interleukin-8 and Squamous-Cell-Carcinoma-of-Head-and-Neck

Oral squamous cell carcinoma (OSCC) is gradually increasing its incidence in our society. Unfortunately, this entity is diagnosed at an advanced stage in most patients, a fact that implies greater difficulty in its treatment and a worse prognosis. This systematic review aims to assess whether the cytokines IL-6, IL-8 and TNF-α are potential salivary biomarkers that allow early diagnosis of cancer.. An electronic search was performed in three databases (Pubmed, Scopus and Web of Science). We used the following keywords: "salivary cytokines", "saliva cytokines", "salivary interleukins", "biomarkers", "oral squamous cell carcinoma" and "diagnosis", combined with the Boolean operators "AND" and "OR".. 128 publications were found and finally 23 articles were included in the review and 15 in the meta-analysis. It has been observed that the majority of OSCC patients express higher salivary concentrations of IL-6, IL-8 and TNF-α compared to the control (CL) and premalignant lesion (OPML) groups. It has also been observed that the different premalignant lesions do not have statistically significant differences in the salivary concentration of the cytokines, and on the other hand, differences have been observed between the different TNM stages. The meta-analysis has shown that the difference in concentration of IL-6, IL-8 and TNF-α is statistically significant between the CL group and the OSCC, and also between the CL group and OPML.. There is sufficient evidence to affirm that IL-6, IL-8 and TNF-α are useful salivary cytokines in the early diagnosis and prognosis of OSCC. Although future studies are necessary to establish greater reliability of these biomarkers and thus be able to develop a valid diagnostic test.

Topics: Biomarkers, Tumor; Carcinoma, Squamous Cell; Cytokines; Head and Neck Neoplasms; Humans; Interleukin-6; Interleukin-8; Mouth Neoplasms; Prognosis; Reproducibility of Results; Saliva; Squamous Cell Carcinoma of Head and Neck; Tumor Necrosis Factor-alpha

Increased angiogenesis in head and neck squamous cell carcinoma correlates to more aggressive tumors with increased morbidity. Because both elevated blood flow and high serum CXCL8 levels are correlated with increased angiogenesis, our objective was to see if elevated blood flow measured with CT perfusion correlated with CXCL8 levels, thereby helping to identify candidates for targeted therapies that inhibit the Bcl-2 proangiogenic pathway associated with CXCL8.. Seven patients with locally recurrent or metastatic head and neck squamous cell carcinoma were enrolled in the trial. These patients underwent CT perfusion and the following parameters were measured: blood volume, blood flow, capillary permeability, and MTT; relative values were calculated by dividing by normal-appearing muscle. Serum was drawn for CXCL8 enzyme-linked immunosorbent assay analysis in these patients.. There was a significant positive correlation between the CXCL8 levels and relative blood flow (r = 0.94; P = .01). No correlation was found between CXCL8 and relative blood volume, relative capillary permeability, or relative MTT.. Relative blood flow may be useful as a surrogate marker for elevated CXCL8 in patients with head and neck squamous cell cancer. Patients with elevated relative blood flow may benefit from treatment targeting the Bcl-2 proangiogenic pathways.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Interleukin-8; Male; Middle Aged; Neovascularization, Pathologic; Perfusion Imaging; Prognosis; Reproducibility of Results; Sensitivity and Specificity; Squamous Cell Carcinoma of Head and Neck; Tomography, X-Ray Computed; Up-Regulation

Cancer-related inflammation (CRI) significantly increases the difficulty of treating oral squamous cell carcinoma (OSCC) and remains a major treatment challenge. Our objective was to determine whether tumor ALDH3A1 could attenuate OSCC tumorigenesis by inhibiting tumor-associated macrophages (TAMs) that promoted CRI.. ALDH3A1 in Cal27 cells was overexpressed, and the tumor-conditioned medium (TCM) was collected. We induced THP-1 cells with TCM and recombinant human IL-6. The phosphorylation of STAT3 and the TLR4/TRAF6/TBK1 cascade reaction in TAMs was analyzed using Western blotting, and mitochondrial ROS (mtROS) production was measured using a MitoSox kit. A tumorigenicity assay was performed to examine the tumor volume and weight, and the expression of CD68, CD11b, IL-6, Ki67, and CD31 was analyzed via immunohistochemistry.. ALDH3A1 attenuated STAT3 phosphorylation at Ser727 rapidly and mtROS production earlier in TAMs via inhibiting TLR4/TRAF6/TBK1 cascade reaction. MtROS reduction inhibited IL-1β and IL-8 secretions by NLRP3/caspase-1/IL-1β/IL-8 pathway. Meanwhile, the inhibition of pro-tumor phenotypes of TAMs, tumor proliferation, and tumor angiogenesis during the process was proved in vivo.. ALDH3A1 was associated closely with CRI and inhibited CRI regulated by TAMs. This finding may achieve clinical transformation and open new therapeutic options for targeting CRI regulated by TAMs.

Topics: Aldehyde Dehydrogenase; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Head and Neck Neoplasms; Humans; Inflammation; Interleukin-6; Interleukin-8; Macrophages; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck; TNF Receptor-Associated Factor 6; Toll-Like Receptor 4; Tumor-Associated Macrophages

Immune-checkpoint blockade (ICB) of programmed-death-1 (PD-1) with pembrolizumab or nivolumab is approved for treating recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). NadiHN and ADRISK are phase IIB trials investigating in locally advanced (LA) HNSCC having low or high risk of recurrence the potential benefits from adding nivolumab to post-operative radiotherapy or pembrolizumab to cisplatin-based radio-chemotherapy.. Along five randomized controlled ICB trials including NadiHN and ADRISK, blood samples were taken before and after starting ICB in. We detected huge heterogeneity between cytokine patterns in pre-and post-ICB plasma and serum. We observed high correlation between concentrations of some cytokines. Despite absent systematic OS differences after ICB with pembrolizumab or nivolumab or between LA-HNSCC versus R/M HNSCC patients, we noticed improved outcome of patients having lower IFN-γ concentrations pre- and post-ICB and following ICB reduced concentrations of VEGF, IL-6, and IL-8 but not MCP-1. Contrarily, increases in IL-6, IL-8, and VEGF levels correlated with impaired outcome. Multivariate Cox regression revealed five independent OS predictors among cytokines; using natural logarithms of their hazard ratios to estimate an individual's risk of dying, three cytokine-expression pattern (CEP)-risk groups with no death within mean (95% confidence interval) follow-up of 29.2 (22.1-36.2) months and median OS of 11.3 (8.8-13.8) and 2.9 (0.4-5.4) months were found.. Whereas individual pre- or post-ICB cytokine concentrations in serum or plasma alone failed to predict the survivor group, CEP-risk groups may support the identification of individual patients with long-lasting benefit from ICB.

Topics: Carcinoma, Squamous Cell; Cytokines; Head and Neck Neoplasms; Humans; Immune Checkpoint Inhibitors; Interleukin-6; Interleukin-8; Neoplasm Recurrence, Local; Nivolumab; Squamous Cell Carcinoma of Head and Neck; Vascular Endothelial Growth Factor A

Vascular adhesion protein-1 (VAP-1) is believed to play a role in inflammation. Studies have suggested that VAP-1-mediated activation of inflammation is dependent on NF-κB, leading to secretion of the interleukin (IL)-8; however, no reports have addressed the association between VAP-1 and NF-κB/IL-8 signaling in oral squamous cell carcinoma (OSCC). This study aimed to investigate the role of VAP-1 in OSCC and further explore whether VAP-1 is involved in the regulation of neutrophil infiltration in the tumor microenvironment (TME).. Immunochemistry staining was used to observe VAP-1 expression. CCK-8 and Transwell assays were used to measure cell proliferation, migration, and invasion. OSCC xenograft mouse models were used for in vivo verification of the VAP-1 function. The expression of NF-κB and IL-8 were determined by qRT-PCR and western blot. ELISA for IL-8 was also conducted. The relationship between VAP-1 expression and neutrophil infiltration was analyzed by immunofluorescence.. VAP-1 was overexpressed in human OSCC tissues. Downregulation of VAP-1 suppressed OSCC cells proliferation, migration, and invasion in vitro and inhibited tumor proliferation and metastasis in vivo. Additionally, downregulation of VAP-1 inhibited NF-κB/IL-8 signaling in vitro and in vivo. VAP-1 expression was positively correlated with neutrophil infiltration in human OSCC tissues. Moreover, blocking VAP-1 decreased neutrophil infiltration by reducing IL-8 production.. VAP-1 downregulation in OSCC suppresses tumor growth and metastasis by inhibiting NF-κB/IL-8 signaling and reducing neutrophil infiltration in the TME, suggesting that VAP-1 may be a potential therapeutic target for OSCC.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Down-Regulation; Head and Neck Neoplasms; Humans; Inflammation; Interleukin-8; Mice; Mouth Neoplasms; Neutrophil Infiltration; NF-kappa B; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment

Head and neck cancer (HNC) is a very popular cancer, with many primary sites and pathological types, at the top of the list of tumors. Chemokines are a class of small molecular basic proteins, whose N-terminal cysteine residues can be divided into four subunits by location and number, which significantly enhances the expression level in all kinds of cancers. However, in HNC, especially in head and neck squamous cell carcinoma, the chemokine CXCL8/9/10/11/13 has not been clearly explored for its diagnosis and prognosis.. The ONCOMINE database was used to analyze the expression of chemokine family in various cancers. After CXCL8/9/10/11/13 was screened out, the expression of CXCL 8/9/11/13 in patients with HNC/normal people were analyzed by UALCAN database. The expression and pathological stages of CXCL 8/9/10/13 in HNC tissues were analyzed by the GEPIA database, and the relationship between its mRNA expression and the overall survival (OS) time of patients with HNC was analyzed by Kaplan-Meier plotter database. In addition, 171 co-expressed genes significantly related to CXCL8/9/10/11/13 mutation were screened by online tool cBioPortal, and the protein interaction network of these genes was constructed by STRING database. Finally, the potential functions of CXCL8/9/10/11/13 and its 171 co-expressed genes were explored by the enrichment and analysis function of David database.. Transcriptional expression of chemokine 8/9/10/11/13 was significantly increased in patients with HNC. Clinical stage of patients with HNC was significantly correlated with overexpression of CXCL9/10/11. In addition, the chemokine CXCL8/9/10/13 was significantly correlated with over-survival of patients with HNC, so it could be distinguished between short-term and long-term survival of patients with HNC. In conclusion, CXCL8/9/10/11/13 closely connected with the expression and prognosis of HNC.. In this study, our results suggest that chemokine CXCL8/9/10/11/13 may play a critical role in the development of HNC, and, according to relevant data, it may affect the survival and prognosis of patients with HNC.

Topics: Biomarkers, Tumor; Head and Neck Neoplasms; Humans; Interleukin-8; Prognosis; Squamous Cell Carcinoma of Head and Neck

Lymph node metastasis is associated with poor prognosis of oral squamous cell carcinoma (OSCC), and few studies have explored the relevance of postoperative lymphatic drainage (PLD) in metastatic OSCC. Alpha-enolase (ENO1) is a metabolic enzyme, which is related to lymphatic metastasis of OSCC. However, the role of ENO1 in PLD in metastatic OSCC has not been elucidated. Herein, we collected lymphatic drainage after lymphadenectomy between metastatic and non-metastatic lymph nodes in OSCC patients to investigate the relationship between ENO1 expression and metastasis, and to identify the proteins which interacted with ENO1 in PLD of patients with metastatic OSCC by MS/GST pulldown assay. Results revealed that the metabolic protein apolipoprotein C-III (ApoC3) was a novel partner of ENO1. The ENO1 bound to ApoC3 in OSCC cells and elicited the production of interleukin (IL)-8, as demonstrated through a cytokine antibody assay. We also studied the function of IL-8 on Jurkat T cells co-cultured with OSCC cells in vitro. Western blot analysis was applied to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Mechanistically, OSCC cells activated the STAT3 signaling pathway on Jurkat T cells through IL-8 secretion, promoted apoptosis, and inhibited the proliferation of Jurkat T cells. Collectively, these findings illuminate the molecular mechanisms underlying the function of ENO1 in metastasis OSCC and provide new strategies for targeting ENO1 for OSCC treatment.

Topics: Apolipoprotein C-III; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Interleukin-8; Lymphatic Metastasis; Mouth Neoplasms; Phosphopyruvate Hydratase; Squamous Cell Carcinoma of Head and Neck; STAT3 Transcription Factor

Tumor-associated macrophages (TAMs) promote cancer cell proliferation and metastasis, as well as anti-tumor immune suppression. Recent studies have shown that tumors enhance the recruitment and differentiation of TAMs, but the detailed mechanisms have not been clarified. We thus examined the influence of cancer cells on the differentiation of monocytes to TAM subsets, including CD163

Topics: Carcinoma, Squamous Cell; Cell Differentiation; Cell Line, Tumor; Head and Neck Neoplasms; Humans; Immunohistochemistry; Interleukin-8; Leukocytes, Mononuclear; Macrophages; Plasminogen Activator Inhibitor 1; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Tumor-Associated Macrophages

Cancer stem cells (CSCs) drive tumor initiation and progression and participate in tumor chemoresistance. We recently discovered that oral squamous cell carcinoma (OSCC) cells that highly express CD10 (CD10H cells) present cancer stem cells (CSC)-associated characteristics, which, in turn, affect the tumor growth, epithelial-mesenchymal transition (EMT), and resistance to cisplatin. In this study, we further investigated this mechanism in vitro and in vivo. We hypothesized that IL8 might regulate migration, invasion, and cisplatin resistance of CD10-positive oral cancer cells through the ERK pathway.. CD10 MicroBead Kit was used to select HN6 cells with high and low expression of CD10. The target protein IL8 was screened via protein chip assay. Lentiviral transduction and specific inhibitor were applied to investigate the signaling pathway. Real-time PCR, Western blot, and immunohistochemistry were used to analyze the mRNA and protein expression; transwell assay, spheroid formation assay, and cell viability assay were used to study the cell biological behavior in vitro; xenograft animal model was used to evaluate the tumor formation rate in vivo.. Overexpression of CD10 promoted CSC-related genes expression and enhanced migration, invasion, spheroid formation, and chemoresistance in HN6 cells. Moreover, the overexpression of IL8 was detected in OSCC tumor tissue and cell lines (HN6 and CAL27) overexpressing CD10. IL8 secreted by CD10H HN6 promoted migration and invasion and restored tumor chemosensitivity via the p-ERK signaling pathway, while the inhibition of IL8 increased the chemosensitivity to cisplatin.. IL8 secretion by CD10 positive cells promotes migration, invasion, and cisplatin resistance of OSCC via the p-ERK signaling pathway.

Topics: Animals; Antineoplastic Agents; Cell Communication; Cell Movement; Cisplatin; Drug Resistance, Neoplasm; eIF-2 Kinase; Female; Gene Expression; Heterografts; Humans; Interleukin-8; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Transplantation; Neoplastic Stem Cells; Neprilysin; Signal Transduction; Spheroids, Cellular; Squamous Cell Carcinoma of Head and Neck

Chemotherapies such as 5-fluorouracil (5-FU) and cisplatin (CDDP) have been widely used to treat laryngeal squamous cell carcinoma (LSCC), the second most common head and neck squamous cell carcinoma. However, chemoresistance seriously impairs chemotherapeutic efficacy. Our present study reveals that 5-FU and CDDP treatment increase the expression of histone deacetylase 1 (HDAC1) in LSCC cells. Consistently, increased levels of HDAC1 are observed in chemoresistant cells. Knockdown of HDAC1 significantly restores the sensitivity of LSCC cells, as HDAC1 increases the expression of interleukin-8 (IL-8), which is essential for LSCC chemoresistance. Mechanistically, HDAC1 directly initiates the transcription of IL-8 though binding to its promoter. Simultaneously, si-HDAC1 increases the levels of miR-93, which binds to the 3'UTR of IL-8 mRNA to trigger its degradation. In summary, the HDAC1/IL-8 axis can confer chemotherapeutic resistance to LSCC cells.

Topics: 3' Untranslated Regions; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; Histone Deacetylase 1; Humans; Interleukin-8; Laryngeal Neoplasms; Signal Transduction; Squamous Cell Carcinoma of Head and Neck

Interleukin-8 (IL-8) expression correlates with poor prognosis in many cancers, including head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism is poorly understood. In this study, we found that overexpression of IL-8 correlated with poor outcome in HNSCC patients. IL-8 significantly increased cellular proliferation, migration, and invasion ability both in vitro and in vivo, which could be blocked by a CXCR1/2 inhibitor. IL-8 promoted the expression of MMP2, MMP9, snail, and vimentin in HNSCC cells. Furthermore, IL-8 could inactivate PTEN via phosphorylation, and then inactivated PTEN affected the phosphorylation of STAT3. Recombinant PTEN that internalized in cytoplasm decreased the expression of phosphorylated STAT3, while knockdown of PTEN led to the increased expression of phosphorylated STAT3. A STAT3 inhibitor could reverse the upregulation of invasion-associated proteins mediated by IL-8 stimulation. Furthermore, overexpression of snail and inactivated PTEN jointly promoted the autocrine effect of IL-8 on tumor cells. Last, there were positive correlations between IL-8 and snail, vimentin expression in HNSCC tissues. In summary, our study demonstrates that PTEN acts as a novel "molecular switch" to regulate IL-8/STAT3 signaling, promoting the progression of HNSCC, and indicating that this pathway may be a potential therapeutic target for HNSCC.

Topics: Cell Line, Tumor; Disease Progression; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Interleukin-8; Phosphorylation; Prognosis; PTEN Phosphohydrolase; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Signal Transduction; Snail Family Transcription Factors; Squamous Cell Carcinoma of Head and Neck; STAT3 Transcription Factor; Up-Regulation; Vimentin

Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors-Cortisol, MLN4924, QNZ and TPCA1-on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.

Topics: Amides; Anti-Inflammatory Agents; Cell Line, Tumor; Cell Proliferation; Cyclopentanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Fas Ligand Protein; Head and Neck Neoplasms; Humans; Hydrocortisone; Interleukin-8; NF-kappa B; Phenyl Ethers; Pyrimidines; Quinazolines; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Thiophenes; Tumor Necrosis Factor-alpha

The let-7 family of microRNAs has been considered as tumor suppressors in various cancers; however, the role of let-7c in oral squamous cell carcinoma has not been determined yet.. In this study, phenotypical behaviors and the radio/chemoresistance were examined subsequent to overexpression of let-7c. In addition, the expression of let-7c in cancer stem cells (CSCs) was evaluated and the effect of let-7c on stemness characteristics was assessed. Also, luciferase activity assays were performed to test whether interleukin (IL)-8 was a putative target of let-7c.. Our results confirmed that the expression of let-7c in CSCs was reduced, while overexpression of let-7c attenuated the oncogenicity. Moreover, ectopic expression of let-7c in CSCs downregulated the stemness hallmarks and the radio/chemoresistance. Expression and secretion of IL-8 in oral CSCs were both reduced following overexpression of let-7c. Besides, the inhibitory effect of let-7c on various stemness phenotypes was reverted by IL-8, indicating that lower expression of let-7c may confer higher cancer stemness through a failure to downregulate IL-8.. These findings revealed the significance of let-7c in the contribution of oral cancer stemness and radio/chemoresistance. Targeting let-7c and its downstream IL-8 may be beneficial to prevent cancer recurrence and metastasis of oral squamous cell carcinoma.

Topics: Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Resistance, Neoplasm; Humans; Interleukin-8; MicroRNAs; Mouth Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Phenotype; Radiation Tolerance; Squamous Cell Carcinoma of Head and Neck; Survival Rate; Tumor Cells, Cultured

Lipid-lowering statins as well as non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to possess cancer-protective effects in many epidemiologic cohort studies. However, the underlying mechanisms of these findings are mostly unknown. To evaluate possible additive antitumor effects of statins and NSAIDs in vitro, PJ-41 and HLaC78 head and neck squamous cell carcinoma cells (HNSCC) were treated with 40 µM celecoxib, 50 µM simvastatin or a combination of both. Analysis of tumor viability, proliferation, apoptosis, cell cycle changes and secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8) was conducted via MTT assay, Annexin V-propidium iodide test, cell cycle analysis, colony assay and enzyme-linked immunosorbent assay (ELISA). Celecoxib and simvastatin alone as well as a combined treatment showed a significant reduction in tumor cell viability, proliferation and secretion of IL-6 and IL-8 compared to the control group. The combined treatment even proved to have significantly greater effects. We postulate that simvastatin and celecoxib have additive antitumor effects on HNSCC in vitro, which warrants further investigation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Squamous Cell; Celecoxib; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Interleukin-6; Interleukin-8; Simvastatin; Squamous Cell Carcinoma of Head and Neck

Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression.

Topics: Animals; Autophagy; Cancer-Associated Fibroblasts; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chloroquine; Culture Media, Conditioned; Cytokines; Drug Resistance, Neoplasm; Female; Fibroblast Growth Factor 2; Head and Neck Neoplasms; Humans; Interleukin-6; Interleukin-8; Male; Mice; Mice, SCID; Neoplasm Invasiveness; Pyridines; Pyrimidinones; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays

The concept of functional neutrophil subsets is new and their clinical significance in malignancies is unknown. Our study investigated the role of CD16

Topics: Aged; Aged, 80 and over; Apoptosis; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Female; GPI-Linked Proteins; Granulocytes; Head and Neck Neoplasms; Humans; Interleukin-8; L-Selectin; Male; Middle Aged; Neutrophils; Receptors, IgG; Squamous Cell Carcinoma of Head and Neck; Survival Rate

Microbial Pattern-recognition receptors (PRRs), such as nucleotide-binding oligomerization domains (NODs), are essential for mammalian innate immune response. This study was designed to determine the effect of NOD1 and NOD2 agonist on innate immune responses and antitumor activity in oral squamous cell carcinoma (OSCC) cells.. NODs expression was examined by RT-PCR, and IL-8 production by NODs agonist was examined by ELISA. Western blot analysis was performed to determine the MAPK activation in response to their agonist. Cell proliferation was determined by MTT assay. Flow cytometry and Western blot analysis were performed to determine the MDP-induced cell death.. The levels of NODs were apparently expressed in OSCC cells. NODs agonist, Tri-DAP and MDP, led to the production of IL-8 and MAPK activation. NOD2 agonist, MDP, inhibited the proliferation of YD-10B cells in a dose-dependent manner. Also, the ratio of Annexin V-positive cells and cleaved PARP was increased by MDP treatment in YD-10B cells, suggesting that MDP-induced cell death in YD-10B cells may be owing to apoptosis.. Our results indicate that NODs are functionally expressed in OSCC cells and can trigger innate immune responses. In addition, NOD2 agonist inhibited cell proliferation and induced apoptosis. These findings provide the potential value of MDP as novel candidates for antitumor agents of OSCC.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Diaminopimelic Acid; Head and Neck Neoplasms; Humans; Immunity, Innate; Interleukin-8; Mitogen-Activated Protein Kinases; Mouth Neoplasms; Nod1 Signaling Adaptor Protein; Nod2 Signaling Adaptor Protein; Oligopeptides; RNA, Messenger; Squamous Cell Carcinoma of Head and Neck

This study evaluated the discriminatory power of salivary transcriptomic and proteomic biomarkers in distinguishing oral squamous cell carcinoma cases from controls and potentially malignant oral disorders (PMOD).. A total of 180 samples (60 OSCC patients, 60 controls, and 60 PMOD patients) were used in the study. Seven transcriptomic markers (IL8, IL1β, SAT1, OAZ1, DUSP1, S100P, and H3F3A) were measured using qPCR, and two proteomic markers (IL8 and IL1β) were evaluated by ELISA.. Among 7 transcriptomic markers, transcript level of DUSP1 was significantly lower in OSCC patients than in controls and PMOD patients. Between the proteomic markers, the protein concentration of IL8 and IL1β was significantly higher in OSCC patients than controls and dysplasia patients. Univariate fractional polynomial (FP) models revealed that salivary IL8 protein (IL8p) has the highest AUC value between OSCC patients and controls (0.74) and between OSCC and PMOD patients (0.72). Applying a 2-marker FP model, salivary IL8p combined with IL1β gave the best AUC value for discrimination between OSCC patients and controls, as well as the IL8p combined with H3F3A mRNA, which gave the best AUC value for discrimination between OSCC and PMOD patients. Multivariate models analysis combining salivary analytes and risk factor exposure related to oral carcinogenesis formed the best combinatory variables for differentiation between OSCC versus PMOL (AUC = 0.80), OSCC versus controls (AUC = 0.87), and PMOD versus controls (AUC = 0.78).. The combination of transcriptomic and proteomic salivary markers is of great value for oral cancer detection and differentiation from PMOD patients and controls. Clin Cancer Res; 22(13); 3340-7. ©2016 AACR.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Dual Specificity Phosphatase 1; Early Detection of Cancer; Enzyme-Linked Immunosorbent Assay; Female; Head and Neck Neoplasms; Humans; Interleukin-1beta; Interleukin-8; Male; Middle Aged; Mouth Neoplasms; Proteomics; Risk Factors; Saliva; Squamous Cell Carcinoma of Head and Neck; Taiwan

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor survival and is the sixth most common cancer worldwide. Gastroesophageal reflux is a common event in SCCHN patients. GPR4 is a proton-sensing G-protein coupled receptor, which can be activated by acidosis. The objective of this study was to explore the role of GPR4 in acid exposure and tumor angiogenesis in SCCHN. In this study, we confirmed that overexpressing GPR4 in SCCHN cells could increase the expression and secretion of IL6, IL8 and VEGFA at pH 5.9. This effect could be inhibited by SB203580 (a p38 inhibitor). Western blot analysis indicated that phosphorylation of p38 increased in GPR4 infected cells at pH 5.9, which could be inhibited by SB203580. In tube formation assay, HMEC-1 cells were incubated with conditioned medium (CM, pH 5.9, 6.5, 7.4) derived from control and GPR4 infected SCCHN cells. Tube length was significantly increased in HMEC-1 cells incubated with CM from GPR4 infected cells compared with control cells at pH5.9, which indicated the pro-angiogenic effect of GPR4 in acidic pH. The neutralizing antibodies of IL6, IL8 and VEGFA could inhibit tube formation of HMEC-1 cells. In vivo, the effect of GPR4 on angiogenesis was investigated with the chick chorioallantoic membrane (CAM) model. Control and GPR4 infected SCCHN cells were seeded onto the upper CAM surface (n = 5 in each group) and 5 μL DMEM/F12 (pH 5.9, 6.5, 7.4) was added to the surface of the cell every 24 h. Four days later, the upper CAM were harvested and the ratio of the vascular area to the CAM area was quantified using Image-Pro Plus 6.0 software. GPR4 infected cells could recruit more vascular than control cells at pH5.9. In conclusion, we suggested that GPR4 induces angiogenesis via GPR4-induced p38-mediated IL6, IL8 and VEGFA secretion at acidic extracellular pH in SCCHN.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Extracellular Space; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Hydrogen-Ion Concentration; Interleukin-6; Interleukin-8; Neovascularization, Pathologic; Receptors, G-Protein-Coupled; Squamous Cell Carcinoma of Head and Neck; Vascular Endothelial Growth Factor A

This study aimed to evaluate the prognostic implications of insulin-like growth factor-II mRNA binding protein-3 (IMP3) and podoplanin (PDPN) as therapeutic targets against oral squamous cell carcinoma (OSCC) with bone invasion.. We elucidated the correlation of IMP3 and PDPN expression with bone invasion in 160 OSCC tissue specimens, and assessed a mouse calvarium xenograft model using an IMP3- and PDPN-depleted OSCC cell line.. The retrospective analysis revealed that the expression of IMP3 and PDPN is significantly correlated with T stage, lymph node metastasis, and the overall survival of OSCC patients. In addition, the dual expression of IMP3 and PDPN but not the single expression of either IMP3 or PDPN was associated with bone invasion and the number of osteoclasts in patients with OSCC. In support of these findings, IMP3 or PDPN depletion inhibited the invasive capacity of OSCC cells in a three-dimensional culture system, tumorigenesis, and regional bone destruction in a xenograft mouse model. In addition, IMP3 or PDPN depletion inhibited the expression of interleukin (IL)-6 and IL-8 in OSCC cells, and decreased the expression of receptor activator of NF-κB ligand (RANKL) in xenograft tumor tissues of OSCC.. These results suggest that IMP3 and PDPN may have strong influence on the pathogenesis of OSCC, especially in bone invasion, and may serve as novel therapeutic targets with prognostic implications for bone-invasive OSCC.

Topics: Adult; Aged; Aged, 80 and over; Animals; Bone Neoplasms; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Female; Head and Neck Neoplasms; Heterografts; Humans; Interleukin-11; Interleukin-6; Interleukin-8; Lymphatic Metastasis; Male; Membrane Glycoproteins; Mice; Middle Aged; Mouth Neoplasms; Osteoclasts; Prognosis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Retrospective Studies; RNA-Binding Proteins; RNA, Messenger; Squamous Cell Carcinoma of Head and Neck

NOD1 (nucleotide-binding oligomerization domain 1) is overexpressed in head and neck squamous cell carcinoma (HNSCC) cells, as is IL-8 in cancer cells. However, the mechanism of the IL-8-mediated overexpression of NOD in HNSCC not been identified. This study determines whether IL-8 promotes tumor progression via the NOD signaling pathway in HNSCC. Higher IL-8, NOD1 and receptor-interacting protein kinase (RIP2) expressions were observed in HNSCC tissue than in non-cancerous matched tissue (NCMT), whereas NOD2 was weakly expressed. Furthermore, IL-8 stimulated the proliferation of HNSCC cells (SCC4, SCC9 and SCC25) but not dysplastic oral mucosa DOK cells. Exposure to IL-8 increased the clonogenicity of HNSCC cells. IL-8 siRNA inhibited cell proliferation and cell colony formation, suggesting that IL-8 is involved in HNSCC cancer progression. The expressions of CXCR1 and CXCR2 were higher in HNSCC tissue than in NCMT. HNSCC cells that were exposed to IL-8 exhibited higher expression of CXCR1/2 than did controls. The blocking of IL-8 by siRNA reduced CXCR1/2 expression in HNSCC cells, suggesting that the cancer progression of HNSCC cells that is induced by IL-8 depends on CXCR1/2. Additionally, IL-8 is associated with increased NOD1 and RIP2 expression and reduced NOD2 expression in three types of HNSCC cells. The blocking of IL-8 by siRNA reduces IL-8, NOD1 and RIP2 expressions in HNSCC cells, but not the level of NOD2. These results suggest that IL-8 has an important role in HNSCC progression via a CXCR1/2-meidated NOD1/RIP2 signaling pathway.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Interleukin-8; Mouth Mucosa; Nod1 Signaling Adaptor Protein; Oligonucleotide Array Sequence Analysis; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptors, Interleukin-8A; Receptors, Interleukin-8B; RNA, Small Interfering; Signal Transduction; Squamous Cell Carcinoma of Head and Neck

Long non-coding RNAs (lncRNAs) have recently attracted more attention about the role in a broad range of biological processes and complex cancers. We aimed to identify differentially expressed lncRNAs that play an important role in the pathogenesis of oral squamous cell carcinoma (OSCC). Microarray data GSE25099 consisting of 57 samples from patients with OSCC and 22 normal samples were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) and lncRNAs were identified between OSCC samples and control using samr package in R and noncoder software. Co-expression network was constructed for lncRNAs and candidate target DEGs, followed by functional and pathway enrichment analysis using the Database for Annotation, Visualization and Integrated Discovery online tool. OSCC-related genes were screened by Genetic-Association-DB-Database analysis, and then protein-protein interaction (PPI) network construction of OSCC-related and co-expressed genes. Bioinformatic analysis revealed that there were 998 DEGs and 160 differentially expressed lncRNAs between OSCC and normal control. We found LOC100130547, FTH1P3, PDIA3F and GTF2IRD2P1 targeted most of DEGs. Predicted targets-related functional annotation showed significant changes in inflammation-related functions and Toll-like receptor signaling pathway. By further conducting PPI network with lncRNA co-expressed DEGs, we found that OSCC-associated genes including MMP1 (matrix metallopeptidase), MMP3, MMP9, PLAU (plasminogen activator, urokinase) and IL8 (interleukin 8) were targeted by FTH1P3, PDIA3F and GTF2IRD2P1. Our results indicate that lncRNAs FTH1P3, PDIA3F and GTF2IRD2P1 may responsible for progression and metastasis of OSCC via targeting MMP1, MMP3, MMP9, PLAU and IL8 which are key regulators of tumorigenesis.

Topics: Carcinoma, Squamous Cell; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Head and Neck Neoplasms; Humans; Interleukin-8; Mouth Neoplasms; Oligonucleotide Array Sequence Analysis; RNA, Long Noncoding; RNA, Messenger; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Up-Regulation

Mesenchymal stromal cells (MSC) are an integral cellular component of the tumor microenvironment. Nevertheless, very little is known about MSC originating from human malignant tissue and modulation of these cells by tumor-derived factors. The aim of this study was to isolate and characterize MSC from head and neck squamous cell carcinoma (HNSCC) and to investigate their interaction with tumor cells.. MSC were isolated from tumor tissues of HNSCC patients during routine oncological surgery. Immunophenotyping, immunofluorescence and in vitro differentiation were performed to determine whether the isolated cells met the consensus criteria for MSC. The cytokine profile of tumor-derived MSC was determined by enzyme-linked immunosorbent assay (ELISA). Activation of MSC by tumor-conditioned media was assessed by measuring cytokine release and expression of CD54. The impact of MSC on tumor growth in vivo was analyzed in a HNSCC xenograft model.. Cells isolated from HNSCC tissue met the consensus criteria for MSC. Tumor-derived MSC constitutively produced high amounts of interleukin (IL)-6, IL-8 and stromal cell-derived factor (SDF)-1α. HNSCC-derived factors activated MSC and enhanced secretion of IL-8 and expression of CD54. Furthermore, MSC provided stromal support for human HNSCC cell lines in vivo and enhanced their growth in a murine xenograft model.. This is the first study to isolate and characterize MSC from malignant tissues of patients with HNSCC. We observed cross-talk of stromal cells and tumor cells resulting in enhanced growth of HNSCC in vivo.

Topics: Animals; Carcinoma, Squamous Cell; Cell Differentiation; Cell Movement; Cell Proliferation; Chemokine CXCL12; Culture Media, Conditioned; Cytokines; Disease Progression; Flow Cytometry; Head and Neck Neoplasms; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Mesenchymal Stem Cells; Mice, Nude; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment

Activating transcription factor-2 (ATF2) is associated with tumor progression but is not well studied in head and neck squamous cell carcinoma (HNSCC). Its effects in stress and its importance in other survival mechanisms were studied.. ATF2 expression and nuclear activation were confirmed in HNSCC. After modulation of ATF2, in vitro effects on proliferation and chemosensitivity were studied. Effects on in vivo tumor growth and interleukin 8 (IL-8) expression were determined. Tumor necrosis factor-alpha (TNF-α) treatment was used to further evaluate cytokine production and chemosensitivity.. Reductions of ATF2 resulted in significant nuclear p-ATF2 activation, cisplatin resistance, and augmented IL-8 expression without affecting in vivo tumor growth. In this setting, TNF increases p-p38 phosphorylation and chemosensitivity while further enhancing IL-8 production.. Our data suggest regulatory roles for ATF2 in TNF-related mechanisms of HNSCC. Its perturbation and nuclear activation are associated with significant effects on survival and cytokine production.

Topics: Activating Transcription Factor 2; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Proliferation; Cisplatin; Cytokines; Drug Resistance, Neoplasm; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Immunohistochemistry; In Vitro Techniques; Interleukin-8; Sensitivity and Specificity; Squamous Cell Carcinoma of Head and Neck; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha