br Introduction Incidence of oral cancers accounts for

Introduction Incidence of oral cancers accounts for ∼3% of all malignancies. Oral squamous cell carcinoma (OSCC) accounts for >95% of all malignancies in the oral cavity, and it is the fifth leading cause of cancer death in the male population in Taiwan. OSCC is treated mainly with surgery. Postoperative adjuvant treatment, (radiotherapy or chemo-radiotherapy) is followed according to the pathological results. The pathological results include several clinicopathological factors: tumor size and nodal metastasis (the TNM system), lymphovascular permeation, perineural invasion, tumor invasion front, differentiation, and tumor depth. This means that identifying the clinicopathologic factors is important to the survival of OSCC patients. Unfortunately, these data were collected at the tissue level, not the cellular level, and there was no reliable method to detect those factors in the surgical specimens except microscopic examination by a pathologist. That suggested to us that small cancer with aggressive behavior could be undertreated because such poor prognosis factors might not be detected in the early stages. MicroRNAs (miRNA) are small noncoding RNAs that mediate the translational repression of target messenger RNAs. miRNA disruption is known to play a number of important roles in the neoplastic process, including OSCC.miR-21, which functions as an oncogene, is noticeably upregulated in most human malignancies, including OSCC.In vivo and in vitro studies have also found that miR-21 is able to serve as a diagnostic/prognostic marker for cancer therapy. In addition, recent studies have shown that miR-21 was expressed in the stromal enba of OSCC that had arisen from the tongue and floor of the mouth. Phosphatidylinositol-3-kinase (PI3K)/AKT has been shown to play important roles in the neoplastic process, especially in the regulation of proliferation and invasion by tumor cells. Only a limited number of studies have ever explored the correlation of miRNAs and the clinicopathological factors. In this study, we investigated the relationship between the expression of miR-21 and clinicopathologic factors in OSCC and explored its possible mechanism. Our purpose was to find a more specific cellular level factor, not the clinicopathological factor, to indicate the prognosis of OSCC patient.
Methods
Results
Discussion Our data supported that miR-21 was an independent factor of disease-free survival in OSCC patients. Our results led us to identify the relationship between miR-21 and PNI in OSCC. miR-21 could promote cancer cells to invade the nerve bundle and spread out. The miR-21/PNI pathway was likely to decrease the expression of PTEN, but its mechanism was still not clear. PNI is a situation and process whereby nerve bundles are invaded by cancer cells. PNI is neither an extension of lymphatic metastasis nor simply tumor cell migration through a low-resistance plane but is instead a distinctive pathological or programmed response to nerve attraction that would seem to be independent from lymphatic or vascular invasion. PNI has been recognized as a prognostic indicator of poor survival in many types of malignancies. It has also been considered to be an indicator of a poor prognosis in OSCC in several studies. However, the molecular mechanisms of PNI have been unclear. Since adjuvant radiotherapy does not appear to reduce the incidence of disease recurrence in PNI-positive patients, understanding the mechanism of PNI in order to help the development of an appropriate target agent is critical. In the future, the blockage of miR-21 and of other factors related to the facilitation of PNI need to be validated as adjuvant therapeutic approaches that might help to counteract perineural tumor spreading; such an approach should help to improve patient prognosis. Previous reports have shown that miR-21 is overexpressed in many solid tumors; furthermore, this overexpression has been shown to be related to tumor progression in hepatocellular carcinomas, breast cancers, and colon carcinoma. Therefore, miR-21 seems to be a useful prognostic factor for various kinds of malignancies. Studies also showed the high expression levels of miR-21 in OSCC are associated with a poorer prognosis for patients. In our study, we have also shown that cases with high miR-21 expression have a significantly worse disease progression. This implies that cases with high miR-21 are suitable for aggressive treatment option, for example, selective neck dissection or adjuvant therapy. Analysis of miR-21 expression may be particularly useful when carrying out a prognostic evaluation of this patient subset.