Cooperative function of oncogenic MAPK signaling and the loss of Pten for melanoma migration through the formation of lamellipodia.

The combination of oncogenes and tumor suppressors is involved in cancer development; however, it is still unknown whether their combination plays a critical role in cancer metastasis. We herein investigated whether genetic combinations affected cell migration ability by establishing the immortalized melanocytes, melan-a cells, with an oncogene, either BRAFV600E or GNA11Q209L, and the loss of mouse Pten. The loss of mouse Pten or human PTEN increased the cell migration ability of our established cells and human melanoma cell lines with oncogenic MAPK signaling and the BRAFV600E or NRASQ61R background, but not with the GNA11Q209L background or no oncogenes. Although increased migration was not related to PI3K-AKT activation, those migration is regulated by the induction of some components in the WAVE regulatory complex, resulting in a higher rate of the formation of lamellipodia. On the other hand, BRAFV600E induced EphA2 phosphorylation at serine 897 through RSK and was also required for cell migration and the formation of lamellipodia. Therefore, the oncogenic MAPK pathway and loss of Pten in melanoma were important for cell migration through the formation of lamellipodia, suggesting the significance of an appropriate combination of genetic alterations not only in cancer development, but also cancer metastasis.

P wave and the development of atrial fibrillation.

BACKGROUND: Terminal P-wave inversion in lead V(1) representing left atrial overload has been considered a precursor of atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to determine whether this P-wave morphologic characteristic can predict the development of AF. METHODS: Digital analysis of 12-lead ECGs was performed to enroll patients with P terminal force > or =0.06 s x 2 mm in lead V(1) from among a database of 308,391 ECG recordings. The prognostic value of ECG characteristics for developing AF was determined. RESULTS: A total of 78 patients (mean age 52 +/- 19 years) with left atrial overload were chosen from among 102,065 patients in the database. During mean follow-up of 43 months, 15 (19%) patients developed AF (AF group) versus 63 (81%) patients who did not (non-AF group). No significant difference was noted between the AF and non-AF groups with regard to the area, duration, and amplitude of the P-wave terminal portion in lead V(1). In contrast, the area, duration, and amplitude of the P-wave initial portion in the same lead were significantly greater in the AF group than in the non-AF group (114.6 +/- 73.0 microV x ms vs 73.1 +/- 59.3 microV x ms, 42.2 +/- 12.4 ms vs 35.7 +/- 10.1 ms, and 94.0 +/- 39.9 microV vs 68.8 +/- 49.4 microV, respectively; P <.05 for each). Multivariate analysis confirmed that the area of the P-wave initial portion was independently associated with the development of AF (hazard ratio 4.02, 95% confidence interval 1.25-17.8; P = .018). CONCLUSION: P-wave initial portion in lead V(1) was an independent risk stratifier of AF development in patients with marked left atrial overload.

Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome.

BACKGROUND: Drugs with I(Kr)-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. METHODS AND RESULTS: Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. CONCLUSIONS: dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I(Kr)-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.