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ERP29 gene encodes a chaperone protein critical for protein folding and secretion. Previous study linked ERP29 inhibition to an elevated risk of pharynx squamous cell carcinoma (PSCC) and reduced patients' survival. However, ERP29 role in PSCC progression remains unknown. Here, we investigated ERP29 impact on PSCC progression in cisplatin (CDDP)-sensitive (FaDu and LAU-2063), CDDP-treated (FaDu-CDDP), and CDDP-resistant (FaDu-R) cells. ERP29 silencing decreased necrosis and increased migration in CDDP-sensitive, treated, and resistant cells; and reduced E-cadherin and increased vimentin immunoexpression in CDDP-sensitive 3D-spheroids. During CDDP treatment, ERP29 silencing enhanced proliferation. In CDDP-sensitive cells, ERP29 silencing upregulated genes associated with WNT, MAPK, and PI3K/AKT signaling pathways while downregulating CASP9 expression. During CDDP treatment, ERP29 silencing downregulated MDM2 and CASP9 expression. In CDDP-resistant cells, ERP29 silencing upregulated SOS1, MAPK1, AKT1, ITGAV, and CCNE1, while downregulating KRAS, JUN, MDM2, and CASP9 expression. In addition, inhibition of microRNA miR-4421 increased ERP29 expression and decreased MAPK1, AKT1, and JUN expression in CDDP-sensitive cells, as well as SOS1, MAPK1, AKT1, and ITGAV in CDDP-resistant cells. Lower ERP29 and higher miR-4421 expressions were predictive of poor survival, suggesting a potential therapeutic use for miR-4421 inhibitors. Upon validation, these findings may contribute to targeted therapies for PSCC based on ensuring ERP29 expression., (© 2024. The Author(s).)

Background: CHRDL1 belongs to a novel class of mRNA molecules. Nonetheless, the specific biological functions and underlying mechanisms of CHRDL1 in oral squamous cell carcinoma (OSCC) remain largely unexplored., Methods: RT-qPCR and immunohistochemical staining were employed to assess the mRNA and protein expression levels of the MED29 gene in clinical samples of OSCC. Additionally, RT-qPCR and Western Blot analyses were conducted to investigate the mRNA and protein expression levels of the MED29 gene specifically in OSCC. The impact of MED29 on epithelial-mesenchymal transition (EMT), invasion, and migration of OSCC was evaluated through scratch assay, transwell assay, and immunofluorescence staining. Furthermore, wound healing assay and Transwell assay were utilized to examine whether CHRDL1 influences the malignant behavior of OSCC by modulating MED29 in vitro. The regulatory role of CHRDL1 on MED29 was further elucidated in vivo through a tail vein lung metastasis model in nude mice., Results: MED29 expression was elevated in tumor tissues of OSCC patients compared with adjacent cancer tissues. Moreover, in CAL27 and SCC25 cell lines, MED29 was upregulated and associated with increased cell migration and invasion abilities. Overexpression of MED29 facilitated EMT in OSCC cell lines, whereas knockdown of MED29 impeded EMT, resulting in diminished cell migration and invasion capacities. CHRDL1 exerted inhibitory effects on the expression of MED29, thereby suppressing EMT progression and consequently restraining the invasion and migration of OSCC cells. Furthermore, CHRDL1 mediated the inhibition of migration of OSCC cell lines to the OSCC through its regulation of MED29., Conclusions: MED29 facilitated the epithelial-mesenchymal transition process in OSCC, thereby promoting migration and invasion. On the other hand, CHRDL1 exerted inhibitory effects on the invasion and metastasis of OSCC by suppressing MED29 through the inhibition of the MAPK signaling pathway., (© 2024. The Author(s).)

Lung squamous cell carcinoma (LUSC) is associated with high mortality and has few therapeutic options. Chemotherapy remains the main treatment for LUSC patients, but multi-drug resistance has become the dominant challenge in the failure of chemotherapy in various cancers. Therefore, the effective therapeutic strategy for LUSC patients is an urgent unmet need. Here, we found vasohibin-2 (VASH2) was a prognostic biomarker for LUSC patients, and VASH2 promoted the malignant biological behaviors of LUSC cells and chemoresistance by increasing the detyrosination of α-tubulin. The high level of detyrosinated-tubulin was negatively associated with patient prognosis. Blocking the tubulin carboxypeptidase (TCP) activity of VASH2 inhibited the xenograft tumor growth and improved the treatment efficacy of paclitaxel in vivo. Results revealed that VASH2-induced increase in tubulin detyrosination boosted the binding of kinesin family member 3C (KIF3C) to microtubules and enhanced KIF3C-dependent endosomal recycling of EGFR, leading to the prolonged activation of PI3K/Akt/mTOR signaling. This study demonstrated that VASH2 was not only a prognostic biomarker but also a promising therapeutic target in LUSC, which offers a novel insight that combination of chemotherapy and EpoY, a TCP inhibitor, may be a promising treatment strategy for LUSC patients., (© 2024. The Author(s).)

Background: Monocyte Chemotactic Protein 1-Induced Protein 1 (MCPIP1, also called Regnase-1) is a negative modulator of inflammation with tumor-suppressive properties. Mice with keratinocyte-specific deletion of the Zc3h12a gene, encoding MCPIP1, (Mcpip1 eKO mice) are more susceptible to the development of epidermal papillomas initiated by 7,12-dimethylbenz[a]-anthracene (DMBA) and promoted by 2-O-tetradecanoylphorbol-13-acetate (TPA)., Methods: The aim of this study was to investigate the MCPIP1 RNase-dependent microRNA (miRNA)‒mRNA regulatory network in chemically induced squamous cell carcinoma (SCC)-like skin papillomas. Next-generation sequencing (NGS) coupled with bioinformatic analysis was used to shortlist the MCPIP1-dependent changes in protein-coding genes and miRNAs. The expression levels of the selected miRNAs were analyzed by quantitative PCR in human keratinocytes with MCPIP1 silencing. Functional studies were performed in human keratinocytes transfected with appropriate miRNA mimics. The DIANA-microT-CDS algorithm and DIANA-TarBase v7 database were used to predict potential target genes and identify the experimentally validated targets of differentially expressed (DE) miRNAs., Results: RNA sequencing (RNA-Seq) analysis of control and Mcpip1 eKO DMBA/TPA-induced papillomas revealed transcriptome changes, with 2400 DE protein-coding genes and 33 DE miRNAs. The expression of miR-223-3p, miR-376c-3p, and miR-139-5p was confirmed to be dependent on MCPIP1 activity in both murine and human models. We showed that MCPIP1 directly regulates the expression of miR-376c-3p via direct cleavage of the corresponding precursor miRNA. The pro-proliferative activity of miR-223-3p, miR-376c-3p, and miR-139-5p was experimentally confirmed in SCC-like keratinocytes. Bioinformatic prediction of the mRNA targets of the DE-miRNAs revealed 416 genes as putative targets of the 18 upregulated miRNAs and 425 genes as putative targets of the 15 downregulated miRNAs. Further analyses revealed the murine interactions that are conserved in humans. Functional analysis indicated that during the development of cutaneous SCC, the most important pathways/processes mediated by the miRNA‒mRNA MCPIP1-dependent network are the regulation of inflammatory processes, epithelial cell proliferation, Wnt signaling, and miRNA transcription., Conclusions: Loss of MCPIP1 modulates the expression profiles of 33 miRNAs in chemically induced Mcpip1 eKO papillomas, and these changes directly affect the miRNA‒mRNA network and the modulation of pathways and processes related to carcinogenesis., (© 2024. The Author(s).)

Laryngeal squamous cell carcinoma (LSCC) with a high incidence and mortality rate, has a serious impact worldwide. Phosphofructokinase-1 liver type (PFKL) is a major enzyme in glycolysis progress, but its role in modulating tumorigenesis and cisplatin (DDP) chemosensitivity of LSCC was still unclear. The mRNA and protein levels of PFKL were detected by qRT-PCR and immunohistochemical assay. Cell Counting Kit-8 assay and flow cytometry were carried out to observe cell viability, as well as apoptosis and mitochondrial reactive oxygen species (mito-ROS). Extracellular acidification rate and lactate content were measured using extracellular flux analysis and lactate assay kit. Immunofluorescent staining was used to evaluate the expression of γ-H2AX foci. DNA damage was detected via single-cell gel electrophoresis. Western blotting was introduced to evaluate the protein level of PFKL, LDHA, γ-H2AX, cleaved PARP, H3K27ac, and H3K9ac. Mice xenograft model of LSCC was built for in vivo validation. The PFKL expression was significantly increased in LSCC and associated with poor survival of LSCC patients. Knockdown of PFKL in LSCC cells significantly inhibited cell viability, ECAR, lactate content, and LDHA expression, but promoted mito-ROS level. Furthermore, knockdown of PFKL enhanced response of LSCC cells to DDP by increasing DDP-induced apoptosis, promoting DDP-induced mito-ROS level, γ-H2AX foci, tail DNA, and the expression of γ-H2AX and cleaved PARP. However, the overexpression of PFKL in LSCC cells had opposite experimental results. Nude mice tumor formation experiment proved that downregulation of PFKL significantly enhanced response of cells to DDP, demonstrated by reduced tumor volume, weight and increased TUNEL-positive cells. Suppression of CBP/EP300-mediated PFKL transcription inhibited cell viability and glycolysis and promoted mito-ROS in LSCC. PFKL promotes cell viability and DNA damage repair in DDP-treated LSCC through regulation of glycolysis pathway., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Propolis is a sticky substance produced by honeybees ( Apis mellifera ) through the collection of plant resins, which they mix with secretions from their palate and wax glands. Propolis can inhibit tumor invasion and metastasis, thereby reducing the proliferation of tumor cells and inducing cell apoptosis. Previous research has shown that propolis has an inhibitory effect on skin squamous cell carcinoma A431 cells. Nevertheless, its inhibitory mechanism is unclear because of many significantly different Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between the ethanol extract of the propolis (EEP) group and the control group of cells. In this study, the main components of EEP and the antitumor mechanism at an IC 50 of 29.04 μg/mL EEP were determined via untargeted metabolomics determined using ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC‒MS/MS), respectively. The results revealed 43 polyphenolic components in the EEP and 1052 metabolites, with 160 significantly upregulated and 143 significantly downregulated metabolites between cells treated with EEP and solvent. The KEGG enrichment results revealed that EEP significantly inhibited A431 cell proliferation via the steroid hormone biosynthesis and linoleic acid metabolism pathways. These findings may provide valuable insights for the development of targeted therapies for the treatment of cutaneous squamous cell carcinoma.

Oral cancer, representing 2-4% of all cancer cases, predominantly consists of Oral Squamous Cell Carcinoma (OSCC), which makes up 90% of oral malignancies. Early detection of OSCC is crucial, and identifying specific proteins in saliva as biomarkers could greatly improve early diagnosis. Here, we proposed a strategy to pinpoint candidate biomarkers. Starting from a list of salivary proteins detected in 10 OSCC patients and 20 healthy controls, we combined a univariate approach and a multivariate approach to select candidates. To reduce the number of proteins selected, a Protein-Protein Interaction network was built to consider only connected proteins. Then, an over-representation analysis (ORA) determined the enriched pathways. The network from 172 differentially abundant proteins highlighted 50 physically connected proteins, selecting relevant candidates for targeted experimental validations. Notably, proteins like Heat shock 70 kDa protein 1A/1B, Pyruvate kinase PKM, and Phosphoglycerate kinase 1 were suggested to be differentially regulated in OSCC patients, with implications for oral carcinogenesis and tumor growth. Additionally, the ORA revealed enrichment in immune system, complement, and coagulation pathways, all known to play roles in tumorigenesis and cancer progression. The employed method has successfully identified potential biomarkers for early diagnosis of OSCC using an accessible body fluid.

Purpose: Evaluate the immunohistochemical expression of the ING3 in actinic cheilitis and squamous cell carcinoma of the lower lip., Methods: Forty-five specimens of actinic cheilitis and 48 specimens of squamous cell carcinoma of the lower lip were submitted to immunohistochemical detection of ING3. The protein expression in different cellular sublocations was compared between the two groups, and associations with the clinicopathological variables were analyzed. A significance level of 5% was adopted for all tests., Results: Deaths were significantly more frequent in tumors with a high histopathological risk score (p < 0.05). In actinic cheilitis, significant differences were found in the nucleus-cytoplasmic expression of ING3 and expression restricted to the cytoplasm with binary histopathological grading (p < 0.05). In squamous cell carcinoma of the lower lip, there was no statistically significant difference when comparing ING3 expressions with clinical and morphological parameters (p > 0.05). Nucleo-cytoplasmic ING3 expression was significantly lower in squamous cell carcinoma of the lower lip when compared to actinic cheilitis (p < 0.05) and the expression restricted to the cytoplasm was significantly higher in squamous cell carcinoma of the lower lip (p < 0.05)., Conclusion: The results of this study suggest that there is a marked decrease in the nuclear expression of ING3 as malignant progression occurs, indicating an impaired tumor suppressor function of this protein in actinic cheilitis and squamous cell carcinoma of the lower lip., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Lactylation, a post-translational modification, is increasingly recognized for its role in cancer progression. This study investigates its prevalence and impact in oral squamous cell carcinoma (OSCC)., Results: Immunohistochemical staining of 81 OSCC cases shows lactylation levels correlate with malignancy grading. Proteomic analyses of six OSCC tissue pairs reveal 2765 lactylation sites on 1033 proteins, highlighting its extensive presence. These modifications influence metabolic processes, molecular synthesis, and transport. CAL27 cells are subjected to cleavage under targets and tagmentation assay for accessible-chromatin with high-throughput sequencing, and transcriptomic sequencing pre- and post-lactate treatment, with 217 genes upregulated due to lactylation. Chromatin immunoprecipitation-quantitative PCR and real-time fluorescence quantitative PCR confirm the regulatory role of lactylation at the K146 site of dexh-box helicase 9 (DHX9), a key factor in OSCC progression. CCK8, colony formation, scratch healing, and Transwell assays demonstrate that lactylation mitigates the inhibitory effect of DHX9 on OSCC, thereby promoting its occurrence and development., Conclusions: Lactylation actively modulates gene expression in OSCC, with significant effects on chromatin structure and cellular processes. This study provides a foundation for developing targeted therapies against OSCC, leveraging the role of lactylation in disease pathogenesis., (© 2024. The Author(s).)

Polydatin, a natural derivative of resveratrol, has shown many anticancer properties. However, the underlying mechanisms of its anticancer properties including its effect on the epigenetic landscape are not well understood. Here, we explored the effect of polydatin on histone deacetylase 1 (HDAC1) activity. We used in silico approaches to assess the possible binding of polydatin to the active site pockets of HDAC1 and in vitro approaches to test the potential effects of the interaction on its enzymatic activity. As compared to SAHA, an approved drug, the polydatin showed stronger and stable binding to the HDAC1. The binding energy, conformational changes, formation of extra hydrogen bonding, and other interactions within and outside the active site all favour largely stable and strong polydatin binding to the enzyme. Further, the ADME and toxicity prediction values are encouraging for the evaluation of polydatin as a drug. The laboratory leg of the study substantiated that the polydatin binding was strong and stable enough to inhibit HDAC1 activity in UMS-CC-22B cells as demonstrated by an increase in H3K9 acetylation. In addition, polydatin treated cells showed attenuated proliferation. The in vitro tube formation and migration by HUVEC and UM-SCC-22B cells were inhibited by polydatin. The decreased tube formation due to HDAC1 inhibition is possibly due to up-regulation of the anti-angiogenic gene - TSP1 in UM-SCC-22B cells. As compared to SAHA, more promising results were shown both in its computational calculations and on the cell physiology features. Stronger and stable binding, more anti-proliferative and anti-angiogenic potential were observed with respect to polydatin. Further, the cell death was more pronounced with SAHA treatment. Therefore, polydatin might be a better anticancer drug and can have a potential to replace SAHA in combinational therapeutic regimen., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cold atmospheric plasma (CAP) has been extensively utilized in medical treatment, particularly in cancer therapy. However, the underlying mechanism of CAP in skin cancer treatment remains elusive. In this study, we established a skin cancer model using CAP treatment in vitro . Also, we established the Xenograft experiment model in vivo . The results demonstrated that treatment with CAP induced ferroptosis, resulting in a significant reduction in the viability, migration, and invasive capacities of A431 squamous cell carcinoma, a type of skin cancer. Mechanistically, the significant production of reactive oxygen species (ROS) by CAP induces DNA damage, which then activates Ataxia-telangiectasia mutated (ATM) and p53 through acetylation, while simultaneously suppressing the expression of Solute Carrier Family 7 Member 11 (SLC7A11). Consequently, this cascade led to the down-regulation of intracellular Glutathione peroxidase 4 (GPX4), ultimately resulting in ferroptosis. CAP exhibits a favorable impact on skin cancer treatment, suggesting its potential medical application in skin cancer therapy., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: Ficolins (FCNs) are a family of proteins, comprising FCN1, FCN2 and FCN3, and integral to the immune system which have been implicated in the onset and progression of tumors. Despite their recognized roles, a comprehensive analysis of FCNs in lung cancer remains elusive., Methods: We employed a variety of bioinformatics tools, including UCSC, SangerBox, Ualcan, cBioPortal, String, Metascape, GeneMANIA, TIDE, CTD, and CAMP databases to investigate the differential expression, diagnostic and prognostic significance, genetic alterations, functional enrichment, immune infiltration, and potential immunotherapeutic implications of FCN1, FCN2, and FCN3 in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). Additionally, RT-qPCR and immunohistochemistry were utilized to validate the expressions of FCNs at the mRNA and protein levels in LUSC and LUAD., Results: Our comprehensive bioinformatic analysis, supported by RT-qPCR and immunohistochemistry, revealed that the expressions of FCN1, FCN2 and FCN3 were consistently downregulated in both LUSC and LUAD tumor tissues. FCNs demonstrated significant diagnostic potential for LUSC and LUAD, with the area under the receiver operating characteristic curve (AUC) for FCN1 and FCN3 exceeding 0.90. Furthermore, FCN2 and FCN3 showed a strong negative correlation with overall survival (OS) in LUSC, whereas FCN1 and FCN2 were positively correlated with OS in LUAD, suggesting their prognostic value in lung cancer. Gene enrichment analysis indicated that FCNs were predominantly associated with the complement system and complement activation pathways. Immune infiltration analysis further revealed a significant positive correlation between FCNs and the presence of neutrophils and resting mast cells. Our analysis of immunotherapy outcomes revealed a significant disparity in the immunophenoscore (IPS) among lung cancer patients treated with immune checkpoint inhibitors (ICIs), distinguishing those with high FCN expression from those with low FCN expression. Additionally, we identified small molecule compounds related to FCNs and drugs pertinent to LUSC and LUAD., Conclusion: FCNs held promise as diagnostic and prognostic biomarkers for LUSC and LUAD. This study also elucidated the relationship of FCNs with the tumor microenvironment, offering novel insights into the immunotherapeutic landscape for LUSC and LUAD., (© 2024. The Author(s).)

The persistent infection of high-risk human papillomavirus (HPV) and the progression of cervical cancer necessitate the involvement of microenvironmental immunity. As cervical lesions advance, there is an observed increase in the infiltration of type 2 (M2) macrophages. However, the precise mechanism driving this increased infiltration of M2 macrophages remains unclear. In this study, we investigated the role of exosomes in polarising M2 macrophages in cervical lesions associated with HPV E6. Through the analysis of bioinformatics data and clinical specimens, we discovered a positive correlation between HPV E6/E7 mRNA copy number and the level of M2 macrophage infiltration. Exosomes derived from HPV E6 overexpressed (HPV E6+) cervical squamous cell carcinoma (CESC) cells were found to induce the polarisation of macrophages towards M2 type. Specifically, miR-204-5p, enriched in HPV E6 + CESC exosomes, was transported into macrophages and triggered M2 macrophage polarisation by inhibiting JAK2. The clinical relevance of exosomal miR-204-5p in the progression of cervical lesions was validated through serum samples from 35 cases. Exosomal miR-204-5p emerges as a critical factor influencing M2 macrophage polarisation and is correlated with the severity of cervical lesions. Consequently, miR-204-5p could be used as a potential treatment and a candidate biomarker for cervical lesions., (© 2024. The Author(s).)

Background: Chemotherapy of head and neck squamous cell carcinoma (HNSCC) is associated with significant side effects. Antimicrobial peptides (AMPs), which are naturally occurring defense molecules like defensin-1 and LL-37 found in human secretions, have demonstrated potential in prompting tumor cell apoptosis and enhancing the effect of chemotherapeutic agents. However, the anticancer potential of histatin has not yet been thoroughly examined. The aim of the study was to explore the anticancer activity of histatin, an AMP present in human saliva and used alone or in combination with cisplatin in HNSCC cell lines., Materials and Methods: The gene expression of histatin was evaluated in the HSC4 and SCC25 cell lines by qRT-PCR. Cell proliferation was investigated at different concentrations of histatin peptide (His-1), cisplatin, and their combination using an MTT assay., Results: SCC25 cells expressed both HTN1 (histatin-1) and HTN3 (histatin-3), whereas the HSC4 cell line expressed only HTN1. The combination of exogenous His-1 and cisplatin demonstrated a synergistic anti-proliferative effect against the HNSCC cell lines in a dosedependent manner., Conclusions: The combination of low-dose cisplatin and histatin inhibits HNSCC cell proliferation. His-1 sensitizes tumor cells to the cytotoxic effects of cisplatin potentially allowing for a reduction in its effective concentration.

Background: The current prognostic markers in oral squamous cell carcinoma (OSCC) have limited accuracy sometimes leading to inappropriate treatment decisions. Identifying new markers would help clinicians tailor treatment plans based on the individual patient risk factors leading to improved survival rates and quality of life., Aim: To estimate the value of the miRNA expression indicators in saliva as prognostic and predictive markers of the effectiveness of neoadjuvant chemotherapy (NACT)., Materials and Methods: The work is based on the results of the examination and treatment of 61 patients with stage II-IV OSCC. The miR-21, miR-155, and miR-375 expression levels in the saliva samples were analyzed by the real-time reverse transcription polymerase chain reaction., Results: The salivary miR-21 and -155 expression levels in healthy volunteers were 2.49 and 2.84 times lower than in OSCС patients (p < 0.05). The positive association of miR-21 and miR-155 expression levels and the negative correlation of miR-375 expression level with T index by TNM (r = 0.68, r = 0.75, and r = -0.67, respectively) (p < 0.05) and the presence of lymph node metastasis (r = 0.78, r = 0.71, and r = ‒0.59, respectively) (p < 0.05) were found. Patients with good response to NACT had lower miR-21 and -155, and higher miR-375 levels in saliva compared to those with resistant tumors., Conclusions: Our study suggests that salivary miR-21, miR-155, and miR-375 may be potential biomarkers for the prognosis of cancer course and the response to NACT in OSCC patients.

Actinic keratosis (AK) is characterized by a reddish or occasionally skin-toned rough patch on sun-damaged skin, and it is regarded as a precursor to squamous cell carcinoma (SCC). Photodynamic therapy (PDT), utilizing 5-aminolevulinic acid (ALA) along with red light, is a recognized treatment option for AK that is limited by the penetration depth of light and the distribution of the photosensitizer into the skin. Cold atmospheric plasma (CAP) is a partially ionized gas with permeability-enhancing and anti-cancer properties. This study analyzed, in vitro, whether a combined treatment of CAP and ALA-PDT may improve the efficacy of the treatment. In addition, the effect of the application sequence of ALA and CAP was investigated using in vitro assays and the molecular characterization of human oral SCC cell lines (SCC-9, SCC-15, SCC-111), human cutaneous SCC cell lines (SCL-1, SCL-2, A431), and normal human epidermal keratinocytes (HEKn). The anti-tumor effect was determined by migration, invasion, and apoptosis assays and supported the improved efficacy of ALA-PDT in combination with CAP. However, the application sequence ALA-CAP-red light seems to be more efficacious than CAP-ALA-red light, which is probably due to increased intracellular ROS levels when ALA is applied first, followed by CAP and red light treatment. Furthermore, the expression of apoptosis- and senescence-related molecules (caspase-3, -6, -9, p16 INK4a , p21 CIP1 ) was increased, and different genes of the junctional network (ZO-1, CX31, CLDN1, CTNNB1) were induced after the combined treatment of CAP plus ALA-PDT. HEKn, however, were much less affected than SCC cells. Overall, the results show that CAP may improve the anti-tumor effects of conventional ALA-PDT on SCC cells. Whether this combined application is successful in treating AK in vivo has to be carefully examined in follow-up studies.

Oral squamous cell carcinoma (OSCC) is the most frequently diagnosed oral malignancy and poses a great threat to public health. According to bioinformatics analysis, long noncoding RNA PCBP1-AS1 is downregulated in OSCC. In this work, the functions and mechanism of PCBP1-AS1 in OSCC were further investigated. PCBP1-AS1 expression in OSCC cells was measured by quantitative polymerase chain reaction. Cell viability and proliferation were detected using CCK-8 assays and colony-forming assays. TUNEL assays as well as flow cytometry analyses were carried out to detect OSCC cell apoptosis. Binding relationship between PCBP1-AS1 and miR-34c-5p or that between miR-34c-5p and ZFP36 in OSCC cells was identified using RNA immunoprecipitation assays, RNA pulldown assays, and luciferase reporter assays. Experimental results revealed that PCBP1-AS1 was downregulated in OSCC cells. PCBP1-AS1 overexpression hampered cell proliferation and enhanced cell apoptosis in OSCC. PCBP1-AS1 interacted with miR-34c-5p in OSCC and negatively regulated miR-34c-5p. ZFP36 3'untranslated region was targeted by miR-34c-5p. PCBP1-AS1 positively regulated ZFP36 expression. ZFP36 silencing abrogated the suppressive impact of PCBP1-AS1 on OSCC cell growth. In summary, PCBP1-AS1 suppresses cell growth in OSCC by upregulating ZFP36 through interaction with miR-34c-5p.

Objective: To investigate the clinicopathological features, prognosis and the expression of HER2 and PD-L1 in invasive stratified mucin-producing carcinoma of the cervix (ISMC). Methods: The clinicopathological data of 18 ISMC cases with radical resection of the cervix diagnosed in the Daping Hospital, Army Medical University from January 2018 to December 2023 were collected and retrospectively analyzed. PD-L1 and HER2 immunohistochemical staining and HER2 FISH were conducted. Results: The patient ages ranged from 31 to 72 years, with an average of 45 years. Approximately 8% of cervical adenocarcinoma cases in our hospital during the same period. Eleven cases were pure ISMC, and 7 cases were mixed-type ISMC, with the component of squamous cell carcinoma or usual-type adenocarcinoma. One case showed concurrent small cell neuroendocrine carcinoma (SCNEC). Three cases were diagnosed through biopsy (3/18). Five cases were of Silva pattern B and 13 cases of Silva pattern C. Three cases showed regional lymph node metastasis. Thirteen patients were disease-free at the end of the follow-up, while the ISMC patient with concurrent SCNEC developed distant metastasis. Fifteen cases (15/18) had PD-L1 expression with CPS≥1, and 7 cases (7/18) had PD-L1 TPS≥1%. One case of HER2 3+ and one case of HER2 2+ were both positive for FISH amplification; two cases HER2 1+, 14 cases HER2 0. Conclusions: Cervical ISMC is rare, has a wide spectrum of morphology, and can coexist with other types of cervical cancer. PD-L1 is positive in most of the ISMC cases, while HER2 is amplified or lowly expressed in a small portion of them. Thus, it is possible to treat ISMC patients with therapies targeting PD-L1 and therapy targeting HER2.

Background: Oral squamous cell carcinoma (OSCC) remains a major death cause in head and neck cancers, but the exact pathogenesis mechanisms of OSCC are largely unclear., Results: Saliva derived from OSCC patients but not healthy controls (HCs) significantly promotes OSCC development and progression in rat models, and metabolomic analyses reveal saliva of OSCC patients but not HCs and OSCC tissues but not adjacent non-tumor tissues contain higher levels of kynurenic acid (KYNA). Furthermore, large amounts of Streptococcus mutans (S. mutans) colonize in OSCC tumor tissues, and such intratumoral S. mutans mediates KYNA overproductions via utilizing its protein antigen c (PAc). KYNA shifts the cellular types in the tumor microenvironment (TME) of OSCC and predominantly expedites the expansions of S100a8 high S100a9 high neutrophils to produce more interleukin 1β (IL-1β), which further expands neutrophils and induces CD8 + T cell exhaustion in TME and therefore promotes OSCC. Also, KYNA compromises the therapeutic effects of programmed cell death ligand 1 (PD-L1) and IL-1β blockades in oral carcinogenesis model. Moreover, KYNA-mediated immunosuppressive program and aryl hydrocarbon receptor (AHR) expression correlate with impaired anti-tumor immunity and poorer survival of OSCC patients., Conclusions: Thus, aberration of oral microbiota and intratumoral colonization of specific oral bacterium such as S. mutans may increase the production of onco-metabolites, exacerbate the oral mucosal carcinogenesis, reprogram a highly immunosuppressive TME, and promote OSCC, highlighting the potential of interfering with oral microbiota and microbial metabolism for OSCC preventions and therapeutics. Video Abstract., (© 2024. The Author(s).)

Malignant tumors of the lung are the leading cancers worldwide. Prognostic biomarkers continue to be investigated for the detection and stratification of lung cancer for clinical use. In breast cancer cells and in lymphomas, the overexpression of galectin-7 led to increased metastasis. In lung cancer, squamous cell carcinoma, galectin-7 was also identified as a factor promoting metastasis. In this study, we investigated the expression of galectin-7 in relation to clinicopathological features and overall survival in patients with different types of lung cancer. By immunohistochemistry, expression of galectin-7 was analyzed in 308 cases of lung cancer; 108 cases of adenocarcinoma, 193 cases of squamous cell lung carcinoma and 7 cases of small cell lung cancer (SCLC) and correlated with clinicopathological characteristics as well as patients' overall survival. Immunohistochemical detection of galectin-7 expression was most evident in squamous cell lung carcinoma (36.27%), followed by adenocarcinoma (5.55%). Negative expression of galectin-7 was found in all patients with SCLC. No significant correlation was found in patients with squamous cell lung carcinoma. Within the adenocarcinoma and squamous cell lung carcinoma subgroups, there were statistically significant correlations between the expression of galectin-7 and some clinicopathologic features of the patients. In our study, we were able to show that galectin-7 could serve as a new prognostic biomarker and is also a potential new drug target in non-small cell lung cancer., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The treatment of oral squamous cell carcinoma (OSCC) remains a significant difficulty, as there has been no improvement in survival rates over the past fifty years. Hence, exploration and confirmation of new dependable treatment targets and biomarkers is imperative for OSCC therapy. TEAD transcription factors are crucial for integrating and coordinating multiple signaling pathways that are essential for embryonic development, organ formation, and tissue homeostasis. In addition, by attaching to coactivators, TEAD modifies the expression of genes such as Cyr61, Myc, and connective tissue growth factor, hence facilitating tumor progression. Therefore, TEAD is regarded as an effective predictive biomarker due to its significant connection with clinical parameters in several malignant tumors, including OSCC. The efficacy of existing drugs that specifically target TEAD has demonstrated encouraging outcomes, indicating its potential as an optimal target for OSCC treatment. This review provides an overview of current targeted therapy strategies for OSCC by highlighting the transcription mechanism and involvement of TEAD in oncogenic signaling pathways. Finally, the feasibility of utilizing TEAD as an innovative approach to address OSCC and its potential clinical applications were analyzed and discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Shao, Gao, Zhao, Kong, Deng, Yang, Shang, Sun and Fu.)

Background: Locally advanced oral cavity squamous cell carcinoma (OCSCC) presents a significant clinical challenge despite being partially responsive to standard treatment modalities. This study investigates the prognostic implications of programmed death-ligand 1 (PD-L1) expression in these tumors, focusing on its association with treatment outcomes and the immune microenvironment., Methods: We assessed tumor-infiltrating lymphocytes (TILs) in 132 patients with OCSCC to evaluate their impact on survival. Multiplex immunohistochemistry staining for CD3, CD68, CD11c, PD-L1, and P40 was used to explore correlations with clinical outcomes in patients with early-stage (n=22) and locally advanced (n=36) OCSCC. These initial findings were validated through differential gene expression analysis, gene set enrichment, and immune cell deconvolution in a The Cancer Genome Atlas cohort of 163 locally advanced OCSCC tumors. Additionally, single-cell RNA sequencing (scRNA-seq) on a smaller cohort (n=10) further characterized the PD-L1 hi or PD-L1 lo cancer cells in these tumors., Results: Elevated PD-L1 expression was associated with poor outcomes in patients with locally advanced OCSCC undergoing standard adjuvant therapy, irrespective of "hot" or "cold" classification based on TILs assessment. PD-L1 hi tumors exhibited an active immune response phenotype, enriched with M1 macrophages, CD8 + T cells and T regulatory cells in the tumor microenvironment. Notably, the negative impact of PD-L1 expression on outcomes was primarily attributed to its expression by cancer cells, rather than immune cells. Furthermore, scRNA-seq revealed that immune interactions were not essential for PD-L1 upregulation in cancer cells, instead, complex regulatory networks were involved. Additionally, PD-L1 lo locally advanced tumors exhibited more complex pathway enrichment and diverse T-cell populations compared with those in the early-stage., Conclusion: Our findings underscore the prognostic significance of PD-L1 expression in locally advanced OCSCC, and unveil the complex interplay between PD-L1 expression, immune responses, and molecular pathways in the tumor microenvironment. This study provides insights that may inform future therapeutic strategies, including the possibility of tailored immunotherapeutic approaches for patients with PD-L1 hi locally advanced OCSCC., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Our objective was to investigate the association between programmed death-ligand (PD-L1) immunoexpression measured as a combined positive score and clinical outcomes in penile SqCC., Materials and Methods: We retrospectively reviewed all penile SqCC cases diagnosed in our institution between 2018 and 2023. PD-L1 immunohistochemistry was performed as a qualitative assay. Immunoexpression in both tumor and immune cells equal or superior to 1 was considered positive., Results: A total of 34 patients with conventional penile SqCC were included. Eleven cases were HPV-associated (32.4%). Twelve cases were PD-L1 CPS < 1 and twenty-two were PD-L1 CPS ≥ 1. Nine cases (32.4%) were PD-L1 CPS ≥ 1 and p16 positive, but this did not translate in worse clinicopathological features. Larger tumors (3.0 cm in PD-L1 CPS ≥ 1 vs 2.5 cm in PD-L1 CPS < 1; p = 0.662), vascular invasion (36.4% in PD-L1 CPS ≥ 1 vs. 25.0% in PD-L1 CPS < 1; p = 0.705) and perineural invasion (40.9% in PD-L1 CPS≥1 vs. 16.7% in PD-L1 CPS < 1; p = 0.252) were associated with PD-L1 expression. Among the high-risk features, only lymph node involvement had statistical significance, with 14 out of 22 PD-L1 CPS ≥ 1 patients (63.6%) having lymph node metastases when lymphadenectomy was performed (p = 0.031). With a median follow-up of 16 months (IQR 27.5), PD-L1 CPS ≥ 1 patients had worse overall survival (53.4 months vs 75.9 months), but no statistical significance could be inferred (p = 0.188)., Conclusions: It is noteworthy the clinical significance of lymph node involvement in PD-L1 CPS ≥ 1 cases and a trend towards worse overall survival in this group of patients.

Vitamin D activates the vitamin D receptor (VDR), which dimerizes preferentially with the retinoid X receptor-α (RXRα). This heterodimer connects with genetic elements responsive to vitamin D, inhibiting or stimulating gene activity. We performed Nanostring® analysis of VDR/RXRα to compare the mRNA expression of this heterodimer and their correlated transcriptomes in non-melanoma skin cancer (basal cell carcinomas (BCC) and squamous cell carcinomas (SCC)) and melanocytic lesions (intradermal nevi (IN), and melanomas (MM)) with control skin. To evaluate VDR, RXRα and other 22 correlated genes in BCC, SCC, IN and MM, paraffin samples had their transcriptomes analysed using Nanostring®, a platform that allows multiple mRNA analyses. There were 46 samples, including 11 BCC, 10 SCC, 10 IN, 12 MM and 3 pools of control skins. Most mRNAs differed between the lesion groups and the control group. BCC and SCC NCOR2 were upregulated; in MM and IN, RXRγ was higher than in the control group. TP53, FOXO3 and MED1 showed a significant difference when we compared the BCC group to the SCC group. Melanoma and intradermal nevi differed only in AhR. VDR and RXRα were lower than the control in all groups. The panel shows a clear difference between the non-melanocytic cancers and, on the other hand, a slight difference between the melanocytic lesions. The study of vitamin D's influence through its receptor and RXRα is an exciting issue for understanding the importance of this pathway, and the present study can impact the prevention and treatment strategies, mainly in non-melanocytic tumours., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer, but treatments for advanced cases have limited efficacy. Trophoblast cell-surface antigen 2 (TROP2) is a cell-surface protein that is widely expressed in various tumours, where it exerts significant influence over critical processes such as tumour cell growth, apoptosis, migration, invasion and metastasis. Sacituzumab govitecan, an antibody-drug conjugate (ADC) targeting TROP2, is emerging as a promising strategy for anticancer therapy. In this study, we investigated TROP2 expression in cSCC tissues from 51 patients and evaluated its function in the A431 human SCC cell line. Immunohistochemical analysis revealed TROP2 expression on the plasma membrane of cSCC tissues and A431 cells. A431 cells showed sensitivity to sacituzumab govitecan with a significant concentration-dependent decrease in viable cell number. In addition, Knockdown of TROP2 resulted in decreased expression of cyclin D1 and BCL-2, along with reduced cell viability. Knockdown of TROP2 also resulted in decreased expression of vimentin, along with reduced migratory capacity. These findings suggest that TROP2 plays a crucial role in cSCC cell proliferation and migration, and highlight the potential of sacituzumab govitecan as a promising therapeutic option for cSCC., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Objective: To assess the effectiveness of periodic acid-Schiff stain and p53 immunohistochemical marker in reducing interobserver variability for diagnosing microinvasive oral squamous cell carcinoma cases., Methods: The cross-sectional study was conducted at a tertiary care diagnostic hospital in Rawalpindi, Pakistan, from March 31 to July 31, 2023, and comprised diagnostically challenging biopsy specimens. The specimens were subjected first to haematoxylin and eosin stain, and then with periodic acid-Schiff stain and tumour protein p53 immunohistochemistry simultaneously. A preliminary diagnosis on routine staining alone and a final diagnosis with the two adjuncts were reported by two observers who were both blinded to the prior diagnosis. Data was analysed using SPSS 25., Results: Of the 30 specimens diagnosed, 21 (70%) belonged to males and 9 (30%) to females. The mean age of the patients was 60.47±11.78 years. Periodic acid-Schiff staining and tumour protein p53 immunohistochemistry demonstrated a significant decrease in interobserver variability in the diagnosis of microinvasive oral squamous cell carcinoma, exhibiting enhanced visualisation in basement membrane breach and identifying the invading cells within the lamina propria that were masked on routine staining (p<0.05)., Conclusion: Periodic acid-Schiff stain and tumour protein p53 immunohistochemistry could assist in reducing interobserver variability in the diagnosis of microinvasive oral squamous cell carcinoma.

Histopathologically, oral squamous cell carcinoma (OSCC) consists of well-defined interfaces with adjacent non-cancerous epithelium. Previously, we found that SCC tissues expressed higher levels of specific proteins at this interface. Ladinin-1 (LAD1) is one of the specific molecules that has increased expressions in cancer fronts; however, its function in OSCC is unknown. Therefore, this study aimed to elucidate the function of LAD1 in human OSCC cells. LAD1 was localized on the actin arc at the distal periphery of cell clusters in the OSCC cell lines HSC-2, HSC-3, and HSC-4. When LAD1 was knocked down, cellular migration was repressed in wound scratch assays but was reversed in three-dimensional collagen gel invasion assays. Characteristic LAD1 localization along actin arcs forming the leading edge of migrating cells was diminished with loss of filopodia formation and ruffling in knockdown cells, in which the expression levels of cell motility-related genes-p21-activated kinase 1 (PAK1) and caveolin-1 (CAV1)-were upregulated and downregulated, respectively. LAD1 expression was also associated with the downregulation of vimentin and increased histological differentiation of OSCC. These results suggest that LAD1 is involved in actin dynamics during filopodia and lamellipodia formation, and in maintaining the epithelial phenotype of OSCC cells., (© 2024. The Author(s).)

Background: Platelet-derived growth factor A (PDGFA) has been shown to be upregulated in several tumors, contributing to their malignant phenotypes. However, its expression and function in head and neck squamous cell carcinoma (HNSC) are not clearly understood. Thus, we aimed to evaluate this issue using bioinformatic analyses and primary experimental validation., Methods: The expression of PDGFA was analyzed using popular bio-databases and further validated by RT-PCR and immunohistochemical staining. Survival analyses were then performed. The association between PDGFA expression levels and immune cell infiltration in the immune microenvironment was assessed., Results: PDGFA has been found to be significantly upregulated in a variety of cancers, including HNSC, and increased PDGFA expression may be an independent prognostic factor associated with immune cell infiltration in HNSC., Conclusion: Overexpression of PDGFA in HNSC is significantly associated with poor prognosis and immune cell infiltration in the tumor microenvironment (TME). PDGFA has potential as a molecular indicator for diagnosis, prognosis, and immune processes in HNSC., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Photobiomodulation therapy, as an emerging treatment modality, has been widely used in dentistry. However, reports on blue light therapy for oral cancer are scarce. This study investigated the effects of 457 and 475 nm LED irradiation on SCC-25 cells and explored the potential mechanisms underlying the impact of blue light. Both wavelengths were found to inhibit cell viability, induce oxidative stress, and cause cell cycle arrest without leading to cell death. Notably, the inhibitory effect of 457 nm blue light on cell proliferation was more sustained. Transcriptome sequencing was performed to explore the underlying mechanisms, revealing that blue light induced endoplasmic reticulum stress in SCC-25 cells, with 457 nm light showing a more pronounced effect. Moreover, 457 nm blue light upregulated the expression of the aryl hydrocarbon receptor pathway, indicating potential therapeutic prospects for the combined use of blue light and pharmacological agents., (© 2024 Wiley‐VCH GmbH.)

Head and neck squamous cell carcinomas (HNSCCs), a heterogeneous group of cancers that arise from the mucosal epithelia cells in the head and neck areas, present great challenges in diagnosis, treatment and prognosis due to their complex aetiology and various clinical manifestations. Several factors, including smoking, alcohol consumption, oncogenic genes, growth factors, Epstein‑Barr virus and human papillomavirus infections can contribute to HNSCC development. The unpredictable tumour microenvironment adds to the complexity of managing HNSCC. Despite significant advances in therapies, the prediction of outcome after treatment for patients with HNSCC remains poor, and the 5‑year overall survival rate is low due to late diagnosis. Early detection greatly increases the chances of successful treatment. The present review aimed to bring together the latest findings related to the molecular mechanisms of HNSCC carcinogenesis and progression. Comprehensive genomic, transcriptomic, metabolomic, microbiome and proteomic analyses allow researchers to identify important biological markers such as genetic alterations, gene expression signatures and protein markers that drive HNSCC tumours. These biomarkers associated with the stages of initiation, progression and metastasis of cancer are useful in the management of patients with cancer in order to improve their life expectancy and quality of life.

Background: The actin-binding protein anillin (ANLN) functions as an oncogene in various cancers but has not been fully studied in oral squamous cell carcinoma (OSCC). This study aimed to investigate the expression of ANLN in OSCC tissues and cell lines, to better understand its role in mediating proliferative, angiogenic, invasive, and metastatic capabilities in this type of cancer., Methods: ANLN mRNA and protein levels were assessed using qPCR and western immunoblotting. The expression intensity of ANLN was evaluated using immunohistochemical (IHC) staining. Biological functional assays were employed to characterize the behavior of OSCC cells influenced by ANLN. Additionally, comprehensive bioinformatics analysis, including GO analysis and KEGG enrichment analysis, was performed on differentially expressed genes in ANLN-mediated pathways., Results: OSCC tumors and cell lines exhibited higher ANLN expression. Silencing of ANLN significantly suppressed OSCC cell proliferation, as evidenced by a significant reduction in the Ki-67 index both in vitro and in vivo. The migration and invasive ability of OSCC cells were markedly diminished, coinciding with a decrease in epithelial-mesenchymal transition activity. ANLN was also found to promote angiogenic activity in OSCC cells, partly through synergistic effects mediated by vascular endothelial growth factor A (VEGFA). Downregulation of ANLN expression led to decreased VEGFA levels, resulting in reduced angiogenesis characterized by fewer vascular branches., Conclusions: Our findings highlight the promising role of ANLN as a biomarker for both diagnostic and prognostic in OSCC. Targeting ANLN with inhibitory strategies could impede the oncogenesis processes at the core of OSCC development, presenting significant opportunities for advancing therapeutic interventions., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Esophageal cancer is the eighth most common cause of cancer-related deaths worldwide. There are two main histological subtypes of esophageal cancer: adenocarcinoma and squamous cell carcinoma. Among the factors associated with the development of esophageal cancer, estrogen receptor beta (ERβ) has been found to have a clinical significance., Aim: To investigate the relationship between ERβ expression and esophageal cancer., Methods: English Medical literature searches were conducted for ERβ expression in patients with esophageal cancer versus healthy controls. Searches were performed up to August 31, 2023, using MEDLINE, PubMed, Embase and Google Scholar. Meta-analysis was performed by using Comprehensive meta-analysis software (Version 4, Biostat Inc., Englewood, NJ, USA). Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated. Heterogeneity was evaluated using Cochrane Q-test, and it was considered present if the Q-test P value was less than 0.10. I 2 statistic was used to measure the proportion of inconsistency in individual studies, with I 2 > 50% representing heterogeneity. We also calculated a potential publication bias., Results: Ten studies representing 11 substudies were selected according to the inclusion criteria. The odds ratio of ERβ expression in fixed effect analysis was 0.448, 95% CI: 0.237 to 0.846, 55.2% lower in esophageal cancer than in normal mucosa. Heterogeneity and inconsistency were low, and no publication bias was demonstrated., Conclusion: This meta-analysis showed that ERβ expression is lower in esophageal cancer biopsy specimens than in healthy controls, this finding may have a significant effect on survival and can lead to new therapeutic avenues.

Objectives: Investigating the expression and prognostic significance of adenovirus receptors DSG-2, CXADR and CD46 in head and neck cancer., Methods: 104 patients with HNSCC (77 OPSCC, 27 LSCC) were retrospectively included in the study. Immunohistochemical staining was performed on all selected slides to detect the expression of DSG-2, CXADR, CD46 and the immunoreactive score (IRS) was determined from the number of positively stained tumor cells and their staining intensity. Furthermore, the respective HPV status was determined by immunohistochemical staining against p16 and HPV-PCR., Results: 81.7 % of the tumors showed DSG-2, 34.6 % of the tumors showed CXADR and 57.7 % of the tumors showed CD46 expression. A high DSG-2 IRS correlated significantly with an advanced tumor size (p= 0.003), increased grading (p=0.012) and positive HPV status (p=0.024) in OPSCC. A high CXADR IRS was significantly associated with a positive lymph node status (p= 0.041) in LSCC and an advanced AJCC stage (p= 0.012) and a positive HPV status (p= 0.009) in OPSCC. No significant correlation could be shown regarding CD46 expression and clinical tumor data. There was no effect of DSG-2, CXADR, and CD46 expression on 5-year overall and on 5-year disease-free survival., Conclusion: No prognostic significance of the expression of DSG-2, CXADR or CD46 in HNSCC was seen. DSG-2, CXADR and CD46 are expressed in HNSCC, so that optimization of oncotherapy with adenoviral vectors appears promising. Due to the significantly increased expression of DSG-2 and CXADR in advanced OPSCC tumors, there is potential for optimizing oncotherapy here in particular., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Previous studies have supported a tumor-suppressive role of semaphorin 3A (SEMA3A) in several tumors including oral squamous cell carcinoma (OSCC). However, in-depth characterization of the role of SEMA3A in OSCC and the underlying molecular mechanisms is lacking. Gene and protein expressions were detected using quantitative real-time PCR, western blot assay, and immunohistochemistry. OSCC cell metastasis was evaluated using Transwell and angiogenesis of human umbilical vein endothelial cells (HUVECs) was determined using tube formation assay. The interactions among molecules were predicted using bioinformatics analysis and validated using luciferase activity experiment and RNA immunoprecipitation assay. Pulmonary metastasis was evaluated using hematoxylin and eosin staining after constructing a lung metastasis tumor model in mice. SEMA3A expression was decreased in OSCC cells and its overexpression led to suppression of epithelial-mesenchymal transition (EMT), migration, and invasion of OSCC cells and angiogenesis of HUVECs. miR-32-5p was identified as an upstream molecule of SEMA3A and long non-coding RNA NR2F2 antisense RNA 1 (NR2F2-AS1) was validated as an upstream gene of miR-32-5p. Further experiments revealed that the inhibitory effects of NR2F2-AS1 overexpression on EMT, migration, invasion of OSCC cells, and angiogenesis of HUVECs as well as tumor growth and metastasis in mice were mediated via the miR-32-5p/SEMA3A axis. To conclude, NR2F2-AS1 may attenuate OSCC cell metastasis and angiogenesis of HUVECs and suppress tumor growth and metastasis in mice via the miR-32-5p/SEMA3A axis., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

The lymph node is the most common site of distant metastasis of cervical squamous cell carcinoma (CSCC), which elicits dismal prognosis and limited efficiency for treatment. Elucidation of the mechanisms underlying CSCC lymphatic metastasis would provide potential therapeutic strategies for nodal metastatic of CSCC. Here, based on in vivo lymphatic metastasis screening model, a circular RNA is identified that is termed as lymph node metastasis associated circRNA (LNMAC), is markedly upregulated in lymphatic metastatic CSCC and correlated with lymph node metastasis. Overexpression of LNMAC dramatically augments the metastatic capability of CSCC cells to the lymph node via inducing lymphangiogenesis. Mechanistically, LNMAC epigenetically upregulates fibroblast growth factor 2 (FGF2) expression by directly associating with histone acacetylase 1 (HDAC1), preventing Importin α6/8-mediated nuclear translocation of HDAC1 and eliciting histone H3K27ac-induced FGF2 transcriptional activation. Treatment with 3F12E7, an anti-FGF2 monoclonal antibody, effectively inhibits LNMAC-induced CSCC lymphatic metastasis. Taken together, these findings indicate that LNMAC plays a crucial role in FGF2-mediated lymphangiogenesis and lymphatic metastasis, highlighting that LNMAC might be a therapeutic target for lymph node metastasis in CSCC patients., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Oral squamous cell carcinoma (OSCC) is a frequently occurring malignancy in the head and neck region. The most commonly mutated gene in OSCC is the tumor suppressor gene p53 (TP53), linked to lower survival and treatment resistance in OSCC patients. Astilbin is a flavonoid amongst several herbal treatments with a variety of pharmacological actions mainly including antioxidant, anti-inflammatory, and anti-cancer characteristics. This study evaluated the effects of astilbin on proliferation of OSCC cell lines SCC90 and SCC4 (bearing a p53 mutation) in relevance to p53 and Mdm-2 pathways. Astilbin inhibited the proliferation of SCC4 and SCC90 cells in a dose- and time-dependent manner. The IC50 values for both the cell lines were about 75 μM for astilbin. A p53 activator (RITA) was used to determine the effects of astilbin on p53 activity, and the results demonstrated synergistic reduction in cell growth. However, when combined with pifithrin-α (a p53 inhibitor), astilbin demonstrated a strong inhibition of its response. Astilbin reduced the mitochondrial membrane potential in SCC4 cells, which is a sign of apoptotic activity. Astilbin decreased the amounts of Mdm-2 (negative regulator of p53) and increased the expression of the p53 gene and protein. In a p53-dependent manner, astilbin suppressed the ability of SCC4 cells to form colonies and heal wounds. This was followed by the induction of mitochondrial intrinsic apoptosis via the activation of caspases 9 and 3, cleavage of PARP, and the suppression of pro-apoptotic Bid. Astilbin-induced p53-mediated apoptosis in OSCC cells as herbal medicinal ingredients., (© 2024. Pleiades Publishing, Ltd.)

Abnormal expression of SEC14L2 has been implicated in many human cancers. However, the role of SEC14L2 in oral squamous cell carcinoma (OSCC) remains unclear. Therefore, this study aimed to evaluate the expression and prognostic roles of SEC14L2 in OSCC. OSCC tumors and adjacent non-tumors were collected from OSCC patients and used for SEC14L2 mRNA expression by quantitative reverse transcription PCR (RT-qPCR). Additionally, the expression of SEC14L2 was further analyzed using The Cancer Genome Atlas-Head Neck Squamous Cell Carcinoma (TCGA-HNSCC) dataset to identify its relationship with HNSCC clinical characteristics. The Kaplan-Meier plot was used to assess survival rates, and the Tumor Immune Estimation Resource (TIMER) database was used to examine the correlation between SEC14L2 expression and tumor immune cell infiltration. In silico tools also looked at SEC14L2 involvement in cancer pathways through its protein network. The mRNA and protein levels of SEC14L2 are notably higher in both OSCC and HNSCC tissues compared to adjacent normal tissues. Upregulation of SEC14L2 was associated with advanced tumor stages, grades, metastasis, HPV-negative, and TP53 mutations in cancer patients. In addition, the high expression of SEC14L2 was negatively correlated with the poor survival of cancer patients and the infiltration of diverse immune cells in cancer patients. According to the findings of this investigation, SEC14L2 is significantly elevated in OSCC/HNSCC patients and associated with a worse prognosis. More investigation and clinical studies are required to completely understand the therapeutic potential of SEC14L2 in HNSCC and convert these findings into better patient outcomes., (© 2024. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)

Laryngeal squamous cell carcinoma (LSCC) is a prevalent human cancer with a complex pathogenesis that remains incompletely understood. Here, we unveil a long non-coding RNA (lncRNA) associated with LSCC tumorigenesis and progression. LOC730101 exhibits significant overexpression in human LSCC tissues, and elevated LOC730101 levels correlate with malignant clinicopathological characteristics. Moreover, we demonstrate that LOC730101 is encapsulated into exosomes in an hnRNPA2B1-dependent manner, serving as a promising plasma biomarker for discriminating LSCC patients from healthy individuals (AUC = 0.92 with 89.36% sensitivity and 86.36% specificity). Exosomes derived from LSCC cells enhance the viability, DNA synthesis rate, and invasiveness of normal nasopharynx epithelial cells, with pronounced effects observed upon LOC730101 overexpression. Additionally, exosomal LOC730101 promotes tumor growth in vivo. Mechanistically, exosomal LOC730101 internalization by normal nasopharynx epithelial cells leads to increased H3K4me3 levels on the p38 MAPK gamma (p38γ) promoter via direct interaction with hnRNPA2B1. This interaction activates p38γ transcription, ultimately driving LSCC tumorigenesis. Collectively, our findings uncover a novel exosomal lncRNA that mediates communication between normal and LSCC cells during LSCC carcinogenesis, suggesting that targeting LOC730101 may represent a promising therapeutic strategy for LSCC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: USP14 (Ubiquitin-specific-processing protease 14) is a deubiquitinating enzyme with oncogenic effects in oral squamous cell carcinoma (OSCC). This study aims to identify new substrates of USP14 and elucidate their role in modulating cancer stem-like cells (CSCs) in OSCC., Materials and Methods: Bioinformatics prediction and docking were performed using UbiBrowser 2.0 and HDOCK, respectively. OSCC cell lines and patient-derived cells were used for experimental validation, employing co-immunoprecipitation, cycloheximide chase assays, and tumor sphere formation to evaluate the effects of USP14 on SOX2 stability, ubiquitination, and CSC phenotypes., Results: USP14 upregulation was associated with worse overall survival and progression-free interval in OSCC. USP14 interacted with SOX2 with its ubiquitin carboxyl-terminal hydrolase domain. USP14 knockdown impaired SOX2 stability by increasing its polyubiquitination. Ectopic overexpression of wild-type USP14, but not the hydrolase-deficient-mutant USP14 C114A , enhanced SOX2 stability by reducing polyubiquitination. USP14 knockdown suppressed OSCC cell proliferation, colony formation, and tumor sphere formation in vitro and tumor growth in vivo. However, the reduction of CSC markers following USP14 knockdown was mitigated by overexpressing SOX2. These findings were verified in OSCC patient-derived CSC cells., Conclusion: This study revealed a USP14-SOX2 axis regulating the CSC properties of OSCC., (© 2024 Wiley Periodicals LLC.)

Objective: C-C motif chemokine receptor 7 (CCR7) significantly influences tumors onset and progression, yet its impact on the tumor microenvironment (TME) and specific mechanisms remain elusive. Inflammatory Cancer-Associated Fibroblasts (iCAF), a vital subtype of Cancer-Associated Fibroblasts (CAF), play a critical role in regulating the TME and tumor growth, though the underlying molecular mechanisms are not fully understood. This study aims to determine whether CCR7 participates in tumor regulation by iCAF and to elucidate the specific mechanisms involved., Methods: Differential gene analysis of CAF subtypes in CCR7 knockout and wild-type groups was conducted using single-cell data. Animal models facilitated the extraction of primary iCAF cells via flow cytometry sorting. Changes in DUSP1 expression and the efficiency of lentivirus-mediated knockdown and overexpression were examined through qPCR and Western Blot. MOC1 and MOC2 cells were co-cultured with iCAF, with subsequent validation of changes in tumor cell proliferation, migration, and invasion using CCK8, EdU, and wound healing assays. ELISA was employed to detect changes in TGF-β1 concentration in the iCAF supernatant., Results: CAF was categorized into three subtypes-myCAF, iCAF, and apCAF-based on single-cell data. Analysis revealed a significant increase in DUSP1 expression in iCAF from the CCR7 knockout group, confirmed by in vitro experiments. Co-culturing MOC1 and MOC2 cells with iCAF exhibiting lentivirus-mediated DUSP1 knockdown resulted in inhibited tumor cell proliferation, invasion, and migration. In contrast, co-culture with iCAF overexpressing DUSP1 enhanced these capabilities. Additionally, the TGF-β1 concentration in the supernatant increased in the DUSP1 knockdown iCAF group, whereas it decreased in the DUSP1 overexpression group., Conclusion: The CCR7/DUSP1 signaling axis regulates tumor growth by modulating TGF-β1 secretion in iCAF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Goal of the review: The utilization of biomarkers to predict cancer risk, prognosis, and treatment outcomes is paramount. Netrin-1 (NTN1), known for its role in commissural axon guidance during embryonic development, has emerged as a versatile molecule with significant implications in cancer and neurobiology. Structurally resembling laminin, Netrin-1 regulates neuronal connectivity and plasticity in adulthood, influencing axonal and dendritic growth, neurotransmission, and cell migration. In addition to its neurological functions, Netrin-1 is increasingly recognized for its involvement in maintaining epithelial tissue and its regulatory roles in fundamental cellular processes, including adhesion, proliferation, differentiation, apoptosis, and angiogenesis. In cancer biology, Netrin-1's interactions with its receptors, such as DCC [Deleted in Colorectal Cancer] and UNC5 (a homolog of DCC), have been implicated in tumor progression across various physiological systems. Elevated levels of Netrin-1 in colorectal cancer and head and neck squamous cell carcinoma are correlated with increased tumorigenic potential, mediated through pathways involving NFκB activation and anti-apoptotic mechanisms. Mechanically induced hypermethylation and downstream signaling cascades that inhibit apoptosis and promote cell survival are observed upon Netrin-1 binding to DCC. Furthermore, Netrin-1 shows promise as a biomarker for detecting inflammatory activity in diseases such as multiple sclerosis and as a potential diagnostic, prognostic, and therapeutic indicator in oral squamous cell carcinoma. Elevated levels of Netrin-1 in bodily fluids, alongside immunohistochemical evidence, support its potential as a valuable clinical marker in cancer management. This abstract emphasizes Netrin-1's diverse biological roles, underscoring its potential as a diagnostic tool and therapeutic target in cancer research. The need for further exploration of Netrin-1's molecular interactions and clinical applications is urgent and crucial to advance personalized medicine approaches and enhance patient outcomes in oncology and neurology., Competing Interests: Declaration of competing interest There is no conflict of interest among authors., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The PI3K/Akt pathway plays a critical role in the progression and treatment of oral squamous cell carcinoma (OSCC). Recent research has uncovered the involvement of long non-coding RNAs (lncRNAs) in regulating this pathway, influencing OSCC cell proliferation, survival, and metastasis. This review explores the latest findings on how certain lncRNAs act as either cancer promoters or cancer inhibitors within the PI3K/Akt signaling pathway. Certain lncRNAs act as oncogenic or tumor-suppressive agents, making them potential diagnostic and prognostic markers. Targeting these lncRNAs may lead to novel therapeutic strategies. The evolving fields of precision medicine and artificial intelligence promise advancements in OSCC diagnosis and treatment, enabling more personalized and effective patient care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Chemotherapeutic drug resistance is a challenge for the effective treatment of OSCC. There are a couple of studies on the involvement of microRNAs (miRNAs) in chemoresistance of oral squamous cell carcinoma (OSCC), but the exact molecular events in many cases are not clearly understood. In this work, we intend to track down key miRNA(s) and unveil their regulatory molecular mechanisms in imparting chemoresistance in this lethal cancer. We analyzed gene and miRNA array profiles of drug-resistant OSCC cells, predicted miRNA targets, performed enrichment analysis, and validated our findings in cisplatin-sensitive and cisplatin-resistant SCC9 and H357 OSCC cells. We evaluated the anticancer and chemosensitivity roles of selected miRNA by adopting several molecular assays like qRT-PCR, MTT assay, wound healing assay, fluorescence imaging by DCFHDA, AO/EB staining, DAPI, and γ-H2AX accumulation assay. We also validated the miRNA-target binding by qRT-PCR and luciferase reporter assay. Among the enriched miRNAs, we found miR-185-5p downregulated in cisplatin-resistant OSCC cells as a signature miRNA modulating chemoresistance. The upregulation of miR-185-5p by mimic transfection restores cisplatin sensitivity by decreasing cell viability in a dose-dependent manner and increasing ROS-induced DNA damage and apoptosis. miR-185-5p overexpression increases miR-203a-3p expression through negative regulation of SOX9. siRNA-mediated silencing of the SOX9 also shows similar results. Mechanistically, miR-185-5p dependent miR-203a-3p expression decreases cisplatin efflux and cisplatin-induced DNA damage repair by regulating ABCC1, ABCB1, RRM2, and RAN. This study will pave the way for employing this miR-185-5p as a combination therapeutic strategy to combat cisplatin resistance in oral cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Peroxiredoxin 1 (PRDX1) is an important member of the peroxiredoxin family (PRDX) and is upregulated in a variety of tumors. Previous studies have found that high PRDX1 expression is closely related to the metastasis of oral squamous cell carcinoma (OSCC), but the specific molecular mechanism is elusive. To elucidate the role of PRDX1 in the metastasis process of OSCC, we evaluated the expression of PRDX1 in OSCC clinical specimens and its impact on the prognosis of OSCC patients. Then, the effect of PRDX1 on OSCC metastasis and cytoskeletal reconstruction was explored in vitro and in nude mouse tongue cancer models, and the molecular mechanisms were also investigated. PRDX1 can directly interact with the actin-binding protein Cofilin, inhibiting the phosphorylation of its Ser3 site, accelerating the depolymerization and turnover of actin, promoting OSCC cell movement, and aggravating the invasion and metastasis of OSCC. In clinical samples and mouse tongue cancer models, PRDX1 also increased lymph node metastasis of OSCC and was negatively correlated with the phosphorylation of Cofilin; PRDX1 also reduced the overall survival rate of OSCC patients. In summary, our study identified that PRDX1 may be a potential therapeutic target to inhibit OSCC metastasis., (© 2024 UICC.)

Objective: This study aimed to determine the role of c-Fos in growth and invasion of oral squamous cell carcinoma (OSCC)., Methods: Immunohistochemistry was used to assess c-Fos expression in 94 OSCC tissues and 30 adjacent normal tissues, the correlation between c-Fos expression and clinicopathological characteristics was examined, and Kaplan-Meier and Cox analysis were used to investigate the role of c-Fos in predicting the prognosis of OSCC patients. The effects of c-Fos on the growth and invasion of OSCC were disclosed by overexpression and knockdown of c-Fos. Furthermore, based on bioinformatics prediction, the effect of miR-155-5p on c-Fos expression was examined, and dual-luciferase reporter assay system was used to determine whether miR-155-5p regulated the transcriptional activity of c-Fos in OSCC., Results: c-Fos was markedly increased in OSCC tissues and cells. c-Fos upregulation indicates a poor prognosis in OSCC patients, and c-Fos promotes cell proliferation, migration, and invasion in OSCC. miR-155-5p could regulate the expression and the transcriptional activity of c-Fos by directly targeting the c-Fos 3'-UTR., Conclusion: This study demonstrated that c-Fos contributed to the progression of OSCC and may act as a potential target for OSCC therapy, and a potential prognostic biomarker of OSCC., (© 2024 Wiley Periodicals LLC.)

Lymphocyte antigen 6 complex locus K (LY6K) has been demonstrated to play a significant role in cancers and identified as a therapeutic biomarker for head and neck squamous cell carcinoma. However, the role of LY6K in oral squamous cell carcinoma (OSCC) has not been explored. The current study discovered that LY6K was aberrantly upregulated in OSCC cell lines and tissues and that high LY6K expression significantly correlated with poorer survival of OSCC patients. Through stable knockdown of LY6K, we found that the growth, colony formation, migration, and invasion of OSCC cells were substantially suppressed. In addition, tumor growth and lung metastasis in vivo were effectively inhibited by LY6K depletion. Mechanically, LY6K binds with CAV-1 and activates CAV-1-mediated MAPK/ERK signaling to exert its oncogenic effects on OSCC. In addition, LY6K expression in OSCC was discovered to be regulated by FTO-mediated RNA N6-methyladenosine (m 6 A) modification in an IGF2BP1-dependent manner. Generally, LY6K expression was upregulated by FTO-mediated demethylation in OSCC, which promoted the tumorigenesis and metastasis of OSCC via activating the CAV-1-mediated ERK1/2 signaling pathway., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Objectives: Tumor-associated neutrophils (TANs) are among the most abundant inflammatory cells in tumor microenvironment (TME). Aldehyde dehydrogenase 3A1 (ALDH3A1) is significantly reduced in oral squamous cell carcinoma (OSCC), ALDH3A1 overexpression suppresses tumorigenesis by inhibiting inflammation. This study investigated the relationship and mechanisms underlying the crosstalk between ALDH3A1 and TANs in OSCC., Materials and Methods: Immunohistochemistry and immunofluorescence were performed to investigate the abundance of TANs and the expression of ALDH3A1. dHL-60 were induced with tumor-conditioned media and recombinant IL-6/IL-8. The expression of key proteins in PI3K/AKT/NF-κB pathway were detected by RT-PCR and western blot. A xenograft model was utilized to examine the effect of ALDH3A1 on tumorigenicity and polarization of TANs., Results: In patients with OSCC, TANs significantly increased and were associated with a worse prognosis. Additionally, ALDH3A1 negatively correlated with TANs infiltration and especially the N2 phenotype which was the prominent part in OSCC. Furthermore, our study demonstrated that tumor-derived IL-8 drives ALDH3A1-mediated TANs N2 polarization in the TME through PI3K/AKT/NF-κB pathway in vitro and in vivo., Conclusion: Our results indicate that TANs can serve as a prognostic biomarker and ALDH3A1 could be a promising therapeutic target for regulating TANs N2 polarization in antitumor therapy., (© 2024 Wiley Periodicals LLC.)

Cisplatin (CDDP) is a cornerstone chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC) and many solid cancers. However, the mechanisms underlying tumor resistance to CDDP obscure the enhancement of its therapeutic efficacy. In this study, we unveil diminished expression of the biological clock gene PER2 in OSCC, negatively correlated with the expression of multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1). The overexpression of PER2 suppressed MDR1 and MRP1 expression and increased intracellular CDDP levels and DNA damage, thereby bolstering OSCC cell sensitivity to CDDP. In vivo tumorigenic assays corroborated that PER2 overexpression notably increased OSCC sensitivity to CDDP, augmenting the suppression of OSCC tumorigenesis. Co-immunoprecipitation, GST pull-down, and cycloheximide tracking assays revealed that PER2, via its C-terminal domain, bound to and diminishes PDK1 stability. The degradation of PDK1 was further dependent on the suppression of the AKT/mTOR pathway to enhance the sensitivity of OSCC cells to CDDP. Our study supports PER2 as a target for improving CDDP sensitivity in OSCC, and the combination of PER2 and CDDP is a novel strategy with potential clinical therapeutic value., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)