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As an important component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) secrete energy metabolites to supply energy for tumor progression. Abnormal regulation of long noncoding RNAs (lncRNAs) is thought to contribute to glucose metabolism, but the role of lncRNAs in glycolysis in oral CAFs has not been systematically examined. In the present study, by using RNA sequencing and bioinformatics analysis, we analyzed the lncRNA/mRNA profiles of normal fibroblasts (NFs) derived from normal tissues and CAFs derived from patients with oral squamous cell carcinoma (OSCC). LncRNA H19 was identified as a key lncRNA in oral CAFs and was synchronously upregulated in both oral cancer cell lines and CAFs. Using small interfering RNA (siRNA) strategies, we determined that lncRNA H19 knockdown affected proliferation, migration, and glycolysis in oral CAFs. We found that knockdown of lncRNA H19 by siRNA suppressed the MAPK signaling pathway, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and miR-675-5p. Furthermore, the lncRNA H19/miR-675-5p/PFKFB3 axis was involved in promoting the glycolysis pathway in oral CAFs, as demonstrated by a luciferase reporter system assay and treatment with a miRNA-specific inhibitor. Our study presents a new way to understand glucose metabolism in oral CAFs, theoretically providing a novel biomarker for OSCC molecular diagnosis and a new target for antitumor therapy.

Background: Despite their high accuracy to recognize oral potentially malignant disorders (OPMDs) with cancer risk, non-invasive oral assays are poor in discerning whether the risk is high or low. However, it is critical to identify the risk levels, since high-risk patients need active intervention, while low-risk ones simply need to be follow-up. This study aimed at developing a personalized computational model to predict cancer risk level of OPMDs and explore its potential web application in OPMDs screening., Methods: Each enrolled patient was subjected to the following procedure: personal information collection, non-invasive oral examination, oral tissue biopsy and histopathological analysis, treatment, and follow-up. Patients were randomly divided into a training set (N = 159) and a test set (N = 107). Random forest was used to establish classification models. A baseline model (model-B) and a personalized model (model-P) were created. The former used the non-invasive scores only, while the latter was incremented with appropriate personal features., Results: We compared the respective performance of cancer risk level prediction by model-B, model-P, and clinical experts. Our data suggested that all three have a similar level of specificity around 90%. In contrast, the sensitivity of model-P is beyond 80% and superior to the other two. The improvement of sensitivity by model-P reduced the misclassification of high-risk patients as low-risk ones. We deployed model-P in web.opmd-risk.com, which can be freely and conveniently accessed., Conclusion: We have proposed a novel machine-learning model for precise and cost-effective OPMDs screening, which integrates clinical examinations, machine learning, and information technology., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The complex interactions between cancer cells and their surrounding stromal microenvironment play important roles in tumor initiation and progression and represent viable targets for therapeutic intervention. Here, we propose a concept of common target perturbation (CTP). CTP acts simultaneously on the same target in both the tumor and its stroma that generates a bilateral disruption for potentially improved cancer therapy. To employ this concept, we designed a systems biology strategy by combining experiment and computation to identify potential common target. Through progressive cycles of identification, TGF-β receptor III (TβRIII) is found as an epithelial-mesenchymal common target in oral squamous cell carcinoma. Simultaneous perturbation of TβRIII in the oral cancerous epithelial cells and their adjacent carcinoma-associated fibroblasts effectively inhibits tumor growth in vivo, and shows superiority to the unilateral perturbation of TβRIII in either cell type alone. This study indicates the strong potential to identify therapeutic targets by considering cancer cells and their adjacent stroma simultaneously. The CTP concept combined with our common target discovery strategy provides a framework for future targeted cancer combinatorial therapies., (©2014 AACR.)

Carcinoma-associated fibroblasts (CAFs) have been confirmed to play an important role in the occurrence and development of many kinds of tumors. Regarding proliferation as one manifestation of malignance, the objective was to observe the effects of oral CAFs on the proliferation of oral squamous carcinoma cells (OSCC) and to explore the role of keratinocyte growth factor (KGF) in this process. The results showed that oral CAFs secreted a higher level of KGF than oral normal fibroblasts (NFs), and the conditioned medium of CAFs could increase the viability of carcinoma cells and promote more of them into G2 and S phase. However, after blocking with KGF antibody, the viability and cell cycle of Tca8113 cultured with CAFs conditioned medium changed to be similar with NFs control groups. It was concluded that CAFs could promote the proliferation of OSCC through secreting high levels of KGF. These findings support the use of carcinoma-associated fibroblasts as a novel target in anticancer therapy.

Background: The purpose of this study was to assess the expression levels for TβRI, TβRII, and TβRIII in epithelial layers of oral premalignant lesions (oral leukoplakia, OLK) and oral squamous cell carcinoma (OSCC), as well as in oral carcinoma-associated fibroblasts (CAFs), with the final goal of exploring the roles of various types of TβRs in carcinogenesis of oral mucosa., Methods: Normal oral tissues, OLK, and OSCC were obtained from 138 previously untreated patients. Seven primary human oral CAF lines and six primary normal fibroblast (NF) lines were established successfully via cell culture. The three receptors were detected using immunohistochemical (IHC), quantitative RT-PCR, and Western blot approaches., Results: IHC signals for TβRII and TβRIII in the epithelial layer decreased in tissue samples with increasing disease aggressiveness (P < 0.05); no expression differences were observed for TβRI, in OLK and OSCC (P > 0.05); and TβRII and TβRIII were significantly downregulated in CAFs compared with NFs, at the mRNA and protein levels (P < 0.05). Exogenous expression of TGF-β1 led to a remarkable decrease in the expression of TβRII and TβRIII in CAFs (P < 0.05)., Conclusion: This study provides the first evidence that the loss of TβRII and TβRIII expression in oral epithelium and stroma is a common event in OSCC. The restoration of the expression of TβRII and TβRIII in oral cancerous tissues may represent a novel strategy for the treatment of oral carcinoma.

Therapeutic radiation is commonly used in the treatment of squamous cell carcinoma of the oral cavity and pharynx. Despite the proven efficacy of this form of anticancer therapy, high-dose radiation treatment is invariably associated with numerous unwanted side effects. This is particularly true for bone, in which radiation treatment often leads to osteoradionecrosis. The aim of this study was to investigate if treatment with arsenic trioxide (As(2)O(3)) could enhance the antitumor effect of radiotherapy whereas minimizing the destructive effects of radiation on bone. As(2)O(3) treatment induced a dose-dependent (1-20 mumol/L) inhibition of endothelial and tumor cell (OSCC-3 and UM-SCC-74A) survival and significantly enhanced radiation-induced endothelial cell and tumor cell death. In contrast, As(2)O(3) treatment (0.5-7.5 mumol/L) induced the proliferation of osteoblasts and also protected osteoblasts against radiation-induced cell death. Furthermore, As(2)O(3) treatment was able to significantly enhance radiation-induced inhibition of endothelial cell tube formation and tumor cell colony formation. To test the effectiveness of As(2)O(3) and radiation treatment in vivo, we used a severe combined immunodeficiency mouse model that has a bone ossicle and tumor growing side by side subcutaneously. Animals treated with As(2)O(3) and radiation showed a significant inhibition of tumor growth, tumor angiogenesis, and tumor metastasis to the lungs as compared with As(2)O(3) treatment or radiation treatment alone. In contrast, As(2)O(3) treatment protected bone ossicles from radiation-induced bone loss. These results suggest a novel strategy to enhance the therapeutic efficacy of radiation treatment while protecting bone from the adverse effects of therapeutic radiation.

Objective: The purpose of this study was to investigate the indication and therapeutic effects of Pingyangmycin injection as a primary therapy of lymphangiomas in oral, maxillofacial and cervical region., Methods: A total of 195 patients (106 males and 89 females) with lymphangiomas in oral and maxillofacial regions were treated in the affiliated dental hospital of Sichuan University from May 1990 to December 2000. The patients' ages ranged from 0.5 to 46 years. The tongue was the most commonly involved site, followed by the cheek and the neck. The 200 lymphangiomas (5 patients had 2 lymphangiomas in different sites) underwent the therapy of Pingyangmycin, which was injected as with 1 mg/ml in saline. The total dose of Pingyangmycin ranged from 5 mg to 70 mg and 5 to 58 times, 1 time per 2-4 weeks., Results: The curative rate of cystic-type lymphangiomas was the highest. Of the 51 cystic lymphangiomas, 110 capillary lymphangiomas, 18 cavernous lymphangiomas and 21 combinations of capillary and cavenous lymphangiomas, the curative rates were respectively 100% (51), 46.36% (51), 16.16% (3) and 19.05% (4), which showed a significant therapeutic effect, respectively. And 40(78.43%), 19(17.27%), 2(11.11%) and 0(0%) of them completely disappeared. There was no serious side effect with Pingyangmycin-injection treatment, such as pulmonary fibrosis., Conclusion: The treatment of injection of Pingyangmycin is a selective primary method of lymphangiomas, which can reduce the size of lymphangiomas, and make them completely disappeared.