Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. By examining the expression of 22 HCC-related miRNAs between precancerous and cancerous liver tissues, we found miR-216a and miR-224 were significantly up-regulated, starting from the precancerous stage. Furthermore, the elevation of miR-216a was mainly identified in male patients. To study this gender difference, we demonstrated that pri-miR-216a is activated transcriptionally by the androgen pathway in a ligand-dependent manner and is further enhanced by the hepatitis B virus X protein. The transcription initiation site for pri-miR-216a was delineated, and one putative androgen-responsive element site was identified within its promoter region. Mutation of this site abolished the elevation of pri-miR-216a by the androgen pathway. One target of miR-216a was shown to be the tumor suppressor in lung cancer-1 gene (TSLC1) messenger RNA (mRNA) through the three target sites at its 3 0 untranslated region. Finally, the androgen receptor level increased in male liver tissues during hepatocarcinogenesis, starting from the precancerous stage, with a concomitant elevation of miR-216a but a decrease of TSLC1. Conclusion: The current study discovered the up-regulation of miRNA-216a by the androgen pathway and a subsequent suppression of TSLC1 as a new mechanism for the androgen pathway in early hepatocarcinogenesis. (HEPATOLOGY 2012;56:632-643) T he incidence of hepatocellular carcinoma (HCC) ranks fifth for cancers worldwide and causes about half a million deaths every year. 1 HCC is usually the ultimate outcome of chronic hepatitis caused by persistent viral infection (hepatitis B or C virus [HBV/HCV]) or by alcoholic/metabolic etiologies. After decades of chronic hepatitis, which might induce persistent necrosis and regeneration and accumulate the carcinogenic events in the hepatocytes, about 30%-40% of patients will progress into liver cirrhosis, and those will subsequently develop HCC with an annual incidence around 1%-5%. 2 Due to the multistep characteristic of cancer development, on average six to seven successive mutations are generally believed to be required to convert a normal hepatocyte into an invasive HCC. 3 As every mutation contributes to the formation of an expanded clone and thus presents a larger target population of cells for the next mutation, the cells surrounding the HCC could be considered precancerous cells, retaining the potential to become the subsequent HCC. 4 This
Despite of the discovery of protein therapeutic targets and advancement in multimodal therapy, the survival chance of high-risk neuroblastoma (NB) patients is still less than 50%. MYCN amplification is a potent driver of NB, which exerts its oncogenic activity through either activating or inhibiting the transcription of target genes. Recently, long noncoding RNAs (lncRNAs) are reported to be altered in cancers including NB. However, lncRNAs that are altered by MYCN amplification and associated with outcome in high-risk NB patients are limitedly discovered. Herein, we examined the expression profiles of lncRNAs and protein-coding genes between MYCN amplified and MYCN non-amplified NB from microarray (n = 47) and RNA-seq datasets (n = 493). We identified 6 lncRNAs in common that were differentially expressed (adjusted P ≤ 0.05 and fold change ≥ 2) and subsequently validated by RT-qPCR. The co-expression analysis reveals lncRNA, SNHG1 and coding gene, TAF1D highly co-expressed in NB. Kaplan-Meier analysis shows that higher expression of SNHG1 is significantly associated with poor patient survival. Importantly, multivariate analysis confirms high expression of SNHG1 as an independent prognostic marker for event-free survival (EFS) (HR = 1.58, P = 2.36E-02). In conclusion, our study unveils that SNHG1 is up-regulated by MYCN amplification and could be a potential prognostic biomarker for high-risk NB intervention.
Steller’s sea cow, an extinct sirenian and one of the largest Quaternary mammals, was described by Georg Steller in 1741 and eradicated by humans within 27 years. Here, we complement Steller’s descriptions with paleogenomic data from 12 individuals. We identified convergent evolution between Steller’s sea cow and cetaceans but not extant sirenians, suggesting a role of several genes in adaptation to cold aquatic (or marine) environments. Among these are inactivations of lipoxygenase genes, which in humans and mouse models cause ichthyosis, a skin disease characterized by a thick, hyperkeratotic epidermis that recapitulates Steller’s sea cows’ reportedly bark-like skin. We also found that Steller’s sea cows’ abundance was continuously declining for tens of thousands of years before their description, implying that environmental changes also contributed to their extinction.
Background RNA-seq emerges as a valuable method for clinical genetics. The transcriptome is “dynamic” and tissue-specific, but typically the probed tissues to analyze (TA) are different from the tissue of interest (TI) based on pathophysiology. Results We developed Phenotype-Tissue Expression and Exploration (PTEE), a tool to facilitate the decision about the most suitable TA for RNA-seq. We integrated phenotype-annotated genes, used 54 tissues from GTEx to perform correlation analyses and identify expressed genes and transcripts between TAs and TIs. We identified skeletal muscle as the most appropriate TA to inquire for cardiac arrhythmia genes and skin as a good proxy to study neurodevelopmental disorders. We also explored RNA-seq limitations and show that on-off switching of gene expression during ontogenesis or circadian rhythm can cause blind spots for RNA-seq-based analyses. Conclusions PTEE aids the identification of tissues suitable for RNA-seq for a given pathology to increase the success rate of diagnosis and gene discovery. PTEE is freely available at https://bioinf.eva.mpg.de/PTEE/
This article was originally published in Proteomics 2011, 11, 2423–2439, DOI
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