Phocaeicola oris sp. nov., an anaerobic bacterium isolated from the saliva of a patient with oral squamous cell carcinoma.

A Gram-stain-negative or -positive, strictly anaerobic, non-spore-forming and pleomorphic bacterium (designated 14-104T) was isolated from the saliva sample of a patient with oral squamous cell carcinoma. It was an acid-tolerant neutralophilic mesophile, growing at between 20 and 40 °C (with optimum growth at 30 °C) and pH between pH 3.0 and 7.0 (with optimum growth at pH 6.0-7.0). It contained anteiso-C15 : 0 and C15 : 0 as the major fatty acids. The genome size of strain 14-104T was 2.98 Mbp, and the G+C content was 39.6 mol%. It shared <87 % 16S rRNA sequence similarity, <71 % orthologous average nucleotide identity, <76 % average amino acid identity and <68 %% of conserved proteins with its closest relative, Phocaeicola abscessus CCUG 55929T. Reconstruction of phylogenetic and phylogenomic trees revealed that strain 14-104T and P. abscessus CCUG 55929T were clustered as a distinct clade without any other terminal node. The phylogenetic and phylogenomic analyses along with physiological and chemotaxonomic data indicated that strain 14-104T represents a novel species in the genus Phocaeicola, for which the name Phocaeicola oris sp. nov. is proposed. The type strain is 14-104T (=BCRC 81305T= NBRC 115041T).

Microbiome dysbiosis inhibits carcinogen-induced murine oral tumorigenesis.

Oral cancer is one of the most common cancers worldwide and ranks fourth for the mortality rate of cancers in males in Taiwan. The oral microbiota is the microbial community in the oral cavity, which is essential for maintaining oral health, but the relationship between oral tumorigenesis and the oral microbiota remains to be clarified. This study evaluated the effect of microbiome dysbiosis on oral carcinogenesis in mice, and the impact of the microbiome and its metabolic pathways on regulating oral carcinogenesis. We found that antibiotics treatment decreases carcinogen-induced oral epithelial malignant transformation. Microbiome analysis based on 16S rRNA gene sequencing revealed that the species richness of fecal specimens was significantly reduced in antibiotic-treated mice, while that in the salivary specimens was not decreased accordingly. Differences in bacterial composition, including Lactobacillus animalis abundance, in the salivary samples of cancer-bearing mice was dramatically decreased. L. animalis was the bacterial species that increased the most in the saliva of antibiotic-treated mice, suggesting that L. animalis may be negatively associated with oral carcinogenesis. In functional analysis, the microbiome in the saliva of the tumor-bearing group showed greater potential for polyamine biosynthesis. Immunochemical staining proved that spermine oxidase, an effective polyamine oxidase, was upregulated in mouse oral cancer lesions. In conclusion, oral microbiome dysbiosis may alter polyamine metabolic pathways and reduce carcinogen-induced malignant transformation of the oral epithelium.

YAP1 acts as a negative regulator of pro-tumor TAZ expression in esophageal squamous cell carcinoma.

PURPOSE: Although YAP1 and TAZ are believed to be equivalent downstream effectors of the Hippo pathway, differential expression of YAP1 or TAZ suggests distinct functions during cancer progression. The exact role of YAP1 and TAZ in esophageal cancer, the 6th leading cancer-related mortality in the world, remains elusive. METHODS: Following single or double manipulation of YAP1 or TAZ expression, we subjected these manipulated cells to proliferation, migration, invasion, and xenograft tumorigenesis assays. We used RT-qPCR and Western blotting to examine their expression in the manipulated cells with or without inhibition of transcription or translation. We also examined the impact of YAP1 or TAZ deregulation on clinical outcome of esophageal cancer patients from the TCGA database. RESULTS: We found that YAP1 functions as a tumor suppressor whereas TAZ exerts pro-tumor functions in esophageal cancer cells. We also found a significant increase in TAZ mRNA expression upon YAP1 depletion, but not vice versa, despite the downregulation of CTGF and CYR61, shared targets of YAP1 and TAZ, in xenografted tissue cells. In addition to transcriptional regulation, YAP1-mediated TAZ expression was found to occur via protein synthesis. Restored TAZ expression mitigated YAP1-mediated suppression of cellular behavior. By contrast, TAZ silencing reduced the promoting effect exerted by YAP1 depletion on cellular behaviors. The observed anti-tumor function of YAP1 was further supported by a better overall survival among esophageal cancer patients with a high YAP1 expression. CONCLUSION: From our data we conclude that YAP1 functions as a suppressor and negatively regulates pro-tumor TAZ expression via transcriptional and translational control in esophageal cancer.

Risk of dialysis in patients receiving intravitreal anti-vascular endothelial growth factor treatment: a population-based cohort study.

We utilized the Longitudinal Health Insurance Database which was stemmed from the Taiwan's National Health Insurance Research Database to conduct a retrospective cohort study investigating the risk of becoming dialysis dependent after receiving intravitreal anti-vascular endothelial growth factor (VEGF) agents for retinal diseases. Patients newly receiving intravitreal ranibizumab or aflibercept from 2000 to 2017 for age-related macular degeneration, polypoidal choroidal vasculopathy, diabetic macular edema, retinal vein occlusions, or myopic choroid neovascularization were included as the study group, and patients with same retinal diseases but did not receive intravitreal anti-VEGFs served as controls extracted by age- and sex-matched (1:4) and further propensity score matching (PSM). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the risk of dialysis. A cohort of 2447 anti-VEGF users and 2447 controls by PSM were evaluated. Higher dialysis risks were observed among patients newly receiving anti-VEGF agents compared to controls (adjusted HR: 1.849; 95% CI: 1.378-2.482) in the PSM cohort. For subgroup analysis, patients newly receiving anti-VEGF treatment for diabetic macular edema had significant risk (adjusted HR: 1.834; 95% CI: 1.448-2.324) of becoming dialysis-dependent, while patients in other subgroups demonstrated similar risks as the controls. In conclusion, intravitreal anti-VEGF agents might increase the risk of becoming dialysis-dependent, especially in patients who are treated for diabetic macular edema.

Taxonomic and Functional Dysregulation in Salivary Microbiomes During Oral Carcinogenesis.

Exploring microbial community compositions in humans with healthy versus diseased states is crucial to understand the microbe-host interplay associated with the disease progression. Although the relationship between oral cancer and microbiome was previously established, it remained controversial, and yet the ecological characteristics and their responses to oral carcinogenesis have not been well studied. Here, using the bacterial 16S rRNA gene amplicon sequencing along with the in silico function analysis by PICRUSt2 (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2), we systematically characterized the compositions and the ecological drivers of saliva microbiome in the cohorts of orally healthy, non-recurrent oral verrucous hyperplasia (a pre-cancer lesion), and oral verrucous hyperplasia-associated oral cancer at taxonomic and function levels, and compared them with the re-analysis of publicly available datasets. Diversity analyses showed that microbiome dysbiosis in saliva was significantly linked to oral health status. As oral health deteriorated, the number of core species declined, and metabolic pathways predicted by PICRUSt2 were dysregulated. Partitioned beta-diversity revealed an extremely high species turnover but low function turnover. Functional beta-diversity in saliva microbiome shifted from turnover to nestedness during oral carcinogenesis, which was not observed at taxonomic levels. Correspondingly, the quantitative analysis of stochasticity ratios showed that drivers of microbial composition and functional gene content of saliva microbiomes were primarily governed by the stochastic processes, yet the driver of functional gene content shifted toward deterministic processes as oral cancer developed. Re-analysis of publicly accessible datasets supported not only the distinctive family taxa of Veillonellaceae and Actinomycetaceae present in normal cohorts but also that Flavobacteriaceae and Peptostreptococcaceae as well as the dysregulated metabolic pathways of nucleotides, amino acids, fatty acids, and cell structure were related to oral cancer. Using predicted functional profiles to elucidate the correlations to the oral health status shows superior performance than using taxonomic data among different studies. These findings advance our understanding of the oral ecosystem in relation to oral carcinogenesis and provide a new direction to the development of microbiome-based tools to study the interplay of the oral microbiome, metabolites, and host health.

Malignant transformation of oral potentially malignant disorders in Taiwan: An observational nationwide population database study.

ABSTRACT: Oral cancer is one of the leading causes of cancer death, which are mostly preceded by oral potentially malignant disorders (OPMDs). Taiwanese government launched a free oral cancer screening program. The aim of this study was to analyze the malignant transformation rate of OPMDs.This study was based on national-wide oral screening databases. 3,362,232 people were enrolled. Patients clinically diagnosed with leukoplakia, erythroplakia, oral submucosal fibrosis (OSF), oral verrucous hyperplasia (OVH), and oral lichen planus (OLP), from 2010 to 2013, were identified. We followed up OPMD patients in cancer registry databases to analyze the malignant transformation rate.The malignant transformation rates from the highest to the lowest were: OVH > OSF > erythroplakia > OLP > leukoplakia. The malignant transformation rate was 24.55, 12.76, 9.75, 4.23, and 0.60 per 1000 person-years in the OVH, OSF, erythroplakia, leukoplakia, and comparison cohort. The hazard ratio was 8.19 times higher in the OPMD group compared with comparison cohort group, after age and habit adjustment. Female patients with OPMDs had a high risk of malignant transformation.Nationwide screening is very important for early diagnosis. OVH had the highest malignant transformation possibility. Female OPMD patients are a rare but have a relatively high malignant transformation rate.

IL-20 antagonist suppresses PD-L1 expression and prolongs survival in pancreatic cancer models.

Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.

The Tumor Suppressor TGFBR3 Blocks Lymph Node Metastasis in Head and Neck Cancer.

The TGF-ß type III receptor (TGFBR3) is an essential constituent of the TGF-ß signaling. In this study, we observed a down-regulation of TGFBR3 in oral cancer, a subtype of head and neck cancer (HNC), and patients with low TGFBR3 had poor clinical outcomes. Ectopic expression of TGFBR3 decreased migration and invasion of oral cancer cells and lymph node metastasis of tumors, whereas depletion of TGFBR3 had the opposite effect. In SMAD4-positive OC-2 oral cancer cells, TGFBR3-mediated suppression requires both of its cytoplasmic interacting partners ARRB2 and GIPC1. We demonstrated that TGFBR3 induces the abundance of secreted angiogenin (ANG), a known pro-angiogenic factor, and ANG is essential and sufficient to mediate TGFBR3-dependent inhibition of migration and invasion of oral cancer cells. Notably, in SMAD4-deficient CAL-27 oral cancer cells, only GIPC1 is essential for TGFBR3-induced suppressive activity. Accordingly, HNC patients with low expressions of both TGFBR3 and GIPC1 had the poorest overall survival. In summary, we conclude that TGFBR3 is as a tumor suppressor via SMAD4-dependent and -independent manner in both tumor and stromal cells during oral carcinogenesis. Our study should facilitate the possibility of using TGFBR3-mediated tumor suppression for HNC treatment.

Cancer-associated fibroblast-derived interleukin-1ß activates protumor C-C motif chemokine ligand 22 signaling in head and neck cancer.

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1ß (IL-1ß) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1ß, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1ß-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.

The p53-S100A2 Positive Feedback Loop Negatively Regulates Epithelialization in Cutaneous Wound Healing.

The S100A2 protein is an important regulator of keratinocyte differentiation, but its role in wound healing remains unknown. We establish epithelial-specific S100A2 transgenic (TG) mice and study its role in wound repair using punch biopsy wounding assays. In line with the observed increase in proliferation and migration of S100A2-depleted human keratinocytes, mice expressing human S100A2 exhibit delayed cutaneous wound repair. This was accompanied by the reduction of re-epithelialization as well as a slow, attenuated response of Mcp1, Il6, Il1ß, Cox2, and Tnf mRNA expression in the early phase. We also observed delayed Vegfa mRNA induction, a delayed enhancement of the Tgfß1-mediated alpha smooth muscle actin (α-Sma) axis and a differential expression of collagen type 1 and 3. The stress-activated p53 tumor suppressor protein plays an important role in cutaneous wound healing and is an S100A2 inducer. Notably, S100A2 complexes with p53, potentiates p53-mediated transcription and increases p53 expression both transcriptionally and posttranscriptionally. Consistent with a role of p53 in repressing NF-κB-mediated transcriptional activation, S100A2 enhanced p53-mediated promoter suppression of Cox2, an early inducible NF-κB target gene upon wound injury. Our study thus supports a model in which the p53-S100A2 positive feedback loop regulates wound repair process.

Angiogenin Attenuates Scar Formation in Burn Patients by Reducing Fibroblast Proliferation and Transforming Growth Factor ß1 Secretion.

BACKGROUND: Deep burn wounds have a high tendency to form hypertrophic scars. Previously, we found that angiogenin promoted neovascularization during deep burn wound healing. However, the association between angiogenin and scar formation is unclear. METHODS: We obtained human burn scar tissues from patients who underwent scar surgery and examined the role of angiogenin in scar tissues and determined its effects in scar fibroblasts and on transforming growth factor ß1 (TGF-ß1) secretion. RESULTS: Our results showed an inverse correlation between angiogenin expression and scar severity. Next, we examined the effects of angiogenin in scar fibroblasts. We found that angiogenin was persistently expressed in human scar fibroblasts and that angiogenin expression significantly increased with time in the culture medium of scar fibroblasts. Treatment of scar fibroblasts with recombinant angiogenin significantly decreased their proliferation and TGF-ß1 secretion. Moreover, angiogenin inhibited TGF-ß1-mediated Smad2 signaling pathway. CONCLUSION: Our data suggest a negative role of angiogenin in fibroblast proliferation via TGF-ß1-mediated Smad2 signaling pathway.

Predominance of CD14+ Cells in Burn Blister Fluids.

BACKGROUND: Burn blister fluid contains several angiogenic factors to promote wound neovascularization. In our previous study, we found that deep partial-thickness burn (DPTB) wounds showed higher expression levels of angiogenin to enhance vascularization compared with superficial partial-thickness burn wounds. Neovascularization is a complex process that involves an interaction between circulating angiogenic cells and mediators. We hypothesized that in addition to angiogenic factors burn blisters may contain specific cell types. The aim of the present study was to characterize the specific cells present in burn blisters. METHODS: Twenty-four burn blister fluid samples were obtained with informed consent from patients with superficial partial-thickness burn (n = 16) or DPTB (n = 8) wounds. Blister cells were isolated from individual intact blisters and characterized with flow cytometry analysis using CD14, CD34, vascular endothelial growth factor receptor 2, and CD133 markers. CD14 and CD34 blister cells were also isolated using a magnetic-activated cell sorting system to examine their potential for endothelial differentiation. Angiogenin levels in the burn blister fluids were evaluated with enzyme-linked immunosorbent assay. RESULTS: CD14 cells were the most highly represented cell type in the burn fluids of both groups, although a significantly greater percentage of CD14 cells were observed in DPTB fluids. CD14 blister cells had a higher potency to differentiate into functional endothelial cells as compared with CD34 cells. The proportion of CD14 cells gradually increased after burn injury. In contrast to CD14 cells, angiogenin showed the highest expression levels at day 1 postburn. With regard to burn wound neovascularization, angiogenin expression was partially correlated with CD14 blister cells in the burn fluids. CONCLUSIONS: We provide the first report on the characterization of blister cells in burn fluids. Our data suggest that CD14 blister cells may play a role in burn wound neovascularization. Measurement of CD14 blister cells serves as a possible tool for assessing burn wound status.

Anti-IL-20 monoclonal antibody inhibited inflammation and protected against cartilage destruction in murine models of osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive destruction of articular cartilage. Interleukin (IL)-20 is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis. We investigated the role of IL-20 in OA and evaluated whether anti-IL-20 antibody (7E) treatment attenuates disease severity in murine models of surgery-induced OA. Immunohistochemical staining was used to detect IL-20 and its receptors expression in synovial tissue and cartilage from OA patients, and in OA synovial fibroblasts (OASFs) and chondrocytes (OACCs) from rodents with surgery-induced OA. RTQ-PCR and western blotting were used to determine IL-20-regulated OA-associated gene expression in OASFs and OACCs. OA rats and OA mice were treated with 7E. Arthritis severity was determined based on the degree of cartilage damage and the arthritis severity score. We found that IL-20 and its receptors were expressed in OASFs and OACCs. IL-20 induced TNF-α, IL-1ß, MMP-1, and MMP-13 expression by activating ERK-1/2 and JNK signals in OASFs. IL-20 not only upregulated MCP-1, IL-6, MMP-1, and MMP-13 expression, but also downregulated aggrecan, type 2 collagen, TGF-ß, and BMP-2 expression in OACCs. Arthritis severity was significantly lower in 7E-treated OA rats, and 7E- or MSC-treated OA mice. Therefore, we concluded that IL-20 was involved in the progression and development of OA through inducing proinflammatory cytokines and OA-associated gene expression in OASFs and OACCs. 7E reduced the severity of arthritis in murine models of surgery-induced OA. Our findings provide evidence that IL-20 is a novel target and that 7E is a potential therapeutic agent for OA.

Dysregulation of Rab37-Mediated Cross-talk between Cancer Cells and Endothelial Cells via Thrombospondin-1 Promotes Tumor Neovasculature and Metastasis.

Purpose: Accumulating evidence indicates that factors secreted by cancer epithelial cells shape the tumor microenvironment to promote cancer invasion and metastasis. Recent studies also shed light on alterations of Rab small GTPase-mediated exocytosis in tumorigenesis. However, the mechanisms for Rab-mediated exocytosis in tumor microenvironment remain elusive. We aimed to investigate the interplay between Rab37-mediated exocytosis and tumor microenvironment, focusing on endothelial cell motility and angiogenesis.Experimental Design: We performed fluorescence IHC for Rab37, thrombospondin-1 (TSP1, an antiangiogenesis factor), and angiogenesis marker CD31 in 183 surgically resected esophageal squamous cell carcinoma (ESCC) patient samples. Cell migration, invasion, angiogenesis, and tumor metastasis were measured.Results: ESCC patients with low expression of Rab37 or TSP1 significantly correlated with high CD31 expression and were associated with worse progression-free survival. The multivariate Cox regression analysis showed that concordant low expression of both Rab37 and TSP1 was an independent prognostic factor of ESCC patients. Rab37-mediated exocytosis of TSP1 led to the inhibition of neovasculature in vitro and in vivo Secreted TSP1 from cancer cells with Rab37 exocytic function inhibited the p-FAK/p-paxillin/p-ERK migration signaling in both cancer epithelial cells and their surrounding endothelial cells. Dysfunction of Rab37 or loss of TSP1 abrogated the suppressive effects on angiogenesis and metastasis.Conclusions: Our findings suggest that Rab37-mediated TSP1 secretion in cancer cells suppresses metastasis and angiogenesis via a cross-talk with endothelial cells and reveal a novel component of the vesicular exocytic machinery in tumor microenvironment and tumor progression. Dysregulation of Rab37/TSP1 axis has clinical implications for prognosis prediction. Clin Cancer Res; 23(9); 2335-45. ©2016 AACR.

Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer.

Hyaluronan (HA) is a major extracellular matrix component. However, its role and mediation in oral cancer remains elusive. Hyaluronan synthase 3 (HAS3), involved in pro-inflammatory short chain HA synthesis, was the predominant synthase in oral cancer cells and tissues. HAS3 overexpression significantly increased oral cancer cell migration, invasion and xenograft tumorigenesis accompanied with the increased expression of tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Conversely, HAS3 depletion abrogated HAS3-mediated stimulation. HAS3 induced oncogenic actions partly through activating EGFR-SRC signaling. HAS3-derived HA release into extracellular milieu enhanced transendothelial monocyte migration and MCP-1 expression, which was attenuated by anti-HAS3 antibodies or a HAS inhibitor, 4-Methylumbelliferone (4-MU). The NF-κB-binding site III at -1692 to -1682 bp upstream from the transcript 1 start site in HAS3 proximal promoter was the most responsive to TNF-α-stimulated transcription. ChIP-qPCR analysis confirmed the highest NF-κB-p65 enrichment on site III. Increased HAS3 mRNA expression was negatively correlated with the overall survival of oral cancer patients. A concomitant increase of TNF-α, a stimulus for HAS3 expression, with HAS3 expression was not only associated with lymph node metastasis but also negated clinical outcome. Together, HAS3 and TNF-α formed an inter-regulation loop to enhance tumorigenesis in oral cancer.

Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma.

Growth differentiation factor-10 (GDF10), commonly referred as BMP3b, is a member of the transforming growth factor-ß (TGF-ß) superfamily. GDF10/BMP3b has been considered as a tumor suppressor, however, little is known about the molecular mechanism of its roles in tumor suppression in oral cancer. Clinical significance of GDF10 downregulation in oral squamous cell carcinoma (OSCC) was evaluated using three independent cohorts of OSCC patients. The molecular mechanisms of GDF10 in the suppression of cell survival, cell migration/invasion and epithelial-mesenchymal transition (EMT) were investigated by using oral cancer cell lines. The present study shows that GDF10 is downregulated during oral carcinogenesis, and GDF10 expression is also an independent risk factor for overall survival of OSCC patients. Overexpression of GDF10 attenuates cell proliferation, transformation, migration/invasion, and EMT. GDF10-inhibited EMT is mediated by ERK signaling but not by typical TGF-ß signaling. In addition, overexpression of GDF10 promotes DNA damage-induced apoptosis and sensitizes the response to all-trans retinoic acid (ATRA) and camptothecin (CPT). Intriguingly, the expression of GDF10 is induced by type III TGF-ß receptor (TGFBR3) through TGF-ß-SMAD2/3 signaling. Our findings suggest that TGFBR3 is an upstream activator of GDF10 expression and they share the same signaling to inhibit EMT and migration/invasion. These results support that GDF10 acts as a hinge to collaborate with TGFBR3 in the transition of EMT-MET program. Taken together, we illustrated the clinical significance and the molecular mechanisms of tumor-suppressive GDF10 in OSCC.

Anti-IL-20 Monoclonal Antibody Suppresses Prostate Cancer Growth and Bone Osteolysis in Murine Models.

Interleukin (IL)-20 is a proinflammatory cytokine in the IL-10 family. IL-20 is associated with tumor promotion in the pathogenesis of oral, bladder, and breast cancer. However, little is known about the role of IL-20 in prostate cancer. We hypothesize that IL-20 promotes the growth of prostate cancer cells. Immunohistochemical staining showed that IL-20 and its receptors were expressed in human PC-3 and LNCaP prostate cancer cell lines and in prostate tumor tissue from 40 patients. In vitro, IL-20 upregulated N-cadherin, STAT3, vimentin, fibronectin, RANKL, cathepsin G, and cathepsin K, and increased the migration and colony formation of prostate cancer cells via activated p38, ERK1/2, AKT, and NF-κB signals in PC-3 cells. We investigated the effects of anti-IL-20 monoclonal antibody 7E on prostate tumor growth in vivo using SCID mouse subcutaneous and intratibial xenograft tumor models. In vivo, 7E reduced tumor growth, suppressed tumor-mediated osteolysis, and protected bone mineral density after intratibial injection of prostate cancer cells. We conclude that IL-20 is involved in the cell migration, colony formation, and tumor-induced osteolysis of prostate cancer. Therefore, IL-20 might be a novel target for treating prostate cancer.

Elevated S100A9 expression in tumor stroma functions as an early recurrence marker for early-stage oral cancer patients through increased tumor cell invasion, angiogenesis, macrophage recruitment and interleukin-6 production.

S100A9 is a calcium-binding protein with two EF-hands and frequently deregulated in several cancer types, however, with no clear role in oral cancer. In this report, the expression of S100A9 in cancer and adjacent tissues from 79 early-stage oral cancer patients was detected by immunohistochemical staining. Although S100A9 protein was present in both tumor and stromal cells, only the early-stage oral cancer patients with high stromal expression had reduced recurrence-free survival. High stromal S100A9 expression was also significantly associated with non-well differentiation and recurrence. In addition to increasing cell migration and invasion, ectopic S100A9 expression in tumor cells promoted xenograft tumorigenesis as well as the dominant expression of myeloid cell markers and pro-inflammatory IL-6. The expression of S100A9 in one stromal component, monocytes, stimulated the aggressiveness of co-cultured oral cancer cells. We also detected the elevation of serum S100A9 levels in early-stage oral cancer patients of a separate cohort of 73 oral cancer patients. The release of S100A9 protein into extracellular milieu enhanced tumor cell invasion, transendothelial monocyte migration and angiogenic activity. S100A9-mediated release of IL-6 requires the crosstalk of tumor cells with monocytes through the activation of NF-κB and STAT-3. Early-stage oral cancer patients with both high S100A9 expression and high CD68+ immune infiltrates in stroma had shortest recurrence-free survival, suggesting the use of both S100A9 and CD68 as poor prognostic markers for oral cancer. Together, both intracellular and extracellular S100A9 exerts a tumor-promoting action through the activation of oral cancer cells and their associated stroma in oral carcinogenesis.

A gp130-Src-YAP module links inflammation to epithelial regeneration.

Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.