The dorsal and the ventral side of hypoglossal motor nucleus showed different response to chronic intermittent hypoxia in rats.

PURPOSE: To study neurochemical reactions to chronic intermittent hypoxia (CIH) in the hypoglossal nucleus (HN) of rats. METHODS: Adult male Sprague-Dawley rats (n = 12) were randomly divided into two groups (the CIH and the control group). The CIH rats were housed in a hypoxic chamber with the fraction of oxygen volume alternating between 21% and 5% by providing air for 60 s and then providing nitrogen for 60 s from 8:30 am to 16:30 pm each day for 35 days. The control group was housed in a cabin with normal oxygen levels. We studied the expression of c-fos protein, 5-hydroxytryptamine (5-HT) positive terminals, and its 2A receptors in hypoglossal nuclei by immunohistochemistry. RESULTS: The expression of c-fos, 5-HT positive terminals, and accordingly 5-HT 2A receptors in the CIH group were significantly higher than that in the controls (p < 0.05). The ventral side of the HN showed a clearly higher expression of 5-HT and its 2A receptors than the dorsal side (p < 0.05). CONCLUSION: There were 2 responses of the HN to CIH. First, CIH induced a higher expression of 5-HT positive terminals and its 2A receptors, and second, this reaction was much more evident in ventral side than in the dorsal side. We postulate that these responses may serve to be a protective and compensatory mechanism for CIH.

IL-1ß promotes malignant transformation and tumor aggressiveness in oral cancer.

Chronic inflammation, coupled with alcohol, betel quid, and cigarette consumption, is associated with oral squamous cell carcinoma (OSCC). Interleukin-1 beta (IL-1ß) is a critical mediator of chronic inflammation and implicated in many cancers. In this study, we showed that increased pro-IL-1ß expression was associated with the severity of oral malignant transformation in a mouse OSCC model induced by 4-Nitroquinolin-1-oxide (4-NQO) and arecoline, two carcinogens related to tobacco and betel quid, respectively. Using microarray and quantitative PCR assay, we showed that pro-IL-1ß was upregulated in human OSCC tumors associated with tobacco and betel quid consumption. In a human OSCC cell line TW2.6, we demonstrated nicotine-derived nitrosamine ketone (NNK) and arecoline stimulated IL-1ß secretion in an inflammasome-dependent manner. IL-1ß treatment significantly increased the proliferation and dysregulated the Akt signaling pathways of dysplastic oral keratinocytes (DOKs). Using cytokine antibodies and inflammation cytometric bead arrays, we found that DOK and OSCC cells secreted high levels of IL-6, IL-8, and growth-regulated oncogene-α following IL-1ß stimulation. The conditioned medium of IL-1ß-treated OSCC cells exerted significant proangiogenic effects. Crucially, IL-1ß increased the invasiveness of OSCC cells through the epithelial-mesenchymal transition (EMT), characterized by downregulation of E-cadherin, upregulation of Snail, Slug, and Vimentin, and alterations in morphology. These findings provide novel insights into the mechanism underlying OSCC tumorigenesis. Our study suggested that IL-1ß can be induced by tobacco and betel quid-related carcinogens, and participates in the early and late stages of oral carcinogenesis by increasing the proliferation of dysplasia oral cells, stimulating oncogenic cytokines, and promoting aggressiveness of OSCC.

Curcumin exerts inhibitory effects on undifferentiated nasopharyngeal carcinoma by inhibiting the expression of miR-125a-5p.

Curcumin suppresses proliferation, migration, invasion, metastasis and angiogenesis and induces apoptosis by regulating multiple signalling pathways and miRNAs in a wide variety of human malignancies. miRNAs play crucial roles in various steps of carcinogenesis in nasopharyngeal carcinoma (NPC); thus, they could serve as critical therapeutic targets for NPC treatment. Curcumin could provide a novel strategy to block or induce specific miRNAs for miRNA-based gene therapies. Nevertheless, there are no reports to date on the miRNAs regulated by curcumin in NPC. In the present study, we have carried out an miRNA microarray to identify the miRNAs regulated by curcumin in NPC. Curcumin treatment down-regulated the expression of hsa-miR-125a-5p, hsa-miR-574-3p and hsa-miR-210 as determined by miRNA microarray analysis and qPCR (real-time quantitative reverse transcription-PCR). Forced expression of miR-125a-5p enhanced proliferation, migration and invasion of HONE1 cells. Primary NPC exhibited a significantly higher expression level of miR-125a-5p than healthy controls. miR-125a-5p inhibited the expression of tumour protein 53 (TP53), and curcumin treatment up-regulated the expression of TP53. Taken together, these results indicate that curcumin exerted inhibitory effects on NPC by inhibiting the expression of miR-125a-5p and, subsequently, enhancing the expression of TP53. Curcumin could provide a novel strategy to block miR-125a-5p for miRNA-based gene therapies in NPC.

Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma.

The strong associations between oral squamous cell carcinoma (OSCC) and dietary habits such as alcohol consumption (A), betel quid chewing (B) and cigarette smoking (C) and its predominance in men have been well documented; however, systemic analysis of OSCC is limited. Our study applied high-throughput screening methods to identify causative epigenetic targets in a cohort of men with ABC-associated OSCC. We identified BEX1 and LDOC1 as two epigenetically silenced X-linked tumour suppressors and demonstrated a functional link between the transcription of BEX1 and LDOC1 and promoter hypermethylation. Methylation of the BEX1 and LDOC1 promoters was associated significantly (p < 0.0001) with OSCC and were detected in 75% (42/56) and 89% (50/56) of the samples, respectively. We observed concordant increases in the methylation of both genes in 71% (40/56) of the tumours, and potent in vitro and in vivo growth inhibitory effects in OSCC cells ectopically expressing BEX1 and/or LDOC1. Restored expression of BEX1 and LDOC1 suppressed the nuclear factor-κB (NF-κB) signalling pathway, which is the most frequently hyperactivated signalling pathway in OSCC. This suppression might result from decreased p50 and p65 expression. These findings suggest that silencing of BEX1 and LDOC1 by promoter hypermethylation might represent a critical event in the molecular pathogenesis of OSCC and account for the oncogenic effects of ABC exposure and the male predominance of OSCC occurrence. Microarray data are available in the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/)

A long non-coding RNA signature in glioblastoma multiforme predicts survival.

Long non-coding RNAs (lncRNAs) represent the leading edge of cancer research, and have been implicated in cancer biogenesis and prognosis. We aimed to identify lncRNA signatures that have prognostic values in glioblastoma multiforme (GBM). Using a lncRNA-mining approach, we performed lncRNA expression profiling in 213 GBM tumors from The Cancer Genome Atlas (TCGA), randomly divided into a training (n=107) and a testing set (n=106). We analyzed the associations between lncRNA signatures and clinical outcome in the training set, and validated the findings in the testing set. We also validated the identified lncRNA signature in another two independent GBM data sets from Gene Expression Omnibus (GEO), which contained specimens from 68 and 101 patients, respectively. We identified a set of six lncRNAs that were significantly associated with the overall survival in the training set (P≤0.01). Based on this six-lncRNA signature, the training-set patients could be classified into high-risk and low-risk subgroups with significantly different survival (HR=2.13, 95% CI=1.38-3.29; P=0.001). The prognostic value of this six-lncRNA signature was confirmed in the testing set and the two independent data sets. Further analysis revealed that the prognostic value of this signature was independent of age and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. The identification of the prognostic lncRNAs indicates the potential roles of lncRNAs in GBM pathogenesis. This six-lncRNA signature may have clinical implications in the subclassification of GBM.

Cryo-EM structure of orphan G protein-coupled receptor GPR21.

GPR21 belongs to class A orphan G protein-coupled receptor (GPCR). The endogenous ligands for human GPR21 remain unidentified. GPR21 expression is associated with developing type 2 diabetes (T2DM), a multifactorial metabolic disease caused by pancreatic ß-cell dysfunction, decreasing insulin production, insulin resistance, and obesity. Animal studies suggested that GPR21 is a potential therapeutic target for T2DM treatment. The underlying mechanisms leading to GPR21 self-activation remain unknown. In our co-expression analysis, we noted that GPR21 could also form a stable complex with an unreported Gα protein subtype, Gαs. To gain further insights into the structural mechanisms of GPR21 activation, we employed cryo-electron microscopy (cryo-EM) and single-particle analysis to resolve the high-resolution structure of GPR21-Gαs complexes. The clear electron density map of the GPR21-Gαs provided direct evidence that GPR21 could couple to Gαs protein at physiological conditions. Thus, GPR21 might mediate previously unexplored pathways in normal or pathological conditions, which warrants further investigation. Structure-guided mutagenesis and biochemical analysis revealed that extracellular loop 2 (ECL2) of GPR21 is essential for the receptor transducing intracellular signal via cAMP. Together, the new structure data reveal a novel signaling cascade of human GPR21 mediated by ECL2 and provide fundamental information for future structure-based drug development.

G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders.

Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.

Curcumin inhibits tongue carcinoma cells migration and invasion through downregulation of matrix metallopeptidase 10.

Squamous cell carcinoma (SCC) of tongue is an aggressive head and neck cancer with high propensity of regional spreading and invasion. Tongue carcinoma cells treated with curcumin, the major curcuminoid of the turmeric, demonstrated reduction in adhesion, migration, and invasion ability. High-throughput microarray analysis indicated that curcumin treatment suppressed matrix metallopeptidase 10 (MMP10) expression. MMP10 is overexpressed in tongue carcinoma tissues in comparison with the normal epithelia. Curcumin treatment on tongue carcinoma cell lines suppressed MMP10 expression at both mRNA and protein levels. Our results suggested that curcumin is a promising inhibitor to tongue cancer cells migration and invasion.

Biomarkers for use in monitoring responses of nasopharyngeal carcinoma cells to ionizing radiation.

Nasopharyngeal carcinoma (NPC) is a common head and neck cancer. The incidence rate is higher in southern China and Southeast Asia in comparison with the Western countries. Radiotherapy is the standard treatment of NPC as the cancer cells are sensitive to ionizing radiation. Radiation treatment has good local control to patients with early NPC. It is essential to monitor the response of the NPC cells to radiation treatment in advance in order to select suitable treatment choice for the patients. This review aims to discuss the potential use of biomarkers in monitoring the responsiveness of NPC cells to radiation treatment.

Cryo-EM structure of G-protein-coupled receptor GPR17 in complex with inhibitory G protein.

GPR17 is a class A orphan G protein-coupled receptor (GPCR) expressed in neurons and oligodendrocyte progenitors of the central nervous system (CNS). The signalling of GPR17 occurs through the heterotrimeric Gi, but its activation mechanism is unclear. Here, we employed cryo-electron microscopy (cryo-EM) technology to elucidate the structure of activated GPR17-Gi complex. The 3.02 Å resolution structure, together with mutagenesis studies, revealed that the extracellular loop2 of GPR17 occupied the orthosteric binding pocket to promote its self-activation. The active GPR17 carried several typical microswitches like other class A GPCRs. Moreover, the Gi interacted with the key residues of transmembrane helix 3 (TM3), the amphipathic helix 8 (Helix8), and intracellular loops 3 (ICL3) in GPR17 to engage in the receptor core. In summary, our results highlight the activation mechanism of GPR17 from the structural basis. Elucidating the structural and activation mechanism of GPR17 may facilitate the pharmacological intervention for acute/chronic CNS injury.

Mitochondrial DHODH regulates hypoxia-inducible factor 1 expression in OTSCC.

Oral tongue squamous cell carcinoma (OTSCC) was one of the most hypoxic tumors with unfavorable outcomes. Hypoxia-inducible factor-1 (HIF-1) signaling was associated with cancer proliferation, lymph node metastasis, angiogenesis and poor prognosis of OTSCC. Dihydroorotate dehydrogenase (DHODH) catalyzed the rate-limiting step in the de novo pyrimidine biosynthesis. The aim of the study was to explore the biological function of DHODH and investigate whether DHODH regulated HIF-1 signaling in OTSCC. Proliferation, migration and anoikis resistance were used to determine the function of DHODH. Western blot and luciferase activity assays were used to determine the regulatory role of DHODH on HIF-1. We found that increased DHODH expression was associated with advanced tumor stage and poorly differentiated tumor in head and neck cancer patients in The Cancer Genome Atlas (TCGA). DHODH enhanced the proliferation and aggressiveness of OTSCC. Moreover, DHODH prompted tumor growth and metastasis in vivo. DHODH promoted transcription, protein stability, and transactivation activity of HIF1A. DHODH-induced HIF1A upregulation in OTSCC can be reversed by reactive oxygen species (ROS) scavenger, indicating that DHODH enhanced HIF1A expression via ROS production. DHODH inhibitor suppressed DHODH-mediated ROS generation and HIF1A upregulation. Targeting DHODH using clinically available inhibitor, atovaquone, might provide a new strategy to treat OTSCC.

Robot-assisted real-time sentinel lymph node mapping in oral cavity cancer: preliminary experience.

This study aims to assess the feasibility of using indocyanine green and robotic near infra-red fluorescent imaging (Firefly®) for sentinel lymph node biopsy in cN0 oral cavity cancer. Ten patients with early squamous cell carcinoma of the tongue (n = 8) and buccal mucosa (n = 2) were included. Peritumoral injection of 10 mg indocyanine green and real-time mapping of sentinel lymph nodes in the neck was performed using Firefly® via a retro-auricular trans-hairline incision. Sentinel lymph node was detected in all patients at 1.2 sentinel lymph node per person. Majority were situated in level II (91.7%). Mean time to detection of sentinel lymph node was 171.0 (68.0-312.0)s. Mean signal-to-background ratio was 5.62 (3.51-7.91). Frozen section of one sentinel lymph node was positive for malignancy, paraffin section of which confirmed the presence of metastatic disease. Modified radical neck dissection was performed for that particular patient, paraffin section of which did not show any tumor deposit. Frozen section and paraffin section of all other sentinel lymph nodes (n = 11) and neck dissection specimens yielded no malignancy. All resection margins were clear. Three patients completed adjuvant radiotherapy for pT2N0 (n = 2) and pT2N1 (n = 1) carcinoma of the tongue. Mean follow-up was 12.0 (4.0-18.0) months. All patients were alive at last follow-up with no disease recurrence. There were no adverse outcomes associated with the use of indocyanine green and robot-assisted neck dissection. Indocyanine green and Firefly® for sentinel lymph node biopsy in cN0 oral cavity cancer is feasible with no adverse effects.

CD38 triggers inflammasome-mediated pyroptotic cell death in head and neck squamous cell carcinoma.

BACKGROUND: Pyroptosis is a form of inflammatory cell death. Although it is recognized that NLRP3 (nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3) inflammasome is involved in pyroptosis activation, the mechanism by which head and neck squamous cell carcinoma (HNSCC) inhibits pyroptotic cell death remains undefined. This study aims to delineate the role of calcium regulator CD38 in NLRP3 inflammasome-dependent pyroptosis in HNSCC. METHODS: CD38 overexpressing HNSCC cell lines (SAS, CAL27, SNU899) were generated using lentiviral vectors. NLRP3 and gasdermin D (GSDMD) quantity were detected using Western blot. Caspase-1 activity changes were measured using the Caspase-Glo® 1 inflammasome assay. Cell death proportion was determined by flow cytometry analysis. Proliferation assay was performed using xCELLigence RTCA system. Mouse xenotransplantation was performed to evaluate the potential oncogenic or tumor-suppressive function of CD38. ChIP assay was conducted to verify whether transcription factor NFAT1-mediated NLRP3 expression. RESULTS: Exogenous calcium treatment can lead to a significant increase in caspase-1 activity in HNSCC. This feature was also observed in HNSCC cells with stable CD38 overexpression. CD38-overexpressing cell lines showed a significant reduction in proliferation. Further, expression of NLRP3 protein level was significantly increased in CD38-overexpressing cell lines. The N-terminal effector domain of GSDMD was remarkably increased in the CD38-overexpressing HNSCC. ChIP assay indicated that calcium-sensitive transcription factor NFAT1 was possibly involved in the transcriptional upregulation of NLRP3 observed in CD38-overexpressing HNSCC. The pre-clinical xenograft model revealed that CD38 expression had an inhibiting function on HNSCC progression. CONCLUSION: In conclusion, our results suggested that activation of pyroptosis in HNSCC is a calcium-dependent process. Reduced expression of calcium ion regulator CD38 functions could prevent inflammasome-induced pyroptosis in HNSCC. CD38 may function as a tumor suppressor in HNSCC progression.

NADPH oxidase 5α promotes the formation of CD271 tumor-initiating cells in oral cancer.

Oral tongue squamous cell carcinoma (OTSCC) has a distinctive cell sub-population known as tumor-initiating cells (TICs). CD271 is a functional TIC receptor in head and neck cancers. The molecular mechanisms governing CD271 up-regulation remains unclear. Oxidative stress is a contributing factor in TIC development. Here, we explored the potential role of NADPH oxidase 5 (NOX5) and its regulatory mechanism on the development of CD271-expressing OTSCC. Our results showed that the splice variant NOX5α is the most prevalent form expressed in head and neck cancers. NOX5α enhanced OTSCC proliferation, migration, and invasion. Overexpression of NOX5α increased the size of OTSCC xenograft significantly in vivo. The tumor-promoting functions of NOX5α were mediated through the reactive oxygen species (ROS)-generating property. NOX5α activated ERK singling and increased CD271 expression at the transcription level. Also, NOX5α reduces the sensitivity of OTSCC to cisplatin and natural killer cells. The findings indicate that NOX5α plays an important part in the development of TIC in OTSCC.

Mature miR-184 as Potential Oncogenic microRNA of Squamous Cell Carcinoma of Tongue.

PURPOSE: The aim of this study was to evaluate the microRNA expression patterns in squamous cell carcinoma (SCC) of the tongue. EXPERIMENTAL DESIGN: Expression levels of 156 human mature microRNAs were examined using real-time quantitative PCR (Taq Man MicroRNA Assays; Human Panel) on laser microdissected cells of 4 tongue carcinomas and paired normal tissues. Expression of mature miR-184 was further validated in 20 paired tongue SCC and the normal tissues. Potential oncogenic functions of miR-184 were evaluated in tongue SCC cell lines (Cal27, HN21B, and HN96) with miR-184 inhibitor. Plasma miR-184 levels were evaluated using real-time quantitative PCR. RESULTS: Using 3-fold expression difference as a cutoff level, we identified 24 up-regulated mature miRNAs including miR-184, miR-34c, miR-137, miR-372, miR-124a, miR-21, miR-124b, miR-31, miR-128a, miR-34b, miR-154, miR-197, miR-132, miR-147, miR-325, miR-181c, miR-198, miR-155, miR-30a-3p, miR-338, miR-17-5p, miR-104, miR-134, and miR-213; and 13 down-regulated mature miRNAs including miR-133a, miR-99a, miR-194, miR-133b, miR-219, miR-100, miR-125b, miR-26b, miR-138, miR-149, miR-195, miR-107, and miR-139. Overexpression of miR-184 was further validated in 20 paired tongue SCC and normal tissues (P = 0.002). Inhibition of miR-184 in tongue SCC cell lines could reduce cell proliferation rate. Down-regulation of c-Myc was observed in two cell lines in response to miR-184 inhibitor. Suppressing miR-184 could induce apoptosis in all three cell lines. Plasma miR-184 levels were significantly higher in tongue SCC patients in comparison with normal individuals, and the levels were significantly reduced after surgical removal of the primary tumors. CONCLUSIONS: Overexpression of miR-184 might play an oncogenic role in the antiapoptotic and proliferative processes of tongue SCC. In addition, plasma miR-184 levels were associated with the presence of primary tumor. Further studies on the aberrantly expressed miRNAs in tongue SCC as well as using plasma miRNAs as novel tumor markers are warranted.

Mature miR-184 and squamous cell carcinoma of the tongue.

Human microRNA 184 (miR-184) is overexpressed in squamous cell carcinoma (SCC) of the tongue. In vitro inhibition of miR-184 levels could induce apoptosis and hinder proliferation of tongue SCC cells. Patients with tongue SCC have high plasma miR-184 levels. Plasma miR-184 is likely associated with the tumor load. Surgical removal of the primary tumor reduced plasma miR-184 levels significantly. The data suggested that miR-184 is linked to the pathogenesis of tongue SCC. Further studies are warranted to evaluate the use of microRNA-based serological markers in monitoring tongue SCC.

Curcumin enhances cisplatin sensitivity by suppressing NADPH oxidase 5 expression in human epithelial cancer.

Cisplatin-based chemotherapy regimens serve a pivotal role in human cancer treatment. Nevertheless, treatment failure may occur if the cancer is inherently resistant to cisplatin or acquires a resistant phenotype during the course of treatment. Although cisplatin resistance can hinder the efficacy of cisplatin treatment for human cancer, the underlying mechanism remains poorly understood. The current study established a cisplatin-resistant human epithelial cancer cell line. Notably, differential upregulation of NADPH oxidase 5 (NOX5) was identified in this resistant cell line. Furthermore, cisplatin treatment induced cancer cells to express NOX5 and cells that overexpressed NOX5 exhibited greater resistance to cisplatin via the activation of Akt. Treatment with curcumin may suppress NOX5 expression in cancer cells and enhance sensitivity to cisplatin treatment. In a xenograft model, a combined regimen of cisplatin with low-dose curcumin significantly reduced malignant tumor growth. These data demonstrate that curcumin has a chemosensitizing effect on cisplatin-resistant epithelial cancer types. Therefore, the use of curcumin in addition to a cisplatin-based treatment regimen may improve treatment outcomes in human patients with epithelial cancer.

Detection of Epstein-Barr virus (EBV)-encoded microRNAs in plasma of patients with nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) latently infected by Epstein-Barr virus (EBV) expresses 40 EBV BART microRNAs (miRNAs). Difference in diagnostic efficacy of these miRNAs on NPC detection was observed. Here, we performed a comprehensive evaluation on the efficacy of these miRNAs. METHODS: Quantitative polymerase chain reaction was performed on plasma nucleic acid isolated from patients with NPC and noncancer donors. RESULTS: For primary NPC, BART2-5P, BART6-3P, BART7-3P, BART7-5P, BART9-5P, BART11-3P, BART17-5P, and BART19-5P were significantly elevated. For recurrent NPC, plasma levels of BART2-3P, BART2-5P, BART5-3P, BART5-5P, BART6-3P, BART8-3P, BART9-5P, BART17-5P, BART19-3P, and BART20-3P were significantly increased. Area under curve (AUC) analysis showed that BART19-5P had the best performance to identify NPC which was serologically EBV DNA undetectable. For recurrent NPC, BART8-3P and BART10-3P had highest AUC value for identifying cancer in EBV DNA undetectable plasma. CONCLUSION: Our data supported the use of circulating EBV miRNAs in NPC and recurrent NPC detection.

Identification of pyruvate kinase type M2 as potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling.

MicroRNAs (miRNAs) are noncoding RNAs with specific regulatory role in gene expression. Recent reports suggested their involvement in human malignancies. Currently, there is no information concerning miRNA expression and functions in squamous cell carcinoma (SCC) of tongue. In this study, we evaluated the expression patterns of 156 mature miRNAs in tongue SCC using Taqman-based microRNA assays. Of these 156 miRNAs, miR-133a and miR-133b were significantly reduced in tongue SCC cells in comparison with the paired normal epithelial cells. Tongue SCC cell lines transfected with miR-133a and miR-133b precursors displayed reduction in proliferation rate. In addition, the number of apoptotic cells was increased in response to the introduction of precursors. Computational target gene prediction suggested that both miR-133a and miR-133b are targeting transcript of pyruvate kinase type M2 (PKM2), a potential oncogene in solid cancers. In tongue SCC cell lines, PKM2 expression was reduced in response to miR-133a and miR-133b precursors transfection. Immunohistochemical staining results of tongue SCC tissues suggested that PKM2 was overexpressed in tongue SCC and was associated with the downregulation of miR-133a and miR-133b. Our results suggested that aberrant reduction of miR-133a and miR-133b was associated with the dysregulation of PKM2 in SCC of tongue.

Epstein-Barr virus-encoded microRNA BART7 downregulates major histocompatibility complex class I chain-related peptide A and reduces the cytotoxicity of natural killer cells to nasopharyngeal carcinoma.

Evasion from natural killer (NK) cell surveillance enables cancer to proliferate and spread at the early stages. NK cells mediate specific cytolysis by activation of the triggering receptors on their cell surface, of which the communication between natural killer group 2, member D (NKG2D) and major histocompatibility complex class I chain-related peptide A (MICA) is a key regulatory axis. It has been indicated that cancer cells can reduce the surface expression of MICA, which thereby reduces the cytotoxicity of NK cells. In nasopharyngeal carcinoma (NPC), however, the underlying mechanism remains unclear. The present study indicated that MICA expression in NPC was regulated by TGFß1. Furthermore, the human MICA gene was demonstrated to contain the c-Myc binding site in the promoter region. Notably, the results suggested that TGFß1 upregulated MICA expression by promoting c-Myc expression. Additionally, the findings demosntrated that TGFß1 expression in NPC was negatively controlled by Epstein-Barr virus-encoded microRNA BART7 (ebv-miR-BART7). In ebv-miR-BART7-expressing NPC, the TGFß1/c-Myc/MICA regulatory axis was significantly inhibited. Notably, functional analysis indicated that NPC cells expressing ebv-miR-BART7 were less sensitive to the cytolysis mediated by NK cells. In conclusion, the present results revealed that ebv-miR-BART7-expressing NPC may impair NK cells recognition and activity, which suggests that targeting ebv-miR-BART7 may be a useful therapeutic strategy in NPC immunotherapy.