The Regulatory Role of Non-coding RNAs on Programmed Cell Death Four in Inflammation and Cancer.

Programmed cell death 4 (PDCD4) is a tumor suppressor gene implicated in many cellular functions, including transcription, translation, apoptosis, and the modulation of different signal transduction pathways. The downstream mechanisms of PDCD4 have been well-discussed, but its upstream regulators have not been systematically summarized. Noncoding RNAs (ncRNAs) are gene transcripts with no protein-coding potential but play a pivotal role in the regulation of the pathogenesis of solid tumors, cardiac injury, and inflamed tissue. In recent studies, many ncRNAs, especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), were found to interact with PDCD4 to manipulate its expression through transcriptional regulation and function as oncogenes or tumor suppressors. For example, miR-21, as a classic oncogene, was identified as the key regulator of PDCD4 by targeting its 3'-untranslated region (UTR) to promote tumor proliferation, migration, and invasion in colon, breast, and bladder carcinoma. Therefore, we reviewed the recently emerging pleiotropic regulation of PDCD4 by ncRNAs in cancer and inflammatory disorders and aimed to shed light on the mechanisms of associated diseases, which could be conducive to the development of novel treatment strategies for PDCD4-induced diseases.

Tumor cell-derived TGF-ß at tumor center independently predicts recurrence and poor survival in oral squamous cell carcinoma.

BACKGROUND: Transforming growth factor-ß (TGF-ß) exerts its versatile function (oncogenic or tumor suppressive role) during the carcinogenesis in tumor microenvironment-dependent manner. Considering the tumor heterogeneity, spatial and temporal distribution of TGF-ß in oral squamous cell carcinoma (OSCC) remained to be elucidated. METHODS: Formalin-fixed, paraffin-embedded sections derived from 73 patients with OSCC were immunostained, revealing expression patterns of TGF-ß, both at the regions of tumor center (TC) and invasive tumor front (ITF). RESULTS: The TGF-ß levels on tumor cells, fibroblast-like cells (FLCs), and tumor-infiltrating lymphocytes (TILs) were comparable and showed to be cell-type-independent manner. Although TC regions harbored less positive staining of TGF-ß than ITF in tumor cells (TGF-ßTumor cell ) (89.0% vs 98.3%; P = 0.037), FLCs (TGF-ßFLC ) (86.3% vs 96.6%; P = 0.043), and TILs (TGF-ßTIL ) (83.6% vs 94.8%; P = 0.044), respectively, TGF-ß at TC regions, not at ITF, correlated to poor clinical outcomes. At TC regions, patients with high TGF-ßTumor cell had high recurrence rate, and patients with high TGF-ßTIL showed inferior worst pattern of invasion. Of note, high TGF-ßTumor cell at TC predicted shorter overall survival time, recurrence-free survival, and disease-free survival in patients with OSCC, whereas high TGF-ßTIL had no association with survival time. Cox regression analyses indicated that tumor cell-derived TGF-ß at TC was an independent risk factor for survival outcome in patients with OSCC. CONCLUSIONS: Tumor cell-derived TGF-ß at TC regions, but not at ITF, could be a promising predictor for disease recurrence and poor prognosis of patients with OSCC.

Higher Ki67 expression in fibroblast like cells at invasive front indicates better clinical outcomes in oral squamous cell carcinoma patients.

Background: Ki67 has been a key role for the treatment options and prognosis evaluation in some kinds of tumors; however, the spatial expression of Ki67 in oral squamous cell carcinoma (OSCC) has not been fully-evaluated. Therefore, in the present study, we aimed to elucidate the prognosis value of Ki67 spatial expression including in different cell types and at different compartments of tumor in OSCC patients. Methods: Immunohistochemical expression of Ki67 in tumor cells (TCs) and fibroblast like cells (FLCs) at center of tumor (CT) and invasive front (IF) was evaluated in 109 OSCC patients. Then correlations of Ki67 expressions with clinicopathological parameters were analyzed by Chi-square test, and survival curves were evaluated by Kaplan-Meier methods. Furthermore, univariate and multivariate analysis were performed to assess the diagnostic values of Ki67 expression by the Cox regression model. Results: Ki67 expression in TCs was much higher than in FLCs both at CT and IF compartments, but Ki67 expression in TCs was simultaneously higher at CT than that at IF (P=0.0004), which was converse to Ki67 expression in FLCs (P<0.0001). Additionally, high Ki67 expression in FLCs at IF was significantly associated with poor tumor differentiation (P=0.003), worse depth of invasion (DOI, P=0.027) and worst pattern of invasion (WPOI, P=0.041), but Ki67 expression in TCs had no correlation with clinical parameters no matter at CT or IF. Moreover, patients with higher Ki67 expression in TCs at CT had significantly increased risk for OS (overall survival; HR:1.935, 95% CI: 1.181-4.823, P=0.0395) and DFS (disease-free survival; HR: 2.974, 95% CI:1.189-5.023, P=0.046). On contrary, higher Ki67 expression in FLCs at IF was correlated with better OS (HR: 0.15, 95% CI: 0.018-0.846, P=0.0396) and DFS (HR: 0.15, 95% CI: 0.018-0.947, P=0.0445). Whereas, Ki67 expression both at TCs in IF and at FLCs in CT had no significant prognostic value for OS and DFS. Furthermore, Cox multivariate analysis revealed that Ki67 expression in FLCs at IF could not be an independent prognostic factor for OSCC patients. Conclusion: These results show that higher Ki67 expression in FLCs at IF indicated better clinical outcomes for OSCC patients.