The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

Cancer is characterized by mutations, genome rearrangements, epigenetic changes, and altered gene expression that enhance cell proliferation, invasion, and metastasis. To accommodate deregulated cellular proliferation, many DNA replication-initiation proteins are overexpressed in human cancers. However, the mechanism that represses the expression of these proteins in normal cells and the cellular changes that result in their overexpression are largely unknown. One possible mechanism is through miRNA expression differences. Here, it is demonstrated that miR26a and miR26b inhibit replication licensing and the proliferation, migration, and invasion of lung cancer cells by targeting CDC6. Importantly, miR26a/b expression is significantly decreased in human lung cancer tissue specimens compared with the paired adjacent normal tissues, and miR26a/b downregulation and the consequential upregulation of CDC6 are associated with poorer prognosis of patients with lung cancer. These results indicate that miR26a/b repress replication licensing and tumorigenesis by targeting CDC6. Implications:The current study suggests that miR26a, miR26b, and CDC6 and factors regulating their expression represent potential cancer diagnostic and prognostic markers as well as anticancer targets.

The contribution of Tra2-regulated alternative splicing to mammalian development is unknown. To address the question, we initiated studies by systemically characterizing the gene expression profile of Tra2beta isoforms in human fetal tissue at two different stages (11 and 16 weeks). Tra2beta has at least five isoforms of transcripts (Tra2beta1 approximately 5). Tra2beta1 encodes full-length Tra2beta proteins, whilst Tra2beta3, 4 and 5 encode the truncated proteins. The results show that Tra2beta1 transcript levels are developmentally regulated in a tissue- and temporal-specific pattern, although expression is ubiquitous. Compared to Tra2beta5, the expression of Tra2beta3 and 4 transcripts is significantly restricted and more vigorously regulated in a tissue- and temporal-specific pattern. Western blot analysis shows that Tra2beta1 proteins are ubiquitously expressed, but at a relatively higher level in neural tissues than non-neural tissues. However, there is no direct correlation between the transcript and protein levels for Tra2beta1, suggesting that multiple mechanisms are involved in the regulation of Tra2beta during development. This study indicates that Tra2beta-regulated splicing may contribute to the regulation of mammalian development in a tissue- and temporal-specific pattern.

We generated the small interference RNAs to specifically silence the expression of neural salient serine/arginine rich protein 1 (NSSR1) and showed that the inhibition of NSSR1 expression in mouse embryonic carcinoma cells (P19) reduces neuronal differentiation. By contrast, its over-expression promotes the differentiation. Neither inhibition nor over-expression shows distinct effect on cell proliferation. The over-expression increases the inclusion of NCAM L1 exon2 while the inhibition reduces the inclusion. The splicing of kinase insert free isoform of TrkC (TrkC-K1) is increased by the over-expression. The results demonstrate that NSSR1 promotes neuronal differentiation and the splicing of NCAML1 exon2 and TrkC-K1.