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-b receptor III (TbRIII) is found as an epithelialmesenchymal common target in oral squamous cell carcinoma. Simultaneous perturbation of TbRIII 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 TbRIII 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. Cancer Res; 74(8); 2306-15. Ó2014 AACR.
BackgroundDespite 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.MethodsEach 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.ResultsWe 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.ConclusionWe have proposed a novel machine‐learning model for precise and cost‐effective OPMDs screening, which integrates clinical examinations, machine learning, and information technology.
Protein regulator of cytokinesis 1 (PRC1), a microtubule-associated protein, has emerged as a critical regulator of proliferation and apoptosis, acting predominantly in numerous tumors. However, its function in oral squamous cell carcinoma (OSCC) is still unknown. To establish the roles of PRC1 in OSCC, 95 oral clinical samples (54 OSCC, 24 oral leukoplakia [OLK], and 17 normal oral mucosa) and seven oral cell lines (6 OSCC and 1 normal oral cell lines) were analyzed using a series of molecular and genomic assays both in vivo and in vitro were conducted in this study. Herein, we provide evidence demonstrating that expression of PRC1 closely correlates with the degree of epithelial dysplasia in OLK (n = 24) (p < 0.001), and the poor differentiation, large tumor volume, lymph node metastasis, and high-clinical stage in OSCC (n = 54) (p < 0.05), illustrating that PRC1 has a promotive influence on tumor progression in OSCC. Simultaneously, we observed that PRC1 knockdown in OSCC cell lines caused G2/M phase arrest (p < 0.05), inhibited cell proliferation in vitro (p < 0.05) and tumor growth in vivo (p < 0.001). Furthermore, the effects of PRC1 on the regulation of proliferation and cell cycle transition in OSCC samples were mediated by p53. The p53/PRC1/EGFR signaling pathway was found to be implicated in the tumor progression of OSCC. Based on our data, we demonstrate that PRC1 is a key factor in regulating proliferation and the cell cycle, pointing to the potential benefits of PRC1-targeted therapies for OSCC.
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