Anti-Cancer Activity of the Combinational Treatment of Noozone Cold Plasma with p-FAK Antibody-Conjugated Gold Nanoparticles in OSCC Xenograft Mice.

Oral squamous cell cancer (OSCC) is the most common type of oral cancer (about 80-90% of cases) and various research is being done to cure the disease. This paper aims to verify whether treatment with no-ozone cold plasma (NCP), which is designed for safe usage of the plasma on oral cavities, in combination with gold nanoparticles conjugated with p-FAK antibody (p-FAK/GNP) can trigger the selective and instant killing of SCC-25 cells both in vitro and in vivo. When SCC25 and HaCaT cells are exposed to p-FAK/GNP+NCP, the instant cell death was observed only in SCC25 cells. Such p-FAK/GNP+NCP-mediated cell death was observed only when NCP was directly treated on SCC25 harboring p-FAK/GNP. During NCP treatment, the removal of charged particles from NCP using grounded electric mesh radically decreased the p-FAK/GNP+NCP-mediated cell death. This p-FAK/GNP+NCP-mediated selective cell death of OSCC was also observed in mice xenograft models using SCC25 cells. The mere treatment of p-FAK/GNP and NCP on the xenograft tumor slowly decreased the size of the tumor, and only about 50% of the tumor remained at the end of the experiment. On the other hand, 1 week of p-FAK/GNP+NCP treatment was enough to reduce half of the tumor size, and most of tumor tissue had vanished at the end. An analysis of isolated tissues showed that in the case of individual treatment with p-FAK/GNP or NCP, the cancer cell population was reduced due to apoptotic cell death. However, in the case of p-FAK/GNP+NCP, apoptotic cell death was unobserved, and most tissues were composed of collagen. Thus, this paper suggests the possibility of p-FAK/GNP+NCP as a new method for treating OSCC.

Mesenchymal stem cell-exosome-mediated matrix metalloproteinase 1 participates in oral leukoplakia and carcinogenesis by inducing angiogenesis.

BACKGROUND: In the malignant progression of oral leukoplakia (OLK) to oral squamous cell carcinoma (OSCC), the density of microvessels and expression of angiogenesis-related molecules increases. Emerging evidence indicates that mesenchymal stem cells (MSCs) play an indispensable role in the tumor microenvironment. However, the role and mechanism of action of oral MSCs in inducing angiogenesis remain unclear. Therefore, it is necessary to explore the molecules and mechanisms that play a role in the tissue microenvironment. METHODS: Exosomes were collected from normal oral mucosa (N-Exo), OLK (OLK-Exo), and OSCC (Ca-Exo) MSCs, and their pro-angiogenic capacity was evaluated in human umbilical vein endothelial cells (HUVECs) and a subcutaneously implanted tumor model in nude mice. Quantitative proteomics analysis was used to compare the exosome-derived proteins between N-Exo, OLK-Exo, and Ca-Exo. RESULTS: Compared with that of the N-Exo and control, OLK-Exo and Ca-Exo treatment significantly promoted HUVEC migration, invasion, and tube-formation capability. In the nude mice model, immunofluorescence of CD31 showed that OLK-Exo and Ca-Exo substantially improved neovascularization around the grafts. Quantitative proteomics analysis revealed that matrix metalloproteinase 1 (MMP1) levels were significantly higher in the OLK-Exo and Ca-Exo groups than in the N-Exo groups. Silencing MMP1 expression reversed the functional promoting effect of OLK-Exo and Ca-Exo on HUVECs. CONCLUSION: Exosomes from OLK-MSCs and Ca-MSCs have a stronger pro-angiogenic ability through high MMP1 content. This new finding provides insight into the intervention with the secretion of MSC-derived exosomes, which may be an innovative strategy for carcinogenesis.

Trichosanthin cooperates with Granzyme B to restrain tumor formation in tongue squamous cell carcinoma.

BACKGROUND: Tongue squamous cell carcinoma (TSCC) is a common type of oral cancer, with a relatively poor prognosis and low post-treatment survival rate. Various strategies and novel drugs to treat TSCC are emerging and under investigation. Trichosanthin (TCS), extracted from the root tubers of Tian-Hua-Fen, has been found to have multiple biological and pharmacological functions, including inhibiting the growth of cancer cells. Granzyme B (GrzB) is a common toxic protein secreted by natural killer cells and cytotoxic T cells. Our group has reported that TCS combined with GrzB might be a superior approach to inhibit liver tumor progression, but data relating to the use of this combination to treat TSCC remain limited. The aim of this study was to examine the effectiveness of TCS on TSCC processes and underlying mechanisms. METHODS: First, we screened the potential antitumor activity of TCS using two types of SCC cell lines. Subsequently, a subcutaneous squamous cell carcinoma xenograft model in nude mice was established. These model mice were randomly divided into four groups and treated as follows: control group, TCS treatment group, GrzB treatment group, and TCS/GrzB combination treatment group. Various tumorigenesis parameters, such as Ki67, PCNA, caspase-3, Bcl-2 and VEGFA, et al., were performed to determine the effects of these treatments on tumor development. RESULTS: Screening confirmed that the SCC25 line exhibited greater sensitivity than the SCC15 line to TCS in vitro studies. TCS or GrzB treatment significantly inhibited tumor growth compared with the inhibition seen in the control group. The TCS/GrzB combination inhibited tumor growth more than either drug alone. TCS treatment inhibited tumor proliferation by downregulating Ki67 and Bcl2 protein expression while accelerating tumor apoptosis. In the TCS/GrzB-treated group, expression of Ki67 was further downregulated, while the level of activated caspase-3 was increased, compared with their expression in either of the single drug treatment groups. CONCLUSION: These results suggest that the TCS/GrzB combination could represent an effective immunotherapy for TSCC.

Cigarette smoke, saliva, the translocator protein 18 kDa (TSPO), and oral cancer.

Oral squamous cell carcinoma (OSCC) incidence is induced primarily by cigarette smoke (CS). The 5-year survival rate for advanced OSCC stands at only 20%. Studies exploring underlying mechanisms of OSCC development have suggested free radicals such as reactive oxygen species generated by CS as contributing to OSCC, with effects enhanced by transition metal ions iron and copper contained in the saliva. Located on the outer mitochondrial membrane of various cell types, the 18-kDa translocator protein (TSPO) is up-regulated under pathological conditions such as cancer and inflammation. We focused on studying the interaction between TSPO, CS, salivary effects, and OSCC. Increased TSPO expression in OSCC tumors correlates significantly with reduced patient survival rate, indicating the possible role of TSPO in OSCC pathogenesis. We speculate that TSPO in OSCC is dysfunctional or mutated, rendering it ineffective in promoting apoptosis and blocking malignant transformation. Basal, precancer lower function of TSPO may diminish the TSPO capacity for pro-apoptotic and anti-cancer activity, resulting in development of OSCC. In order to overcome this, TSPO over-expression is induced, unfortunately with no benefit, as it is a malfunctioning TSPO, similar to cases where over-expression of a mutated form of the p53 gene in tumors is associated with carcinogenesis.

Polymorphisms in four microRNAs and risk of oral squamous cell cancer: a meta-analysis.

OBJECTIVES: Single nucleotide polymorphisms in microRNAs (microRNA-196a2 rs11614913, microRNA-146a rs2910164, microRNA-149 rs2292832 and microRNA-499 rs3746444) have been inconsistently associated with risk for oral squamous cell cancer (OSCC). This meta-analysis aimed to assess the correlation between microRNA polymorphisms and susceptibility to OSCC. MATERIALS AND METHODS: Free words were used to search for the relevant studies without language limitations in electronic databases including PubMed, Embase, Web of Science and SCOPUS through June 15, 2017. Odds ratios (ORs) were calculated to investigate the effects of microRNA polymorphisms on oral cancer risk. RESULTS: Eleven studies were included. Analysis under the recessive model of microRNA-146a (CC vs GG+CG) showed significant differences (ORs = 0.874, P = 0.041). The G allele and the GG genotype of microRNA-499 were associated with OSCC risk (ORs >1, P < 0.05). MicroRNA-196a2 rs11614913 and microRNA-149 polymorphisms appeared to have no relationship with OSCC risk (P > 0.05). In the sensitivity analysis, there was a significant association between the TT genotype of microRNA-196a2 and OSCC risk (TT vs TC + CC, ORs < 1, P < 0.05). CONCLUSIONS: There may be no significant relationship between microRNA-149 polymorphisms and OSCC risk, and the CC genotype of microRNA-146a may have protective effects against oral cancer. However, the G allele and the GG genotype of microRNA-499 may increase OSCC risk.

Oral squamous cell cancer protein-protein interaction network interpretation in comparison to esophageal adenocarcinoma.

AIM: The aim of this study is to present the oral Squamous Cell Cancer protein-protein interaction network interpretation in comparison to esophageal adenocarcinoma. BACKGROUND: Oral squamous cell cancer (OSCC) is a common disease worldwide, with poor prognosis and limited treatment. Thus, introducing molecular markers through network analysis can be helpful. METHODS: STRING database (DB) was applied for network construction through Cytoscape 3.4.0. Clue GO handled the gene annotation for the retrieved clusters. Eight proteins were indicated to be differential in the network constitution. RESULTS: The centrality and clustering analysis indicate that TP53 plays an over-significant role in network integrity among eight most central proteins including TP53, AKT1, EGFR, MYC, JUN, CDH1, CCND1, and CTNNB1. The suggested biomarker set is very similar to the related biomarker panel of esophageal adenocarcinoma. CONCLUSION: The ontology analysis implies that the prominent proteins are involved in regulation of smooth muscle cell proliferation, regulation of fibroblast proliferation, and response to UV-A processes. In conclusion, these proteins and their associated biological processes may be more critical compared to other reported biomarkers for OSCC. Nevertheless, validation studies are required for confirming the pivotal role of potential candidates. Similar biomarker panel of this disease and esophagus adenocarcinoma is corresponded to the origin of the two malignancies.