田中 知明

Although the E3 ligase Mdm2 and its homologue and binding partner MdmX are the major regulators of the p53 tumor suppressor protein, it is now evident that Mdm2 and MdmX have multiple functions that do not involve p53. As one example, it is known that Mdm2 can regulate cell migration, although mechanistic insight into this function is still lacking. Here we show in cells lacking p53 expression that knockdown of Mdm2 or MdmX, as well as pharmacological inhibition of the Mdm2/MdmX complex, not only reduces cell migration and invasion, but also impairs cell spreading and focal adhesion formation. In addition, Mdm2 knockdown decreases metastasis in vivo. Interestingly, Mdm2 downregulates the expression of Sprouty4, which is required for the Mdm2 mediated effects on cell migration, focal adhesion formation and metastasis. Further, our findings indicate that Mdm2 dampening of Sprouty4 is a prerequisite for maintaining RhoA levels in the cancer cells that we have studied. Taken together we describe a molecular mechanism whereby the Mdm2/MdmX complex through Sprouty4 regulates cellular processes leading to increase metastatic capability independently of p53.

Objective: Pancreatic neuroendocrine neoplasms (pNENs) are histologically classified as well-differentiated, poorly-differentiated, or mixed neuroendocrine-non-neuroendocrine neoplasms. There are unresectable pNENs owing to metastases or invasion in not only functional pNENs but also non-functional. However, the exact origin of pNENs has not been elucidated. This study aims to characterize the molecular biology of pNENs based on clinical information and histopathological analysis and identify prognostic biomarkers. Methods: We investigated the relationship between the biological characteristics and immunostaining of pathological tissues in 75 patients. Staining density was evaluated on a 4-point scale from 0 to 3, and the percentage of tumor cells was calculated and scored from 0 to 300 (H-score). We performed receiver operating characteristic (ROC) curve analysis of the H-score. Progression-free survival and overall survival analyses were performed based on the Kaplan–Meier curves. Results: The H-score showed that patients who died of pNEN had high Ki-67 and low somatostatin receptor (SSTR) 2 levels, and those who relapsed had high Ki-67 and low SSTR5 levels. The ROC showed that the SSTR2 H-score > 80.25 was associated with lower mortality, which was further confirmed by Kaplan–Meier curves [hazard ratio (HR): 6.039, 95 % confidence interval (CI): 1.233–29.59, P = 0.0006). SSTR5 H-score > 93.9 had less recurrence, which was confirmed using Kaplan–Meier curves (HR: 3.321, 95 % CI: 1.426–7.734, P = 0.0336). Conclusion: Ki-67 > 4.95 is associated with a significantly increased risk of death. Quantification of SSTR2 and SSTR5 immunostaining using the H-score may serve as prognostic markers.