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Hepatocellular carcinoma (HCC) is the most common type of liver cancer. HDAC6 is a transcriptional regulator of the histone deacetylase family, subfamily 2. Previous studies have shown that HDAC6 plays critical roles in transcription regulation, cell cycle progression and developmental events. However, its biological roles in the development of HCC remain largely unexplored. In the present study, we found that mRNA and protein levels of HDAC6 were up-regulated in HCC tissues and cell lines. The proinflammatory cytokines, which were up-regulated in the human HCC microenvironment, increased HDAC6 expression through a proximal NF-kappaB binding site on the HDAC6 gene promoter. Furthermore, overexpression of HDAC6 could promote cell proliferation in HCC cell lines. In contrast, HDAC6 knockdown using small interfering RNA inhibited cell proliferation. At the molecular level, we demonstrated that HDAC6 could interact with p53 and attenuate its transcriptional activity through promotion of its degradation. Therefore, our results suggest a previously unknown HDAC6-p53 molecular network controlling HCC development.

Deregulated microRNAs (miRNAs) are small noncoding RNAs that are involved in the carcinogenesis of various cancers, including lung cancer. HIF1α has been suggested to be a master regulator of hypoxia-induced cell proliferation. The relationship between HIF1α expression and the progression of non-small cell lung cancer (NSCLC) is not fully understood, and whether HIF1α expression is regulated by miRNAs in this process remains unclear. In this study, we found that the upregulation of HIF1α expression and the reduction in miR-199a levels were highly associated with NSCLC progression. NSCLC cells derived from cancer tissues with low miR-199a levels showed high HIF1α expression and high proliferation capacity. Moreover, HIF1α and glycolysis inhibitors suppress the proliferation of NSCLC cells. MiR-199a overexpression suppressed the hypoxia-induced proliferation of NSCLC cells through targeting elevated HIF1α and blocking the downstream upregulation of PDK1 without affecting AKT activation. Together, these results indicate that downregulation of miR-199a is essential for hypoxia-induced proliferation through derepressing the expression of HIF1α expression and affecting HIF1α mediated glycolytic pathway in NSCLC progression.

Cytochrome P450 1A1 (CYP1A1), an important phase I xenobiotic metabolizing enzyme, is responsible for metabolizing numerous carcinogens, particularly polycyclic aromatic hydrocarbons. The genetic polymorphism of CYP1A1 at the site of MspI (CYP1A1 MspI) has been implicated in prostate cancer risk, but the results of individual studies remain conflicting and inconclusive. The aim of this meta-analysis was to investigate the association of CYP1A1 MspI polymorphism with prostate cancer risk more precisely. We performed a comprehensive search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases from their inception up to September 20, 2012 for relevant publications. The pooled odds ratios with the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association of CYP1A1 MspI polymorphism with prostate cancer risk. In addition, stratified analyses by ethnicity and sensitivity analyses were conducted for further estimation. Sixteen eligible publications with 6,411 subjects were finally included into the meta-analysis after checking the retrieved papers. Overall, meta-analysis of total studies suggested that individuals carrying the TC genotype and a combined C genotype (CC + TC) were more susceptible to prostate cancer (OR(TC vs. TT) = 1.33, 95% CI 1.10-1.61, P(OR) = 0.004; OR(CC+TC vs. TT) = 1.27, 95% CI 1.05-1.55, P(OR) = 0.016). Stratified analysis of high quality studies also confirmed the significant association (OR(TC vs. TT) = 1.32, 95% CI 1.04-1.67, P(OR) = 0.024; OR(CC+TC vs. TT) = 1.30, 95% CI 1.02-1.66, P(OR) = 0.035). In subgroup analyses by ethnicity, a significant association between the CYP1A1 MspI polymorphism and risk of prostate cancer was found among Asians (OR(TC vs. TT) = 1.44, 95% CI 1.20-1.72, P(OR) < 0.001; OR(CC+TC vs. TT) = 1.33, 95% CI 1.12-1.58, P(OR) = 0.001), but not in Caucasians or mixed populations. The meta-analysis suggests an important role of the CYP1A1 MspI polymorphism in the risk of developing prostate cancer, especially in Asians.

The ATR–ATRIP protein kinase complex plays a crucial role in the cellular response to replication stress and DNA damage. Recent studies found that ATR could be activated in response to hypoxia and be involved in hypoxia-induced genetic instability in cancer cells. However, the underlying mechanisms for ATR activation in response to hypoxic stress are still not fully understood. We reported that ATRIP is a direct target of HIF-1. Silencing the expression of HIF-1α in cancer cells by RNA interference abolished hypoxia-induced ATRIP expression. Silencing the expression of ATRIP by RNA interference abolished hypoxia induced ATR activation and CHK1 phosphorylation in cancer cells. Taken together, these data shed novel insights on the mechanism of hypoxia-induced activation of the ATR pathway.