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  • thapsigargin Only a limited number of studies have ever expl

    2019-04-28

    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 thapsigargin 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. Previous studies have demonstrated localization of miR-21 staining in stromal cells of OSCC associated with the tongue and mouth floor—this might be a useful prognostic predictor. We also observed miR-21 staining in the stromal cells of tumors. However, since multiple lines of evidence indicate the involvement of miR-21 in the aggressiveness of OSCC, our approach has rather focused on studying the epithelial tumor cells. We have been able to show that there is modest miR-21 staining in the tumor cell component of OSCC, and that this activity is involved in modulating cell migration in OSCC cells. It seems likely that the discrepancies among oral sites, in the clinical stage of the tumor and in the race of the patient, may underlie the differences in stromal miR-21 staining that occur across different study subsets. Decreased expression of PTEN is an indicator of a poor prognosis in many cancers, including colorectal cancer, prostate cancer, and breast cancer. A deficiency of PTEN expression is also a poorly prognostic factor for OSCC. As miR-21 targets multiple oncogenic events, including PTEN, during pathogenesis, and because PTEN is an inhibitor of the activator PI3K/AKT/S6 pathway, our study was able to show a reverse association between miR-21 expression and PTEN expression. Nevertheless, our analysis also showed high immunoreactivity for phosphor-S6 across all OSCC samples in this cohort, even in tumors with medium PTEN immunoreactivity. Similar ambiguity is found in other studies. Therefore, this study is unable to link PNI to the PI3K/AKT pathway. Our results seem to imply that, although miR-21-PTEN cascade may reinforce OSCC cells with a PNI propensity, the PI3K/AKT/S6 pathway does not seem to be the single factor involved in causing PNI in OSCC. These findings are in agreement with a previous investigation of PNI associated with pancreatic carcinoma. In conclusion, this study provides a new line of evidence demonstrating that there is an association between miR-21-PTEN disregulation and PNI in OSCC. miR-21 is an independent factor associated with disease-free survival in OSCC. High miR-21 expression is able to predict worse prognosis among OSCC patients. Our data also hint that miR-21 expression may be an indicator of PNI-positive and more aggressive treatment may be of benefit to the OSCC patient without PNI in the surgical specimen.