JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma.

Inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene causes both hereditary and sporadic clear-cell renal-cell carcinoma (ccRCC). Although the best-characterized function of the VHL protein (pVHL) is regulation of hypoxia-inducible factor-α (HIFα), pVHL also controls the development of pheochromocytoma through HIF-independent pathways by regulating JunB. However, it is largely unknown how these pathways contribute to the development and progression of ccRCC. In the present study, we confirmed that JunB was upregulated in VHL-defective ccRCC specimens by immunostaining. Short-hairpin RNA (shRNA)-mediated knockdown of JunB in 786-O and A498 VHL null ccRCC cells suppressed their invasiveness. In addition, JunB knockdown significantly repressed tumor growth and microvessel density in xenograft tumor assays. Conversely, forced expression of wild-type, but not dimerization-defective, JunB in a VHL-restored 786-O subclone promoted invasion in vitro and tumor growth and vessel formation in vivo. Quantitative PCR array analysis revealed that JunB regulated multiple genes relating to tumor invasion and angiogenesis such as matrix metalloproteinase-2 (MMP-2), MMP-9 and chemokine (C-C motif) ligand-2 (CCL2) in 786-O cells. JunB knockdown in these cells reduced the proteolytic activity of both MMPs in gelatin zymography and the amount of CCL2 in the culture supernatant. Moreover, shRNA-mediated knockdown of MMP-2 or inhibition of CCL2 activity with a neutralizing antibody repressed xenograft tumor growth and angiogenesis. Collectively, these results suggest that JunB promotes tumor invasiveness and enhances angiogenesis in VHL-defective ccRCCs.

Transient characteristics of chaos synchronization in a semiconductor laser subject to optical feedback.

We have investigated the transient characteristics of two types of chaos synchronization in a semiconductor laser subject to optical feedback: complete synchronization and strong injection locking-type synchronization. We have calculated the statistical distribution of the transient response time of synchronization when the initial position in the starting attractor is varied. For complete synchronization, the distribution of the transient response time has much larger average and variance than the average period of the chaotic oscillations. Conversely, a short transient response time is obtained for strong injection locking-type synchronization. We found that the transient response time is dependent upon the maximum Lyapunov exponent of the chaotic temporal waveform for complete synchronization, whereas it is almost constant for strong injection locking-type synchronization.