The regulation network consisting of microRNAs (miRNAs) and their target genes remains largely elusive in hepatocellular carcinoma (HCC), especially the reciprocal loop between specific miRNAs and the miRNA processing machinery. In this study, we found that miR-99a was remarkably decreased in 111 of 152 (73.03%) primary HCC tissues and low-level expression of miR-99a was correlated with low tumor differentiation (P=0.001), liver cirrhosis (P=0.015), poor tumor-free survival (P=0.004) and overall survival (P=0.006) for HCC patients. By restoration of miR-99a, the HCC growth could be considerably inhibited both in vitro and in vivo. Subsequently, Argonaute-2 (Ago2), a central component of RNA-induced silencing complex, was found to be directly regulated by miR-99a via translational repression. Overexpression of Ago2 could partly impair the inhibitory effect of miR-99a on HCC cells in vitro. Then, we demonstrated that Ago2 was upregulated in HCC tissues at both RNA and protein levels and the expression of AGO2 protein and miR-99a was negatively correlated within detected HCC tissues (r=−0.727, P=0.004). Interestingly, the tumorigenicity of Ago2-knockdown HCC cells was severely impaired (4/10 vs 10/10, P<0.05), and this was in contrast to the miR-99a-overexpressing HCC cells. Functionally, the increased AGO2 protein could specifically facilitate oncogenic miR-21 to repress its targeted gene phosphatase and tensin homolog (Pten) in HCC, whereas leave the regulatory capacity of let-7a on its targeted oncogenes almost unaltered. In summary, our study has revealed a novel pathway for the tumor suppressor miR-99a to control tumor growth in HCC, via its downstream signaling of AGO2/miR-21/PTEN. In addition, this study provides potential strategies for HCC therapy by reintroduction of miRNA suppressors.

BackgroundDespite the great burden of chronic respiratory diseases in China, few large multicentre, spirometry-based studies have examined its prevalence, rate of underdiagnosis regionally or the relevance of socioeconomic and lifestyle factors.MethodsWe analysed data from 512 891 adults in the China Kadoorie Biobank, recruited from 10 diverse regions of China during 2004–2008. Air flow obstruction (AFO) was defined by the lower limit of normal criteria based on spirometry-measured lung function. The prevalence of AFO was analysed by region, age, socioeconomic status, body mass index (BMI) and smoking history and compared with the prevalence of self-reported physician-diagnosed chronic bronchitis or emphysema (CB/E) and its symptoms.FindingsThe prevalence of AFO was 7.3% in men (range 2.5–18.2%) and 6.4% in women (1.5–18.5%). Higher prevalence of AFO was associated with older age (p<0.0001), lower income (p<0.0001), poor education (p<0.001), living in rural regions (p<0.001), those who started smoking before the age of 20 years (p<0.001) and low BMI (p<0.001). Compared with self-reported diagnosis of CB/E, 88.8% of AFO was underdiagnosed; underdiagnosis proportion was highest in 30–39-year olds (96.7%) compared with the 70+ age group (81.1%), in women (90.7%), in urban areas (89.4%), in people earning 5K–10 K ¥ monthly (90.3%) and in those with middle or high school education (92.6%).InterpretationIn China, the burden of AFO based on spirometry was high and significantly greater than that estimated based on self-reported physician-diagnosed CB/E, especially in rural areas, reflecting major issues with diagnosis of AFO that will impact disease treatment and management.

The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.

Obesity is a strong determinant of blood pressure. Uncertainty remains, however, about which indices of adiposity most strongly predict blood pressure, particularly among those who were relatively lean, such as those from rural China. We analyzed cross-sectional data on 55 687 (38.3% men) participants aged 30–79 years who were enrolled into the China Kadoorie Biobank from a rural county in southwest of China during 2004–2008. Measured body mass index (BMI) and waist circumference (WC) were related to blood pressure in multivariable linear regression analyses. The overall mean values of BMI, WC, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 23.3 kg m−2, 78.0 cm, 129.2 mm Hg and 77.2 mm Hg, respectively. There was a strongly positive, and apparently linear, relationship of BMI and WC with blood pressure, with 1 s.d. higher BMI associated with 4.3/2.3 mm Hg higher SBP/DBP and 1 s.d. WC associated with 3.8/2.1 mm Hg (P<0.0001). Additional adjustment for WC only slightly attenuated the association of BMI with blood pressure, whereas additional adjustment for BMI almost completely eliminated the association of WC with blood pressure. Our findings suggest that in relatively lean Chinese adults, general adiposity is more strongly assciated with blood pressure than central adiposity.