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Background: Various antigen‐presenting cells and tumor cells‐expressing PD‐L1 inhibits antitumor immune responses in the tumor microenvironment. Recently, numerous studies have shown that tumor cell intrinsic PD‐L1 also plays important roles in tumor growth and progression. On the other hand, oral squamous cell carcinoma (OSCC) cells overexpress epidermal growth factor receptor (EGFR) and EGFR signal pathway exacerbates tumor progression. Therefore, this study assessed whether tumor‐intrinsic PD‐L1 facilitates malignant potential of OSCC cells through regulation of EGFR signaling. Methods: Two OSCC cell lines, SAS and HSC‐3, were transfected with PD‐L1 and EGFR‐specific small interfering RNA (siRNA). Influences of PD‐L1 knockdown on malignant potentials of OSCC cells were examined by Cell Counting kit‐8 assay, transwell assay, sphere formation assay, flow cytometry, and Western blot. Effects of PD‐L1 and EGFR knockdown on each expression were examined by quantitative real‐time PCR (qRT‐PCR), Western blot, and flow cytometry. Results: Transfection of an PD‐L1‐siRNA into OSCC cells decreased the abilities of proliferation, stemness, and mobility of these cells significantly. PD‐L1 knockdown also decreased EGFR expression through the promotion of proteasome‐ and lysosome‐mediated degradation and following activation of the EGFR/protekin kinase B (AKT) signal pathway. Meanwhile, EGFR knockdown did not influence PD‐L1 expression in SAS and HSC‐3 cells, but treatment with a recombinant human EGF induced its expression. Treatment with erlotinib and cetuximab suppressed rhEGF‐induced PD‐L1 expression and localization in the cellular membrane of both OSCC cells. Conclusion: OSCC cells‐expressing PD‐L1 induced by EGF stimulation may promote malignancy intrinsically via the activation of the EGFR/AKT signaling cascade. [ABSTRACT FROM AUTHOR]

Background: Constitutive activation of STAT3 promotes oncogenesis and growth of oral squamous cell carcinoma (OSCC). We investigated the mechanism of action of suppressor of cytokine signaling 1 (SOCS1), an endogenous inhibitor of JAK, as gene therapy for OSCC. Methods: Antitumor effect of SOCS1 was compared to JAK inhibitor I by cell proliferation assay, cell cycle analysis, and apoptosis analysis in vitro. In addition, antitumor effect was evaluated using xenograft mouse models in vivo. Results: JAK inhibitor I inhibited the proliferation of KOSC2 cl3‐43 or T3M‐1 clone2 OSCC cell lines in vitro. While JAK inhibitor I arrested both cell lines at the G2/M phase, induction of apoptosis was observed in T3M‐1 clone2 cells, but not KOSC2‐cl3‐43 cells. An adenoviral vector expressing SOCS1 (AdSOCS1) significantly decreased the proliferation of both OSCC cell lines and induced G2/M phase cell cycle arrest and apoptosis, suggesting that induction of apoptosis of KOSC2 cl3‐43 cells by AdSOCS1 is regulated by the JAK/STAT independent pathway. Overexpression of SOCS1 inhibited activation of the JAK/STAT and p44/42 MAPK pathways, while JAK inhibitor I inhibited activation of the JAK/STAT pathway only. Consistently, expression of Mcl‐1 was decreased by overexpression of SOCS1, but not JAK inhibitor I. Additionally, KOSC2 cl3‐43 or T3M‐1 clone2 OSCC cells were subcutaneously implanted in the flanks of two xenograft mouse models. As compared to a control adenovirus vector (AdLacZ), intratumor injection of AdSOCS1 significantly decreased the tumor volume and induced apoptosis in vivo. Conclusion: SOCS1 gene therapy may be a beneficial approach for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Various cell types secrete exosomes into their surrounding extracellular space, which consequently affect the function and activity of recipient cells. Numerous studies have showed that tumor cell‐derived exosomes play important roles in tumor growth and progression. Although a variety of endocytic pathways are reportedly involved in the cellular uptake of exosomes, detailed mechanisms remain unknown. The present study demonstrated that treatment with recombinant epidermal growth factor (EGF) time‐ and dose‐dependently promoted cellular uptake of oral squamous cell carcinoma (OSCC) cell‐derived exosomes into OSCC cells themselves. Conversely, EGF receptor (EGFR) knockdown and treatment with EGFR inhibitors, including erlotinib and cetuximab, abrogated OSCC cell uptake of exosomes. The macropinocytosis inhibitor 5‐(N‐ethyl‐N‐isopropyl) amiloride (EIPA) blocked the effects of active EGF/EGFR signaling on uptake of OSCC cell‐derived exosomes. These EGFR inhibitors also suppressed OSCC cell‐derived exosome‐induced proliferation, migration, invasion, stemness, and chemoresistance of OSCC cells. Taken together, the data presented herein suggest that EGFR inhibitors might inhibit the malignant potential of OSCC cells through direct inhibition of not only EGFR downstream signaling pathway but also cellular uptake of OSCC cell‐derived exosomes through macropinocytosis. [ABSTRACT FROM AUTHOR]

We present a review of the case reports of tongue/lingual necrosis caused by systemic vascular diseases. An electronic search of PubMed/MEDLINE was carried out for studies published from January 2009 to December 2018 using the following three keywords: tongue, lingual, and necrosis. The literature analysis identified 32 reports (38 cases) of tongue/lingual necrosis among the 325 studies originally identified by the PubMed/MEDLINE search. In all, 19 of the 38 cases were on vasculitis, followed by 10 on cardiogenic/septic shock, 7 on tongue infarction (due to carotid artery stenosis or systemic thrombosis), and 2 on other causes (systemic lupus erythematosus and systemic vascular amyloidosis). Among the 19 cases on vasculitis, 15 cases were reported about giant cell arteritis; 3 on polyarteritis nodosa; and 1 on necrotizing vasculitis of the tongue secondary to giant cell arteritis. In conclusion, the diagnosis of tongue/lingual necrosis is diverse and challenging because of the polymorphous clinical pattern at onset and similarity with different diseases. Our findings will be useful to clinicians in the differential diagnosis of unusual tongue/lingual necrosis cases. [ABSTRACT FROM AUTHOR]

Some members of the Toll-like receptor (TLR) family, which plays key roles in both innate and adaptive immune responses, are involved in the pathogenesis of autoimmune, chronic inflammatory and infectious diseases. However, the role of TLR in the pathogenesis of oral lichen planus (OLP) has not been investigated. The aim of this study was to understand the roles of TLR in OLP. The expression of TLR genes in OLP tissues was analyzed by cDNA microarray and reverse transcription polymerase chain reaction, and TLR protein expression in OLP tissues and peripheral blood monocytes was examined by immunohistochemical analysis and flow cytometry, respectively. Furthermore, TLR ligand-induced cytokine production from peripheral blood monocytes was measured by enzyme-linked immunosorbent assay. Among 10 TLR genes, the average expression ratio of the genes for TLR1, 2, 3, 5, 6 and 10 in OLP tissues compared to that in the normal buccal mucosae was more than 1.0. In contrast, the average ratio of the genes for TLR7, 8 and 9 was less than 1.0. TLR2 but not TLR4 was highly expressed in the cells of the spinous layer and infiltrating monocytes in OLP tissues, and the mean fluorescence intensity of TLR2 on peripheral blood monocytes was significantly higher in OLP patients than in healthy controls. Furthermore, the peripheral blood monocytes from OLP patients produced considerably higher amounts of interleukin (IL)-12 and lower amounts of IL-10 than those from healthy controls. In OLP, the T-helper cell (Th)1/Th2 balance appears to shift toward Th1 dominance, probably depending on the upregulation of TLR2 expression and these alterations in TLR2-mediated immunity may be involved in the pathogenesis and maintenance of OLP. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) repair systems are thought to be associated with the susceptibility of cancer cells to anticancer agents. The present study investigated the relationship between the susceptibility to γ-rays and the mtDNA repair ability of oral squamous cell carcinoma (OSC) cell lines. The levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and mtDNA common deletion in both nuclear and mitochondrial DNA of OSC-2, OSC-3 and OSC-6 cells (radio-sensitive cell lines) after γ-ray-irradiation were higher than those of OSC-1, OSC-4 and OSC-5 cells (radio-resistant cell lines). Compared with OSC-2, OSC-3 and OSC-6 cells, OSC-1, OSC-4 and OSC-5 cells had higher levels of activity of phosphoinositide-3 kinase (PI-3K)/Akt and more strongly expressed 8-hydroxyguanine DNA glycosylase (OGG1), DNA polymerase γ (POLG) and mitochondrial transcription factor A (Tfam). Down-regulation of these mtDNA-repair-associated molecules by the RNA interference technique enhanced the susceptibility of OSC-2 and OSC-5 cells to γ-rays, and the expression of Tfam and POLG was down-regulated by inhibitors of PI-3K/Akt signaling. These results indicate that the inhibition of mtDNA repair capacity by PI-3K/Akt signal inhibitors and OGG1 down-regulator in cancer cells may be a useful strategy for cancer treatment when combined with ionizing irradiation and chemotherapeutic drugs. ( Cancer Sci 2008; 99: 2230–2237) [ABSTRACT FROM AUTHOR]

The transcriptional factor hypoxia-inducible factor-1 (HIF-1) plays an important role in solid tumor cell growth and survival. Overexpression of HIF-1α has been demonstrated in many human tumors and predicts a poor response to chemoradiotherapy. We examined the HIF-1α-induced survival pathways in human oral squamous cell carcinoma cell (OSCC) lines. The results showed that forced expression of HIF-1α suppressed hypoxia-induced apoptosis of OSCC lines by inhibiting cytochrome c release from mitochondria. Overexpression of HIF-1α inhibited the generation of reactive oxygen species (ROS), elevation of intracellular Ca2+ concentration, reduction of mitochondrial membrane potential, and cytosolic accumulation of cytochrome c, which resulted in the inactivation of caspase-9 and caspase-3. In addition, antiapoptotic Bcl-2 and Bcl-XL levels were increased and pro-apoptotic Bax and Bak levels were decreased in the HIF-1α-overexpressing OSCC line. Overexpression of HIF-1α also increased the levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK). These findings indicate that HIF-1α prevents apoptotic cell death through two mechanisms, including inhibition of cytochrome c release and activation of Akt and ERK. ( Cancer Sci 2005; 96: 394–402) [ABSTRACT FROM AUTHOR]

The mammalian master molecular clock consisting of several clock gene products in the suprachiasmatic nucleus (SCN) drives circadian rhythms in behavior and physiology. Molecular clocks consisting of the same components also exist in various peripheral organs. DEC1 and DEC2, basic helix-loop-helix transcription factors, were recently reported to be involved in the central clock in the SCN. We examined the expression profile of DEC1 and DEC2 in the periphery and their roles in the regulation of oscillating target genes in the liver. Levels of DEC1 and DEC2 mRNA exhibited a day-night variation in various peripheral tissues of rats. In the liver, their expression was high during the subjective night. Transfection assays showed that DEC2, but not DEC1, suppressed the transcription of the cholesterol 7α-hydroxylase gene (CYP7A), overwhelming the potent enhancement by D-site binding protein (DBP). Electrophoretic mobility shift assays indicated that DEC2 binds to the E-box (CACATG) at the -219/-214 region of CYP7A. The transcriptional activities of the other sterol metabolizing cytochorme P450s (Cyps), CYP8B and CYP51, were also suppressed by DEC2 but not DEC1. DEC2, but not DEC1, works as a direct output mediator that transmits the circadian signals to the hepatic functions, including the CYP7A, CYP8B, and CYP51 expression. [ABSTRACT FROM AUTHOR]