Solitary intraosseous neurofibroma of the oral cavity: rare localization in the maxilla.

BACKGROUND: Neurofibroma is a common benign tumor of neuronal origin that can occur as a solitary tumor or as a component of the generalized syndrome of neurofibromatosis. Neurofibromas are primarily located in the subcutaneous soft tissues and commonly involve extra-oral sites. Solitary intraosseous neurofibromas of the oral cavity are infrequent, with occurrences in the maxilla being exceedingly rare. CASE PRESENTATION: A 22-year-old male patient presented with an asymptomatic mass in the maxilla. Cone-beam computed tomography revealed a round, well-outlined, radiolucent lesion with expansive growth. The neoplasm with the complete capsule was completely removed and confirmed as a neurofibroma based on histopathological and immunohistochemical findings. The reported cases of solitary intraosseous neurofibromas located in the maxilla published in the English literature were compiled to assist in the diagnosis of solitary intraosseous neurofibromas of the maxilla. Nine months after the surgery, there were no signs of tumor recurrence or malignant transformation. CONCLUSIONS: This report emphasizes that rare locations of neurofibromas, such as solitary intraosseous neurofibromas in the maxilla, typically demonstrate nonspecific clinical and radiological features. Clinicians should consider solitary intraosseous neurofibromas as possible differential diagnoses and recognize the histopathological and immunohistochemical features to confirm the correct diagnosis. A longer follow-up period is required because of the potential for local recurrence and malignant transformation of these tumors.

4sc-202 and Ink-128 cooperate to reverse the epithelial to mesenchymal transition in OSCC.

Treatment of oral squamous cell carcinoma remains a challenge due to a high incidence of treatment resistance, which is followed by tumor recrudescence and metastasis to the lymph nodes. Thus, it is important to explore novel inhibitors of OSCC. Here, we aimed to identify drugs that may cooperate with histone deacetylase inhibitors to reverse the EMT, inhibit EMT and cell migration and invasion, and contribute to therapeutic efficacy. We found that treatment with 4sc-202 potently reversed the EMT and thereby inhibited cell migration and invasion in vitro, in part by inducing expression of the FoxO1 tumor-suppressor gene. Furthermore, 4sc-202 also synergized with Ink-128 to inhibit tumor migration and invasion in vitro. Mechanistically, 4sc-202 induced FoxO1 expression, whereas Ink-128 promoted nuclear translocation of FoxO1. Our findings indicated that FoxO1 might reverse the EMT by interacting with Twist1 in OSCC. In conclusion, we identified an effective combination therapy involving class I histone deacetylase and mammalian target of rapamycin complex 1/2 inhibition that effectively blocked the EMT of tumor cells by upregulating FoxO1 expression to inhibit Twist1 transcription. These data have implications for developing new targets for early diagnosis and treatment of OSCC.

Chemokine (CC motif) ligand 18 upregulates Slug expression to promote stem-cell like features by activating the mammalian target of rapamycin pathway in oral squamous cell carcinoma.

Chemokine (CC motif) ligand 18 (CCL18) is involved in remodeling of the tumor microenvironment and plays critical roles in oncogenesis, invasiveness, and metastasis. We previously investigated the overexpression of CCL18 in primary oral squamous cell carcinoma (OSCC) tissues and its association with advanced clinical stage in OSCC patients. However, the underlying mechanisms of this CCL18-derived activity remains unidentified. This study showed exogenous CCL18 increased cell migration and invasion and induced cell epithelial-mesenchymal transition (EMT), and that E-cadherin, an epithelial marker, decreased and N-cadherin, a mesenchymal marker, increased, compared to negative control in OSCC cells. Furthermore, we detected that CCL18 induced the acquisition of cancer stem(-like) cell characteristics in oral cancer cells, but also found a significantly positive correlation between the expression of CCL18 and Bmi-1 (P < 0.001) in OSCC surgical specimens by immunohistochemistry analysis. The expression of octamer-binding transcription factor 4 and Bmi-1 were significantly upregulated, and proportions of aldehyde dehydrogenasehigh+ cells and CD133+ cells were markedly increased in CCL18-treated cells compared to untreated cells. Sphere formation ability was observably enhanced when cells were continually exposed to high levels of CCL18. Moreover, CCL18 upregulated Slug expression by stimulating the mammalian target of rapamycin (mTOR) signaling pathway in OSCC cell lines. Inhibition of the mTOR pathway by INK128, or Slug knockdown by RNA interference, reversed CCL18-induced EMT and the stemness response at both molecular and functional levels. In conclusion, our data suggested that CCL18 upregulated Slug expression to promote EMT and stem cell-like features by activating the mTOR pathway in oral cancer. These findings provide new potential targets for the early diagnosis and treatment of OSCC.

Tumor-related markers in histologically normal margins correlate with locally recurrent oral squamous cell carcinoma: a retrospective study.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is characterized by a high rate of local recurrence (LR) even when the surgical margins are considered histopathologically 'normal'. The aim of our study was to determine the relationship between early tumor-related markers detected in histologically normal margins (HNM) and LR as well as disease-free survival in OSCC. METHODS: The loss of heterozygosity (LOH) of markers on 9p21 (D9s1747, RPS6, D9s162) and 17p13 (TP53) and the immunostaining results of the corresponding mutant P53, P14, P15, and P16 proteins were assessed and correlated with LR and disease-free survival in 71 OSCC patients who had HNM. RESULTS: Fifteen of 71 patients with HNM developed LR. The presence of the following molecular markers in surgical margins was significantly correlated with the development of LR: LOH on chromosome 9p21 (D9s1747 + RPS6 + D9s162), any LOH, P16, and P53 (chi-square test, P < 0.05). The presence of TP53 LOH, 9p21 LOH, any LOH, P15, P16, P53, P16 + D9s1747, and P53 + TP53 had a significant effect on LR (Kaplan-Meier analysis, P < 0.05). P16 + D9s1747 was the most predictive factor using multivariate Cox analyses. CONCLUSIONS: Detection of tumor-related markers in histologically 'normal' resection margins may be a useful method for assessing LR in OSCC patients.

Pancreatic cancer stem cell-derived exosomal miR-210 mediates macrophage M2 polarization and promotes gemcitabine resistance by targeting FGFRL1.

Pancreatic cancer (PC) is a serious threat to human health, with most patients diagnosed at the advanced stages of the disease. Treatment with gemcitabine (GEM) leads to PC GEM resistance. In addition, cancer stem cell (CSC)-derived exosomes play an important role in cancer progression. We aimed to investigate the role and mechanism of action of PC stem cell-derived exosomes in PC drug resistance and progression. CSC-derived exosomes increased the proportion of F4/80+/CD86 + cells and levels of M2 polarization factors. miR-210 is expressed in CSC-derived exosomes. Thus, following co-culture, miR-210 was taken up by macrophages. Transfection or the addition of miR-210 mimics increased the proportion of F4/80+/CD206 + cells and levels of M2 polarization factors. Further, the miR-210 targets inhibited the levels of FGFRL1. The FGFRL1 overexpression plasmid also inhibited miR-210-mediated M2 polarization. After co-culture of THP-M2 cells with PC cells and treatment with GEM, the survival rate, migration rate, and levels of MDR, YB-1, BCRP, p-PI3K, p-AKT, and p-mTOR in PC cells increased. And THP-M2 increased the tumor volume and MDR, YB-1, BCRP, p-PI3K, p-AKT, and p-mTOR levels. Overall, miR-210 from PC stem cell-derived exosome targets and inhibits FGFRL1 to promote macrophage M2 polarization, which activates the p-PI3K/p-AKT/p-mTOR pathway and increases GEM resistance.

Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis.

BACKGROUND: The tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive. METHODS: We used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo. RESULTS: TRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15. CONCLUSIONS: TRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.

Increasing CCL5/CCR5 on CD4+ T cells in peripheral blood of oral lichen planus.

Oral lichen planus (OLP) is a T cell-mediated autoimmune disease of oral mucosa, in which T helper 1 (Th1) cells are greatly involved. Chemokine CCL5 is required for T cells infiltration and activation. CCR5, one of its receptors, specifically expressed on Th1 cells among CD4(+) T cells, can be up-regulated by Th1 cytokines like interleukin2 (IL-2) and interferon-gamma (IFN-γ), and down-regulated by Th2 cytokines like IL-4. The present study aimed to determine whether CCL5 and CCR5 had effects on the immune response of OLP. We analyzed the proportion of CCR5(+)CD4(+) T cells in CD4(+) T cells using flow cytometry and the serum levels of CCL5, IL-2, IFN-γ, and IL-4 with ELISA. MicroRNA-125a (miR-125a), a blocker of CCL5, was examined with RT-PCR. The results showed both the serum CCL5 and the percentage of CCR5(+)CD4(+) T cells elevated in OLP patients. Serum IL-2 and IFN-γ increased in OLP patients, but IL-4 decreased. MiR-125a was down-regulated in OLP patients, and there was a negative correlation between miR-125a content and the OLP severity which was measured with a RAE (reticular, atrophic and erosive lesion) scoring system. In conclusion, increasing CCl5/CCR5 might participate in the immune response of OLP. Th1-type cytokines environment presented in OLP probably performed as a magnifier for the CCR5. Moreover, miR-125a might be a candidate biomarker to estimate the severity of OLP.

Broadening the lens on bisphenols in coastal waters: Occurrence, partitioning, and input fluxes of multiple novel bisphenol S derivatives along with BPA and BPA analogues in the Pearl River Delta, China.

Bisphenol S derivatives (BDs) are being widely used as novel substitutes for BPA and BPA analogues (BPAs), causing pollution in various environmental compartments. However, the occurrence and fate of BDs in coastal waters are currently unknown. To broaden the lens on bisphenols in coastal waters, this study measured a broad suite of 23 bisphenols, including 12 BDs along with BPA and 10 BPAs, in water, suspended particulate matter (SPM), and sediment from eight major outlets of the Pearl River Delta, China (PRD). In addition to BPA and BPAs, all the 12 BDs were detected in the collected samples. The total concentration of 12 BDs ranged from 1.2 to 25 ng/L (median of 4.3 ng/L) in water samples, 0.80-13 ng/g dw (median of 3.0 ng/g dw) in SPM samples and 0.48-3.7 ng/g dw (median of 0.64 ng/g dw) in sediment samples. For most individual BDs, they had comparable concentrations to individual BPAs. In addition, logKd values of the frequently detected bisphenols, including BPA, BPS, BPF, 4-((4-Isopropoxyphenyl)sulfonyl)phenol (BPSIP), 2,4-bis(phenylsulfonyl)phenol (DBSP), and other 9 bisphenols, were significantly correlated with their logKow values (R2 = 0.38, p < 0.05), indicating that the partitioning of bisphenols between the aqueous and SPM phases were strongly influenced by hydrophobic interaction. Based on bisphenols' concentrations in water from the eight outlets of PRD, the estimated input fluxes of novel BDs (1900 kg/y) were found to be even higher than that of BPAs (550 kg/y). This indicates that the riverine input of BDs into the coastal environment is gradually increasing, which should be taken seriously in the future.

USP8 promotes gemcitabine resistance of pancreatic cancer via deubiquitinating and stabilizing Nrf2.

Gemcitabine (Gem) is the first-line chemotherapy drug for pancreatic cancer, but the acquired chemoresistance also hinders its application. Therefore, research about Gem resistance plays a crucial role in enhancing the therapeutic effect of Gem. As a deubiquitinating enzyme, ubiquitin-specific protease 8 (USP8) was shown to play vital roles in the tumorigenesis processes of several cancers; however, the effect of USP8 on Gem resistance of pancreatic cancer still remains largely unknown. In the current study, we observed that the expression of USP8 was increased in pancreatic cancer patients, it is related to the recurrence of Gem chemotherapy, and USP8 expression could be induced by Gem application. Furthermore, USP8 was found to promote Gem resistance both in vivo and in vitro via regulating cell viability and apoptosis. Moreover, USP8 enhanced the activation of Nrf2 signaling which is dependent on its deubiquitinase ability. At last, we illustrated that USP8 interacted with Nrf2 directly and deubiquitinated K48-linked polyubiquitin chains from Nrf2, stabilizing the expression of Nrf2. In summary, the manuscript revealed the role of USP8 in Gem chemoresistance and suggested USP8 as a potential therapeutic target for pancreatic cancer.

Tumor Cell Derived Exosomal GOT1 Suppresses Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression.

Recently, evidence has shown that GOT1 expression is upregulated in pancreatic cancer tissues and promotes cancer development, but the specific mechanism remains unclear. We found that GOT1 expression was upregulated in pancreatic cancer cell-derived exosomes. When PANC-1 cells were incubated with exosomes alone or transfected together with si-GOT1, we found that exosomes enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-GOT1 reversed the effects of exosomes. The results of online bioinformatics database analysis indicated that CCR2 was a potential binding protein of GOT1 and is highly expressed in pancreatic cancer tissues. PANC-1 cells were transfected with pcDNA-CCR2 or si-CCR2, and it was found that pcDNA-CCR2 enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-CCR2 had an opposite effect. Next, exosome-treated cells were transfected with si-GOT1 alone or together with pcDNA-CCR2, and we found that exosomes promoted CCR2 expression, promoted cell proliferation and invasion, and inhibited ferroptosis, the transfection of si-GOT1 abolished the effect of exosomes, and the transfection of pcDNA-CCR2 again reversed the effect of si-GOT1. Furthermore, when exosome-treated cells were transfected with si-GOT1 alone or co-incubated with Nrf2 activator NK-252, we found that si-GOT1 reversed the promoting effect of exosomes on Nrf2 and HO-1 expression, as well as its inhibitory effect on ferroptosis, but this effect was abrogated by NK-252. In vivo studies showed that knockdown of GOT1 expression inhibited tumor formation compared with tumor tissues formed upon exosome induction, which was mediated by promoting ferroptosis via suppressing the protein expression of GOT1, CCR2, Nrf2 and HO-1 in tumor tissues.

Nerve Growth Factor (NGF) Encourages the Neuroinvasive Potential of Pancreatic Cancer Cells by Activating the Warburg Effect and Promoting Tumor Derived Exosomal miRNA-21 Expression.

Background: It has been reported that signaling from the nerve growth factor (NGF) pathway associated with peripheral nerves is able to contribute to perineural invasion (PNI) of pancreatic cancer (PC). Nevertheless, the underlying mechanism by which NGF leads to PNI remained poorly understood. Methods: Western blotting was employed to determine NGF level in PC and paracarcinoma tissues and in PC cell lines as well as pancreatic ductal epithelial cells. MiaPaCa-2 and CFPAC-1 cells were treated with 100 ng/ml of NGF or the NGF inhibitor Tanezumab for 24 h, CCK-8 and Transwell assays were employed to test cell proliferation, invasion, and migration, respectively. TrkA expression was knocked down in MiaPaCa-2 and dorsal root ganglion (DRG) cells treated with NGF to determine its effect on the Warburg effect. To reveal that the NGF-TrkA signaling pathway was closely associated with PC PNI, in vitro neuroinvasion model was established by using MiaPaCa-2 cells via coculturing DRG cells in Matrigel. Further, exosomes were extracted from PC cells and identified by examining the levels of specific markers for exosomes. Then RT-qPCR was applied to test miR-21-5p level in tumor derived exosomal (TDE-miR-21-5p). RIP assay was performed to validate NGF and miR-21 binding ability in MiaPaCa-2 cells. Rescue experiments were performed by using coprocessing of Tanezumab and miR-21-5p mimic on MiaPaCa-2 cells, followed by coculture with DRG cells. Subsequently, we used a model of neuroinvasion in nude mice to assess the effect of NGF in vivo on tumor nerve invasion as well as on nociceptive transmission. Results: NGF level was preeminently higher in PC tissues and cell lines than in paracarcinoma tissues and normal pancreatic epithelial cell lines. NGF promoted MiaPaCa-2 and CFPAC-1 cell invasion and migration, while Tanezumab treatment showed the opposite results. Besides, NGF binding to TrkA receptors encouraged the intracellular Warburg effect in PC and DRG cells. TrkA blocking-up could restrain NGF induced PC cell migration and neural invasion. Mechanistically, NGF could upregulate TDE-miR-21-5p levels, and DRG cells took up TDE to activate the Warburg effect and stimulate nociceptor gene expression. miR-21-5p inhibitor could abolish the facilitative effect of NGF on PNI in MiaPaCa-2 cells. In vivo tumorigenesis experiments, Tanezumab markedly alleviated nerve invasion of PC cells as well as relieved nociceptive conduction in animal models. Conclusions: These findings displayed that NGF/TrkA encouraged the neuroinvasive potential of PC cells by activating the Warburg effect in DRG cells through upregulation of TDE-miR-21-5p expression.

HDAC5 modulates PD-L1 expression and cancer immunity via p65 deacetylation in pancreatic cancer.

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a dismal 5-year survival less than 10%. Most patients with PDAC exhibit poor response to single-agent immunotherapy. Multimodal therapies targeting mechanisms of resistance to immunotherapy are urgently needed. We found that the class IIa histone deacetylase (HDAC) member, HDAC5 is downregulated in multiple solid tumors and its level were associated with favorable prognosis in PDAC patients. Upregulated genes in patients harboring HDAC5 deletions were enriched in adaptive immune responses and lymphocyte-mediated immunity in The Cancer Genome Atlas (TCGA) pancreatic cancer dataset. Methods: Tissue microarray of pancreatic cancer were used to analysis the correlation between HDAC5 and PD-L1. RNA-seq, transcription factor motif analysis, drug screening and molecular biology assays were performed to identify the mechanism of HDAC5's repression on PD-L1. Allografts of pancreatic cancer in mouse were applied to test the efficiency of HDAC5 inhibition and anti-PD1 co-treatment. Results: HDAC5 regulated PD-L1 expression by directly interacting with NF-κB p65; this interaction was suppressed by p65 phosphorylation at serine-311. Additionally, HDAC5 diminished p65 acetylation at lysine-310, which is essential for the transcriptional activity of p65. Importantly, we demonstrated that HDAC5 silencing or inhibition sensitized PDAC tumors to immune checkpoint blockade (ICB) therapy in syngeneic mouse model and KPC mouse derived PDAC model. Conclusion: Our findings revealed a previously unknown role of HDAC5 in regulating the NF-κB signaling pathway and antitumor immune responses. These findings provide a strong rationale for augment the antitumor effects of ICB in immunotherapy-resistant PDAC by inhibiting HDAC5.

Prognostic Analysis of Different Metastatic Patterns in Invasive Intraductal Papillary Mucinous Neoplasm: A Surveillance, Epidemiology, and End Results Database Analysis.

Objective: To evaluate the impacts of different metastatic patterns on the prognosis of patients with invasive intraductal papillary mucinous neoplasm (IPMN). Materials and Methods: All patients who were diagnosed with invasive IPMN in the Surveillance, Epidemiology, and End Results SEER database (2010-2015) were included in this study. They were grouped according to different metastatic patterns. Kaplan-Meier analysis and log-rank test were used for the comparison of their survival rates. The hazard ratio (HR) with 95% confidence interval (CI) was analyzed using the Cox proportional-hazards model. Results: A total of 2264 cases were included in this study. The most common metastatic site was the liver. The patients with the nonorgan metastasis demonstrated the best survival outcomes, while those with multiple metastases showed the worst survival outcomes. As compared to the patients with isolated liver metastasis, those with isolated lung and other organ metastases showed better overall survival rates and tumor-specific survival rates. The patients with liver, lung, multiple, and other organ metastases or of age >60 years were the independent predictors of poor prognosis. Conclusions: The patients with isolated lung and other organ metastases demonstrated better survival outcomes as compared to those with isolated liver metastasis. The patients with nonorgan metastasis demonstrated the best survival outcomes, while those with multiple metastases showed the worst survival outcomes. Further studies are needed to determine a highly selected subset of patients, who might benefit from surgery or chemotherapy.

Targeting methyltransferase PRMT5 retards the carcinogenesis and metastasis of HNSCC via epigenetically inhibiting Twist1 transcription.

Protein arginine methyltransferase 5 (PRMT5) is an important type II arginine methyltransferase that can play roles in cancers in a highly tissue-specific manner, but its role in the carcinogenesis and metastasis of head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we detected PRMT5 expression in HNSCC tissues and performed series of in vivo and in vitro assays to investigate the function and mechanism of PRMT5 in HNSCC. We found that PRMT5 was overexpressed in dysplastic and cancer tissues, and associated with lymph node metastasis and worse patient survival. PRMT5 knockdown repressed the malignant phenotype of HNSCC cells in vitro and in vivo. PRMT5 specific inhibitor blocked the formation of precancerous lesion and HNSCC in 4NQO-induced tongue carcinogenesis model, prevented lymph node metastasis in tongue orthotopic xenograft model and inhibited cancer development in subcutaneous xenograft model and Patient-Derived tumor Xenograft (PDX) model. Mechanistically, PRMT5-catalyzed H3R2me2s promotes the enrichment of H3K4me3 in the Twist1 promoter region by recruiting WDR5, and subsequently activates the transcription of Twist1. The rescue experiments indicated that overexpressed Twist1 abrogated the inhibition of cell invasion induced by PRMT5 inhibitor. In summary, this study elucidates that PRMT5 inhibition could reduce H3K4me3-mediated Twist1 transcription and retard the carcinogenesis and metastasis of HNSCC.

Combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the initiation and recurrence of oral squamous cell carcinomas by repressing SOX2.

Treatment of oral squamous cell carcinoma (OSCC) remains a challenge because of the lack of effective early treatment strategies and high incidence of relapse. Here, we showed that combined 4SC-202 (a novel selective class I HDAC inhibitor) and INK128 (a selective mTORC1/C2 inhibitor) treatment exhibited synergistic effects on inhibiting cell growth, sphere-forming ability, subcutaneous tumor formation and ALDH1+ cancer stem cells (CSCs) in OSCC. The initiation of OSCC was significantly inhibited by combined treatment in 4NQO-induced rat model. In addition, upregulated SOX2 was associated with advanced and metastatic tumors in OSCC patients and was responsible for the drug-resistance property of OSCC cells. The inhibitory effect of combined treatment on cell viability and ALDH1+ CSCs were attenuated by SOX2 verexpression. Furthermore, combined treatment can effectively overcome chemoresistance and inhibit the growth of recurrent OSCC in vitro and in vivo. Mechanistically, 4SC-202 and INK128 repressed SOX2 expression through miR-429/miR-1181-mediated mRNA degradation and preventing cap-dependent mRNA translation, respectively. These results suggest that combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the carcinogenesis and recurrence of OSCC by repressing SOX2.

Prognostic Value of Cancer Stem Cell Markers in Head and Neck Squamous Cell Carcinoma: a Meta-analysis.

Bmi-1, CD133, Nanog and Oct-4 have been reported as cancer stem cell (CSC) markers in head and neck squamous cell carcinoma (HNSCC). However, the prognostic value of them in HNSCC remains controversial. Hence, this meta-analysis was conducted to access the association between the four CSC markers and survival outcome of HNSCC patients. A total of 22 articles with 27 studies met the inclusion criteria and the combined hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated. Data analysis showed that high expression of CSC markers was associated with poor overall survival (OS) (HR = 1.93; 95% CI: 1.46-2.55, P < 0.001) and disease free survival (DFS) (HR = 4.78; 95% CI: 2.95-7.75, P < 0.001) but not disease specific survival (DSS) (HR = 1.17; 95% CI: 0.74-1.84, P = 0.50) of HNSCC patients. Subgroup analysis indicted that high expression of CD133 (HR = 2.33, 95%CI: 1.42-3.83, P < 0.001), Oct-4(HR = 2.10, 95%CI: 1.36-3.22, P = 0.007) and Nanog (HR = 2.49, 95%CI: 1.66-3.72, P < 0.001) could predict poor OS in HNSCC patients respectively whereas overexpression of Bmi-1 was not related to the reduced OS in HNSCC patients (HR = 1.32, 95%CI: 0.66-2.65, P = 0.43). Therefore, we concluded that CSC markers, especially CD133, Nanog and Oct-4, might be predictive factors in HNSCC patients.

Different Expression of MicroRNA-146a in Peripheral Blood CD4(+) T Cells and Lesions of Oral Lichen Planus.

Oral lichen planus (OLP) is a common T cell-mediated chronic inflammatory disease of unknown etiology. Recent increasing evidence indicates that microRNA-146a (miR-146a) plays a vital role in inflammatory diseases and T cell regulation. This study aimed to investigate the expression of miRNA-146a in peripheral blood CD4(+) T cells and local OLP lesions and to evaluate its relationship with clinical forms of OLP. Sixteen patients with OLP were divided into two groups: erosive OLP and nonerosive OLP. The expression of miR-146a was examined by quantitative real-time polymerase chain reaction. The expression of miR-146a in peripheral blood CD4(+) T cells showed no significant difference between OLP group and control group (P > 0.05), and among erosive OLP, nonerosive OLP, and control groups (P > 0.05 for all). The expression in local lesions of the OLP group was significantly higher than that of the control group (P = 0.003), and it was significantly higher in the erosive OLP group than in the non-erosive OLP (P = 0.010) and control groups (P = 0.007). However, miR-146a expression in the nonerosive OLP group did not significantly differ from that in the control group (P > 0.05). These data indicate that miR-146a might be more involved in the local immune disorder of OLP. MiR-146a might be utilized as a candidate biomarker to estimate the severity of OLP.

[Detection of miR-155, miR-146a in PBNCs and tissues from patients with oral lichen planus].

PURPOSE: To investigate the miRNA (including miR-155, miR-146a and miR-146b) expression in peripheral blood mononuclear cells (PBNCs) or lesions tissues in oral lichen planus (OLP) patients and healthy controls and the relationship between miRNA and OLP clinical features. METHODS: The expression of miRNA（miR-155, miR-146a and miR-146b）was assessed by quantitative fluorescent PCR in peripheral blood cells or lesions tissues in OLP patients and healthy controls. U6 was used as reference gene. Statistical analysis was performed with SPSS17.0 software package. RESULTS: Real-time PCR showed that the expression of miR-155 in OLP PBNCs was significantly higher than that in controls, miR-155 expression in OLP lesions tissues was 7.0 times higher than that of PBMCs. Correlation analysis showed that the level of miR-155 expression in PBMCs was positively correlated with REU score(correlation coefficient R=0.887, P<0.01). There was no significant difference in miR-146a and miR-146b expression in PBMCs between OLP and control group. On the contrary, the miR-146a expression in OLP lesions tissues was significantly upreguated than that in control group (P=0.003). CONCLUSIONS: The results indicated that miR-155 and miR-146a might play important roles in the pathogenesis of OLP and OLP is likely a chronic inflammatory disease characterized by local inflammation.

MicroRNA-155-IFN-γ Feedback Loop in CD4(+)T Cells of Erosive type Oral Lichen Planus.

Oral lichen planus (OLP) is a T cell-mediated immune disorder, and we have indicated a Th1-dominated immune response in OLP. MicroRNA-155 (miR-155) could promote Th1 cells polarization. The present study aims to determine the role of miR-155 in immune response of OLP. The expression of miR-155 and the target mRNA was tested by Real-Time PCR. The serum levels of IL-2, 4, 10 and IFN-γ were examined with ELISA. Furthermore, in vitro study was built to observe the function of miR-155 in erosive-type OLP (EOLP). Finally, we determined the expression and correlation of miR-155 and SOCS1 in EOLP CD4(+) T cells. The results showed miR-155 was high related with the disease severities. Besides, serum IFN-γ was specifically increased in EOLP group, while IL-4 was decreased. In vitro studies showed miR-155 could reinforce IFN-γ signal transducer, and the induction of IFN-γ could also promote miR-155 expression in EOLP CD4(+) T cells. In addition, miR-155 levels were negatively related with SOCS1 mRNA expression in EOLP CD4(+) T cells. Our study revealed a positive miR-155- IFN-γ feedback loop in EOLP CD4(+) T cell, which might contribute to the Th1-dominated immune response. Furthermore, miR-155 could be used for the evaluation and treatment of OLP.