STAT3 regulated ARF expression suppresses prostate cancer metastasis

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

Lake Kumphawapi revisited – The complex climatic and environmental record of a tropical wetland in NE Thailand

Kumphawapi, which is Thailand’s largest natural freshwater lake, contains a >10,000-year-long climatic and environmental archive. New data sets (stratigraphy, chronology, hydrogen isotopes, plant macrofossil and charcoal records) for two sedimentary sequences are here combined with earlier multi-proxy studies to provide a comprehensive reconstruction of past climatic and environmental changes for Northeast Thailand. Gradually higher moisture availability due to a strengthening of the summer monsoon led to the formation of a large shallow lake in the Kumphawapi basin between >10,700 and c. 7000 cal. BP. The marked increase in moisture availability and lower evaporation between c. 7000 and 6400 cal. BP favoured the growth and expansion of vegetation in and around the shallow lake. The increase in biomass led to gradual overgrowing and infilling, to an apparent lake level lowering and to the development of a wetland. Multiple hiatuses are apparent in all investigated sequences between c. 6500 and 1400 cal. BP and are explained by periodic desiccation events of the wetland and erosion due to the subsequent lake level rise. The rise in lake level, which started c. 2000 cal. BP and reached shallower parts c. 1400 cal. BP, is attributed to an increase in effective moisture availability. The timing of hydroclimatic conditions during the past 2000 years cannot be resolved because of chronological limitations.