Bone morphogenetic protein-7 expression reflects the high proliferative ability and aggressiveness of thymic epithelial tumors.

BACKGROUND: Bone morphogenetic protein-7 (BMP-7) is a transforming growth factor-ß superfamily member. We examined whether BMP-7 expression in thymic epithelial tumors is associated with their clinicopathological features. METHODS: One hundred and thirty-two clinical specimens were analyzed in this study. The expression of BMP-7 was detected using immunohistochemistry and was scored as 0, 1, 2, or 3 according to its intensity and was then classified as negative (score 0 and 1) or positive (2 and 3). In addition, Ki-67 staining was performed in type B3 thymoma and thymic cancer. RESULTS: The positive ratio of BMP-7 was 80% in thymic cancer and 70% in thymoma type B3. In contrast, the positive ratios of BMP-7 in type B2 (29.1%), B1 (3.7%), AB (26%), and A (31%) were relatively low. The mean Ki-67 labeling index of the BMP-7 positive group (10.1%±5.9%) was significantly higher than that of the BMP-7 negative group (4.9%±5.9%) in type B3 thymoma and thymic cancer (P=0.012). The BMP-7 positive group showed significantly poorer overall survival (OS) than the BMP-7 negative group across all patients with thymic epithelial tumors and in all types of thymomas (P=0.006, P=0.018); however, no difference was observed in thymic cancers. CONCLUSIONS: This study showed that high expression of BMP-7 correlated with a poor prognosis in patients with thymic epithelial tumors, and the expression of BMP-7 was higher in type B3 thymomas and thymic cancers than in other types of thymomas. BMP-7 might serve as a novel prognostic biomarker for thymic epithelial tumors.

Induction of the SHARP-2 mRNA level by insulin is mediated by multiple signaling pathways.

The rat enhancer of split- and hairy-related protein-2 (SHARP-2) is an insulin-inducible transcription factor which represses transcription of the rat phosphoenolpyruvate carboxykinase gene. In this study, a regulatory mechanism of the SHARP-2 mRNA level by insulin was analyzed. Insulin rapidly induced the level of SHARP-2 mRNA. This induction was blocked by inhibitors for phosphoinositide 3-kinase (PI 3-K), protein kinase C (PKC), and mammalian target of rapamycin (mTOR), actinomycin D, and cycloheximide. Whereas an adenovirus infection expressing a dominant negative form of atypical PKC lambda (aPKCλ) blocked the insulin-induction of the SHARP-2 mRNA level, insulin rapidly activated the mTOR. Insulin did not enhance transcriptional activity from a 3.7 kb upstream region of the rat SHARP-2 gene. Thus, we conclude that insulin induces the expression of the rat SHARP-2 gene at the transcription level via both a PI 3-K/aPKCλ- and a PI 3-K/mTOR- pathways and that protein synthesis is required for this induction.

5-Aminoimidazole-4-carboxyamide-1-ß-D-ribofranoside stimulates the rat enhancer of split- and hairy-related protein-2 gene via atypical protein kinase C lambda.

The 5'-AMP-activated protein kinase (AMPK) functions as a cellular energy sensor. 5-Aminoimidazole-4-carboxyamide-1-ß-D-ribofranoside (AICAR) is a chemical activator of AMPK. In the liver, AICAR suppresses expression of thephosphoenolpyruvate carboxykinase(PEPCK) gene. The rat enhancer of split- and hairy-related protein-2 (SHARP-2) is an insulin-inducible transcriptional repressor and its target is thePEPCKgene. In this study, we examined an issue of whether theSHARP-2gene expression is regulated by AICAR via the AMPK. AICAR increased the level of SHARP-2 mRNA in H4IIE cells. Whereas an AMPK inhibitor, compound-C, had no effects on the AICAR-induction, inhibitors for both phosphoinositide 3-kinase (PI 3-K) and protein kinase C (PKC) completely diminished the effects of AICAR. Western blot analyses showed that AICAR rapidly activated atypical PKC lambda (aPKCλ). In addition, when a dominant negative form of aPKCλ was expressed, the induction of SHARP-2 mRNA level by AICAR was inhibited. Calcium ion is not required for the activation of aPKCλ. A calcium ion-chelating reagent had no effects on the AICAR-induction. Furthermore, the AICAR-induction was inhibited by treatment with an RNA polymerase inhibitor or a protein synthesis inhibitor. Thus, we conclude that the AICAR-induction of theSHARP-2gene is mediated at transcription level by a PI 3-K/aPKCλ pathway.