Previously, we reported that Akt inactivation determines the sensitivity of hepatocellular carcinoma (HCC) cells to bortezomib. In this study, we report that cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediates the apoptotic effect of bortezomib in HCC. Silencing PP2A by small interference RNA (siRNA) abolishes bortezomib-induced down-regulation of phospho-Akt and apoptosis. Bortezomib increases PP2A activity in sensitive HCC cells, including Sk-Hep1, Hep3B and Huh-7, but not in resistant PLC5 cells. Bortezomib down-regulates CIP2A in a dose- and time-dependent manner in all sensitive HCC cells, whereas no alterations in CIP2A were found in resistant PLC5 cells. Knockdown of CIP2A by siRNA restored bortezomib's effects on apoptosis and PP2A activity in PLC5 cells. Moreover, over-expression of CIP2A up-regulated phospho-Akt and protected Sk-Hep1 cells from bortezomib-induced apoptosis. It is significant that, ectopic expression of CIP2A decreased Akt-related PP2A activity, whereas silencing CIP2A increased this activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells, furthermore, our in vivo data showed that bortezomib down-regulates CIP2A and up-regulates PP2A activity in Huh-7 tumors, but not in PLC5 tumors. In conclusion, inhibition of CIP2A determines the effects of bortezomib on apoptosis and PP2A-dependent Akt inactivation in HCC.
Data on the outcomes of more than 15,000 pregnancies originating between May 1966 and February 1969 were analyzed. The accuracy of the data was evaluated, rates of induced abortion and stillbirth were reported, and the demographic effect of induced abortion was estimated. The demographic effect was defined as the percentage increase in fertility that would have occurred in the absence of induced abortion, assuming no compensating change in alternative fertility control practices. Our principal findings were as follows: 1. We were unable to determine the completeness with which induced abortion was reported in the Registration Study. During the three years covered by the study, rates of induced abortion increased by 54 percent, reflecting a trend in the incidence or in the reporting of events or in both. We concluded that, in any case, the data for the final year of the study, 1968, were more complete than for the earlier two years. 2. Age-specific rates of induced abortion for 1968 displayed a strong urban-rural gradient, being much higher in the city areas than in the rural areas. Within each urban--rural stratum, the rates increases monotonically with age and reached maximum values in the age group 40 and older (553, 436, and 374 per 1,000 pregnancies for city, urban, and rural areas, respectively). 3. Estimates of the demographic effect indicated that, in the absence of induced abortion, the TFR for all Taiwan would have been 12 percent higher in 1968. Under the same assumption, it was estimated that the TFR would have been higher by 16 percent in city areas, 11 percent in urban areas, and 9 percent in rural areas. This urbanization gradient implies that induced abortion contributed to urban-rural fertility differentials. We estimated that about one-third of those differentials were due to induced abortion. 4. Estimates of the demographic effect were also made after adjusting the rates of induced abortion for an assumed level of underreporting of 50 percent. The adjusted estimate of the demographic effect for all Taiwan in 1968 was 19 percent.
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