed to various therapeutic interventions and complex prognostic factors. Consequently, there is a pressing demand for enhanced predictive biomarkers that can facilitate clinical management and treatment decisions. This study recruited 491 ESCC patients who underwent surgical treatment at Huashan Hospital, Fudan University. We incorporated 14 blood metabolic indicators and identified independent prognostic indicators for overall survival through univariate and multivariate analyses. Subsequently, a metabolism score formula was established based on the biochemical markers. We constructed a nomogram and machine learning models utilizing the metabolism score and clinically significant prognostic features, followed by an evaluation of their predictive accuracy and performance. We identified alkaline phosphatase, free fatty acids, homocysteine, lactate dehydrogenase, and triglycerides as independent prognostic indicators for ESCC. Subsequently, based on these five indicators, we established a metabolism score that serves as an independent prognostic factor in ESCC patients. By utilizing this metabolism score in conjunction with clinical features, a nomogram can precisely predict the prognosis of ESCC patients, achieving an area under the curve (AUC) of 0.89. The random forest (RF) model showed superior predictive ability (AUC = 0.90, accuracy = 86%, Matthews correlation coefficient = 0.55). Finally, we used an RF model with optimal performance to establish an online predictive tool. The metabolism score developed in this study serves as an independent prognostic indicator for ESCC patients.

A positive feedback loop between PFKP and c-Myc drives head and neck squamous cell carcinoma progression

BackgroundThe aberrant expression of phosphofructokinase-platelet (PFKP) plays a crucial role in the development of various human cancers by modifying diverse biological functions. However, the precise molecular mechanisms underlying the role of PFKP in head and neck squamous cell carcinoma (HNSCC) are not fully elucidated.MethodsWe assessed the expression levels of PFKP and c-Myc in tumor and adjacent normal tissues from 120 HNSCC patients. A series of in vitro and in vivo experiments were performed to explore the impact of the feedback loop between PFKP and c-Myc on HNSCC progression. Additionally, we explored the therapeutic effects of targeting PFKP and c-Myc in HNSCC using Patient-Derived Organoids (PDO), Cell Line-Derived Xenografts, and Patients-Derived Xenografts.ResultsOur findings indicated that PFKP is frequently upregulated in HNSCC tissues and cell lines, correlating with poor prognosis. Our in vitro and in vivo experiments demonstrate that elevated PFKP facilitates cell proliferation, angiogenesis, and metastasis in HNSCC. Mechanistically, PFKP increases the ERK-mediated stability of c-Myc, thereby driving progression of HNSCC. Moreover, c-Myc stimulates PFKP expression at the transcriptional level, thus forming a positive feedback loop between PFKP and c-Myc. Additionally, our multiple models demonstrate that co-targeting PFKP and c-Myc triggers synergistic anti-tumor effects in HNSCC.ConclusionOur study demonstrates the critical role of the PFKP/c-Myc positive feedback loop in driving HNSCC progression and suggests that simultaneously targeting PFKP and c-Myc may be a novel and effective therapeutic strategy for HNSCC.

Unraveling the independent role of METTL3 in m6A modification and tumor progression in esophageal squamous cell carcinoma

METTL3 and METTL14 are traditionally posited to assemble the m6A methyltransferase complex in a stoichiometric 1:1 ratio, modulating mRNA fate via m6A modifications. Nevertheless, recent investigations reveal inconsistent expression levels and prognostic significance of METTL3 and METTL14 across various tumor types, challenging their consistent functional engagement in neoplastic contexts. A pan-cancer analysis leveraging The Cancer Genome Atlas (TCGA) data has identified pronounced disparities in the expression patterns, functional roles, and correlations with tumor burden between METTL3 and METTL14, particularly in esophageal squamous cell carcinoma (ESCC). Knockdown experiments of METTL3 in EC109 cells markedly suppress cell proliferation both in vitro and in vivo, whereas METTL14 knockdown shows a comparatively muted effect on proliferation and does not significantly alter METTL3 protein levels. mRNA sequencing indicates that METTL3 singularly governs the expression of 1615 genes, with only 776 genes co-regulated with METTL14. Additionally, immunofluorescence co-localization studies suggest discrepancies in cellular localization between METTL3 and METTL14. High-performance liquid chromatography–mass spectrometry (HPLC–MS) analyses demonstrate that METTL3 uniquely associates with the Nop56p-linked pre-rRNA complex and mRNA splicing machinery, independent of METTL14. Preliminary bioinformatics and multi-omics investigations reveal that METTL3’s autonomous role in modulating tumor cell proliferation and its involvement in mRNA splicing are potentially pivotal molecular mechanisms. Our study lays both experimental and theoretical groundwork for a deeper understanding of the m6A methyltransferase complex and the development of targeted tumor therapies focusing on METTL3.

CCZ1 Accelerates the Progression of Cervical Squamous Cell Carcinoma by Promoting MMP2/MMP17 Expression.

Cervical squamous cell carcinoma (CSCC) represents a significant global health concern among females. Identifying new biomarkers and therapeutic targets is pivotal for improving the prognosis of CSCC. This study investigates the prognostic relevance of CCZ1 in CSCC and elucidates its downstream pathways and targets using a combination of bioinformatics analysis and experimental validation. Transcriptomic analysis of 239 CSCC and 3 normal cervical samples from The Cancer Genome Atlas database reveals a marked upregulation of CCZ1 mRNA levels in CSCC, and elevated CCZ1 mRNA levels were associated with poor prognosis. Immunohistochemical analysis of clinical samples also confirmed these findings. Furthermore, functional assays, including Cell Counting Kit-8, colony formation, Transwell, and flow cytometry, elucidated the influence of CCZ1 on CSCC cell proliferation, migration, invasion, and cell cycle progression. Remarkably, CCZ1 knockdown suppressed CSCC progression both in vitro and in vivo. Mechanistically, CCZ1 knockdown downregulated MMP2 and MMP17 expression. Restoring MMP2 or MMP17 expression rescued phenotypic alterations induced by CCZ1 knockdown. Hence, CCZ1 promotes CSCC progression by upregulating MMP2 and MMP17 expression, emerging as a novel biomarker in CSCC and presenting potential as a therapeutic target in CSCC.

Stabilization of EREG via STT3B-mediated N-glycosylation is critical for PDL1 upregulation and immune evasion in head and neck squamous cell carcinoma

Dysregulated Epiregulin (EREG) can activate epidermal growth factor receptor (EGFR) and promote tumor progression in head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underlying EREG dysregulation remain largely unknown. Here, we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues. Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway. Of note, we found that N-glycosylation of EREG was essential for its stability, membrane location, biological function, and upregulation of its downstream target PDL1 in HNSCC. EREG was glycosylated at N47 via STT3B glycosyltransferases, whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG. Consistently, knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells. Moreover, treatment of HNSCC cells with NGI-1, an inhibitor of STT3B, blocked STT3B-mediated glycosylation of EREG, leading to its degradation and suppression of PDL1. Finally, combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo. Taken together, STT3B-mediated N-glycosylation is essential for stabilization of EREG, which mediates PDL1 upregulation and immune evasion in HNSCC.

MiR-493-5p Silenced by DNA Methylation Promotes Angiogenesis via Exosomes and VEGF-A-Mediated Intracellular Cross-Talk Between ESCC Cells and HUVECs.

Exosomal microRNAs (miRNAs) in the tumor microenvironment play crucial roles in tumorigenesis and tumor progression by participating in intercellular cross-talk. However, the functions of exosomal miRNAs and the mechanisms by which they regulate esophageal squamous cell carcinoma (ESCC) progression are unclear. RNA sequencing and GEO analysis were conducted to identify candidate exosomal miRNAs involved in ESCC development. Receiver operating characteristic curve analysis was performed to assess the diagnostic value of plasma exosomal miR-493-5p. EdU, tube formation and Transwell assays were used to investigate the effects of exosomal miR-493-5p on human umbilical vein endothelial cells (HUVECs). A subcutaneous xenograft model was used to evaluate the antitumor effects of miR-493-5p and decitabine (a DNA methyltransferase inhibitor). The relationship between miR-493-5p and SP1/SP3 was revealed via a dual-luciferase reporter assay. A series of rescue assays were subsequently performed to investigate whether SP1/SP3 participate in exosomal miR-493-5p-mediated ESCC angiogenesis. We found that miR-493-5p expression was notably reduced in the plasma exosomes of ESCC patients, which showed the high potential value in early ESCC diagnosis. Additionally, miR-493-5p, as a candidate tumor suppressor, inhibited the proliferation, migration and tube formation of HUVECs by suppressing the expression of VEGFA and exerted its angiostatic effect via exosomes. Moreover, we found that SP1/SP3 are direct targets of miR-493-5p and that re-expression of SP1/SP3 could reverse the inhibitory effects of miR-493-5p. Further investigation revealed that miR-493-5p expression could be regulated by DNA methyltransferase 3A (DNMT3A) and DNMT3B, and either miR-493-5p overexpression or restoration of miR-493-5p expression with decitabine increased the antitumor effects of bevacizumab. Exosomal miR-493-5p is a highly valuable ESCC diagnosis marker and inhibits ESCC-associated angiogenesis. miR-493-5p can be silenced via DNA methylation, and restoration of miR-493-5p expression with decitabine increases the antitumor effects of bevacizumab, suggesting its potential as a therapeutic target for ESCC treatment.

Selenomethionine suppresses head and neck squamous cell carcinoma progression through TopBP1/ATR and TCAB1 signaling.

Head and neck squamous cell carcinoma (HNSCC) is a histological type of cancer originating from the head and neck. Selenium complexes have been considered as a potential treatment for HNSCC. Therefore, the present work focused on probing the mechanism of L-selenomethionine (SeMet) in HNSCC treatment. MTT and colony formation assays were carried out to analyze the survival rate and proliferation of HNSCC cells, respectively. TUNEL staining was performed to examine apoptosis of HNSCC cells. Additionally, qRT-PCR and Western blotting assays were performed to measure mRNA and protein levels, separately. SeMet treatment significantly hindered the survival and promoted the apoptosis of HNSCC cells in a dose- and time-dependently. SeMet administration promoted expression of TopBP1, ATR, H2AX, p-ATR and γ-H2AX, and suppressed that of TCAB1. Importantly, SeMet treatment suppressed the proliferation and facilitated the apoptosis of HNSCC cells, which were partly reversed by down-regulation of TopBP1 or up-regulation of TCAB1. The activation of SeMet to TopBP1/ATR signaling was rescued by TCAB1 up-regulating, and the inhibition of SeMet to TCAB1 expression was rescued by TopBP1 silencing. Our findings show that SeMet inhibits the proliferation of HNSCC cells and promotes their apoptosis by targeting TopBP1/ATR and TCAB1 signaling. SeMet is a potential method for HNSCC treatment.

Identification of Cuproptosis-related Gene Lipoyltransferase 1 as a Promising Biomarker in Oral Squamous Cell Carcinoma.

To find efficient cuproptosis-related biomarkers to explore the oncogenesis and progression of oral squamous cell carcinoma (OSCC). All the original data were downloaded from the Cancer Genome Atlas (TCGA) database. Univariate Cox analysis and Kaplan-Meier survival analysis were used to identify the gene related to survival. Tumor Immune Estimation Resource 2.0 (TIMER 2.0) was used to reveal the different expression of cuproptosis-related gene lipoyltransferase 1 (LIPT1) in various kinds of tumours. LIPT1, as a cuproptosis-related gene, was found to be differentially expressed in the OSCC group and the control group. It was also found to be related to the prognosis of OSCC. Pan cancer analysis showed LIPT1 was also involved in various kinds of tumours. All the results demonstrate that the cuproptosis-related gene LIPT1 is highly involved in the oncogenesis and progression of OSCC. These findings give new insight for further research into the cuproptosis-related biomarkers in OSCC.

EphA2 promotes the transcription of KLF4 to facilitate stemness in oral squamous cell carcinoma

Ephrin receptor A2 (EphA2), a member of the Ephrin receptor family, is closely related to the progression of oral squamous cell carcinoma (OSCC). Cancer stem cells (CSCs) play essential roles in OSCC development and occurrence. The underlying mechanisms between EphA2 and CSCs, however, are not yet fully understood. Here, we found that EphA2 was overexpressed in OSCC tissues and was associated with poor prognosis. Knockdown of EphA2 dampened the CSC phenotype and the tumour-initiating frequency of OSCC cells. Crucially, the effects of EphA2 on the CSC phenotype relied on KLF4, a key transcription factor for CSCs. Mechanistically, EphA2 activated the ERK signalling pathway, promoting the nuclear translocation of YAP. Subsequently, YAP was bound to TEAD3, leading to the transcription of KLF4. Overall, our findings revealed that EphA2 can enhance the stemness of OSCC cells, and this study identified the EphA2/KLF4 axis as a potential target for treating OSCC.

Anti-angiogenic therapy in head and neck squamous cell carcinoma - current limitations and future directions

Angiogenesis, the formation of new blood vessels, plays a crucial role in the progression and metastasis of various cancers, including head and neck squamous cell carcinoma (HNSCC). HNSCCs are characterized by altered levels of angiogenesis-related factors, including the overexpression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), as well as the dysregulation of angiogenesis inhibitors. Together, these factors drive the formation of new blood vessels within the tumor microenvironment and are considered therapeutic targets in HNSCC. Although preclinical studies are promising, challenges have emerged in the clinical use of anti-angiogenic agents in the clinic, including treatment-related toxicities and the development of resistance to therapy. There is an unmet need for further research to elucidate the molecular pathways involved in HNSCC angiogenesis, identify novel therapeutic targets, and discover predictive biomarkers to improve patient selection.

HOXC6-mediated transcriptional activation ofENO2 promotes oral squamous cell carcinoma progression through the Warburg effect.

Oral squamous cell carcinoma (OSCC) requires an in-depth exploration of its molecular mechanisms. The Warburg effect, along with the oncogenesenolase 2(ENO2) andhomeobox C6 (HOXC6), plays a central role in cancer. However, the specific interaction between ENO2 and HOXC6 in driving the Warburg effect and OSCC progression remains poorly understood. Through differential gene expression analysis in head and neck squamous cell carcinomas using Gene Expression Profiling Interactive Analysis, we identified upregulated ENO2 in OSCC. Silencing ENO2 in OSCC cells revealed its involvement in migration, invasion, and aerobic glycolysis of OSCC cells. Further exploration of ENO2's regulatory network identified HOXC6 as a potential transcriptional regulator. Subsequently, HOXC6 was silenced in OSCC cells, and expressions of ENO2 were assessed to validate its relationship with ENO2. Chromatin Immunoprecipitation and luciferase assays were utilized to investigate the direct transcriptional activation of ENO2 by HOXC6. A rescue assay co-overexpressing ENO2 and silencing HOXC6 in OSCC cells affirmed HOXC6's role in ENO2-associated glycolysis. High ENO2 expression in OSCC was validated through quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry analyses, which correlated with poor patient survival. Functional assays demonstrated that ENO2 silencing inhibited glycolysis and attenuated the aggressiveness of OSCC cells. In vivo studies confirmed the oncogenic role of ENO2 in OSCC growth. Notably, HOXC6 exhibited a positive correlation with ENO2 expression in clinical samples. Mechanistically, HOXC6 was identified as a direct transcriptional activator of ENO2, orchestrating the Warburg effect in OSCC cells. This study reveals the intricate link between HOXC6-mediated ENO2 transcriptional activation and the Warburg effect in OSCC, offering a potential therapeutic target for treating OSCC patients.

The Notch inhibitor, FLI-06, increases the chemosensitivity of head and neck Squamous cell carcinoma cells to taxanes-based treatment

Aberration of Notch signaling is one of the key events involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). The Notch pathway controls the tissue-specific differentiation of normal squamous epithelial cells and is frequently altered in squamous carcinomas, thus affecting their proliferation, growth, survival, and chemosensitivity or resistance against anti-cancer agents. In this study, we show that the use of novel, small-molecule inhibitors of Notch signaling, such as FLI-06, can have a beneficial effect on increasing the chemosensitivity of HNSCC to taxane-based chemotherapy. Inhibition of Notch signaling by FLI-06 alone virtually blocks the proliferation and growth of HNSCC cells in both 2D and 3D cultures and the zebrafish model, which is accompanied by down-regulation of key Notch target genes and proteins. Mechanistically, FLI-06 treatment causes cell cycle arrest in the G1-phase and induction of apoptosis in HNSCC, which is accompanied by increased c-JunS63 phosphorylation. Combining FLI-06 with Docetaxel shows a synergistic effect and partially blocks the cell growth of aggressive HNSCC cells via enhanced apoptosis and modification of c-JunS243 phosphorylation via GSK-3β inhibition. In conclusion, inhibition of Notch signaling in HNSCC cells that retain active Notch signaling significantly supports taxane-based anticancer activities via modulation of both the GSK-3β and the c-Jun.