microRNAs (miRNAs) are a class of non‐coding RNAs that function as endogenous triggers of the RNA interference pathway. Studies have shown that thousands of human protein‐coding genes are regulated by miRNAs, indicating that miRNAs are master regulators of many important biological processes, such as cancer development. miRNAs frequently have deregulated expression in many types of human cancers, and play critical roles in tumorigenesis, which functions either as tumor suppressors or as oncogenes. Recent studies have shown that miRNAs are highly related with cancer progression, including initiating, growth, apoptosis, invasion, and metastasis. Furthermore, miRNAs are shown to be responsible for the cancer‐related inflammation, anti‐cancer drug resistance, and regulation of cancer stem cells. Therefore, miRNAs have generated great interest as a novel strategy in cancer diagnosis and therapy. Here we review the versatile roles of miRNAs in cancers and their potential applications for diagnosis, prognosis, and treatment as biomarkers.
Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair‐defective tumors, in particular homologous recombination (HR), are highly sensitive to DNA‐damaging agents. Thus, HR‐defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly (adenosine diphosphate (ADP)‐ribose) polymerase (PARP) inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR‐defective tumor cells.
Oral squamous cell carcinoma (OSCC) has a high incidence of cervical micrometastases and sometimes metastasizes contralaterally because of the rich lymphatic intercommunications relative to submucosal plexus of oral cavity that freely communicate across the midline, and it can facilitate the spread of neoplastic cells to any area of the neck consequently. Clinical and histopathologic factors continue to provide predictive information to contralateral neck metastases (CLNM) in OSCC, which determine prophylactic and adjuvant treatments for an individual patient. This review describes the predictive value of clinical‐histopathologic factors, which relate to primary tumor and cervical lymph nodes, and surgical dissection and adjuvant treatments. In addition, the indications for elective contralateral neck dissection and adjuvant radiotherapy (aRT) and strategies for follow‐up are offered, which is strongly focused by clinicians to prevent later CLNM and poor prognosis subsequently.
The presence of matrix metalloproteinase‐2 (MMP‐2) in dentin has been reported, but its distribution and activity level in mature human coronal dentin are not well understood. The purpose of this study was to determine the MMP‐2 distribution and relative activity in demineralized dentin. Crowns of twenty eight human molars were sectioned into inner (ID), middle (MD), and outer dentin (OD) regions and demineralized. MMP‐2 was extracted with 0.33 mol·L−1 EDTA/2 mol·L−1 guanidine‐HCl, pH 7.4, and MMP‐2 concentration was estimated with enzyme‐linked immunoabsorbant assay (ELISA). Further characterization was accomplished by Western blotting analysis and gelatin zymography. The mean concentrations of MMP‐2 per mg dentin protein in the dentin regions were significantly different (P=0.043): 0.9 ng (ID), 0.4 ng (MD), and 2.2 ng (OD), respectively. The pattern of MMP‐2 concentration was OD>ID>MD. Western blotting analysis detected ∼66 and ∼72 kDa immunopositive proteins corresponding to pro‐ and mature MMP‐2, respectively, in the ID and MD, and a ∼66 kDa protein in the OD. Gelatinolytic activity consistent with MMP‐2 was detected in all regions. Interestingly, the pattern of levels of Western blot immunodetection and gelatinolytic activity was MD>ID>OD. The concentration of MMP‐2 in human coronal dentin was highest in the region of dentin that contains the dentinoenamel junction and least in the middle region of dentin. However, levels of Western blot immunodetection and gelatinolytic activity did not correlate with the estimated regional concentrations of MMP‐2, potentially indicating region specific protein interactions.
Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16INK4A and promyelocytic leukemia protein (PML) in normal cells. E2F‐binding protein 1 (E2FBP1), a transcription regulator for E2F, induces PML reduction and suppresses the formation of PML‐nuclear bodies, whereas the down‐regulation of E2FBP1 provokes the PML‐dependent premature senescence in human normal fibroblasts. Here we report that the depletion of E2FBP1 induces the accumulation of PML through the Ras‐dependent activation of MAP kinase signaling. The cellular levels of p16INK4A and p53 are elevated during premature senescence induced by depletion of E2FBP1, and the depletion of p16INK4A, but not p53 rescued senescent cells from growth arrest. Therefore, the premature senescence induced by E2FBP1 depletion is achieved through the p16INK4A‐Rb pathway. Similar to human normal fibroblasts, the growth inhibition induced by E2FBP1 depletion is also observed in human tumor cells with intact p16INK4A and Rb. These results suggest that E2FBP1 functions as a critical antagonist to the p16INK4A‐Rb tumor suppressor machinery by regulating PML stability.
Periodontal disease has been recently linked to a variety of systemic conditions such as diabetes, cardiovascular disease, preterm delivery, and oral cancer. The most common bacteria associated with periodontal disease, Porphyromonas gingivalis (P. gingivalis) has not yet been studied in the malignant gingival tissues. The objective of this study was to investigate the presence of P. gingivalis in specimens from squamous cell carcinoma patients. We have performed immunohistochemical staining to investigate the presence of P. gingivalis and Streptococcus gordonii (S. gordonii), a non invasive oral bacteria, in paraffin embedded samples of gingival squamous cell carcinoma (n=10) and normal gingiva (n=5). Staining for P. gingivalis revealed the presence of the bacteria in normal gingival tissues and gingival carcinoma, with higher levels (more than 33%, P<0.05) detected in the carcinoma samples. The staining intensity was also significantly enhanced in the malignant tissue by 2 folds (P<0.023) compared to specimens stained for the non‐invasive S. gordonii. P. gingivalis is abundantly present in malignant oral epithelium suggesting a potential association of the bacteria with gingival squamous cell carcinoma.
Although a few studies have shown that vascularity is increased from normal mucosa to dysplasia to carcinoma suggesting that disease progression in the oral mucosa is accompanied by angiogenesis. The role in lymph node metastasis in oral squamous cell carcinoma (OSCC) is equivocal. Role of angiogenesis in OSCC development and metastasis is evaluated in this study. This retrospective study of 50 samples consisted of 9 normal buccal mucosa, 22 leukoplakias, and 19 OSCC. Polyclonal antibodies to von‐Willebrand factor were used to highlight the microvessels. Images were captured and morphometric image analysis was done for microvessel density (MVD), area, and perimeter. Highest, as well as mean values of these three parameters were compared. MVD and perimeter, but not area, are significantly different between normal mucosa and OSCC, and leukoplakia and OSCC. There were no differences between normal mucosa and leukoplakia. MVD, area, and perimeter were not significantly different between the OSCC with and without lymph node metastasis. The highest and mean values of MVD are significantly correlated. In the development of OSCC, angiogenic phenotypic change occurs in carcinomas rather than in the pre‐cancerous stage, and quantification of angiogenesis in OSCC does not predict the risk of lymph node metastasis.
We present a case of a patient with rare anatomy of a maxillary second molar with three mesiobuccal root canals and a maxillary third molar with four separate roots, identified using multi‐slice computed topography (CT) and three‐dimensional reconstruction techniques. The described case enriched/might enrich our knowledge about possible anatomical aberrations of maxillary molars. In addition, we demonstrate the role of multi‐slice CT as an objective tool for confirmatory diagnosis and successful endodontic management.
