Integrative bioinformatic analysis of p53 and pathway alterations in two different lung cancer subtypes.

Whether p53, either wild type (WT) or mutant, plays cell-specific or uniform role remains controversial. Using The Cancer Genome Atlas, we examined p53 in the lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), two lung cancers with different cellular origins and frequent p53 mutation (52% and 83%, respectively). Mutant p53 more strongly correlates with different genomic alteration and protein expression profiles in LUAD than in LUSC. p53 mutation in LUAD and LUSC is associated with multiple exacerbated clinical outcomes. Although the presence of p53 mutation does not change the survival of LUAD patients, LUSC patients containing p53 mutation exhibit surprisingly prolonged survivals. Ingenuity Pathway Analyses with genes co-expressed with WT or mutant p53 in both LUAD and LUSC show that mutant p53 in these two cancers are correlated with different signaling. Additionally, WT p53 in LUAD are largely associated with activation of tumor suppressive pathways and suppression of the tumor promotive ones, a pattern different from what is observed for WT p53 in LUSC. Furthermore, pathway analyses of genes differentially expressed between cancers with mutant and WT p53 for both LUAD and LUSC revealed different pathway fashions for these two cancers. Our study indicates that both WT and mutant p53 may have cell-specific functions, which needs to be validated with future experimental investigations.

In silico analysis of DND1 and its co-expressed genes in human cancers.

Dead-End (DND1) is an RNA-binding protein involved in translational regulation. Defects in DND1 gene causes germ cell tumors and sterility in rodents. Experimental studies with human somatic cancer cells indicate that DND1 has anti-proliferative and pro-apoptotic function in some while oncogenic function in other cells. We examined The Cancer Genome Atlas data for gene alterations and gene expression changes in DND1 in a variety of human cancers. We found that DND1 is amplified, deleted or mutated in multiple human cancers. In different cancers, DND1 alteration correlates with increased diagnosis age of patients, shift in tumor spectrum or change of tumor sites and in some cases is significantly associated with worse survival for cancer patients. For 15 cancers, we retrieved expression data of thousands of genes that co-expressed with DND1. We found that these cancers contain different percentage of genes that are positively or negatively co-expressed with DND1. Ingenuity Pathway Analysis was performed to explore the biological implications of these genes. More than 10 canonical pathways were identified and each cancer type exhibits unique pathway profiles. Comparison analysis across all 15 cancer types showed that some cancers exhibit strikingly similar profiles of DND1-correlated signaling pathway activation or suppression. Our data reinforce the notion that the biological role of DND1 is cell-type specific and suggest that DND1 may play opposing role by exerting anti-proliferative effects in some cancer cells while being pro-proliferative in others. Our study provides valuable insights to direct experimental investigations of DND1 function in somatic cancers.

The Role of DND1 in Cancers.

The Ter mutation in Dead-End 1 (Dnd1), Dnd1Ter, which leads to a premature stop codon, has been determined to be the cause for primordial germ cell deficiency, accompanied with a high incidence of congenital testicular germ cell tumors (TGCTs) or teratomas in the 129/Sv-Ter mice. As an RNA-binding protein, DND1 can bind the 3'-untranslated region (3'-UTR) of mRNAs and function in translational regulation. DND1 can block microRNA (miRNA) access to the 3'-UTR of target mRNAs, thus inhibiting miRNA-mediated mRNA degradation and up-regulating translation or can also function to degrade or repress mRNAs. Other mechanisms of DND1 activity include promoting translation initiation and modifying target protein activity. Although Dnd1Ter mutation causes spontaneous TGCT only in male 129 mice, it can also cause ovarian teratomas in mice when combined with other genetic defects or cause germ cell teratomas in both genders in the WKY/Ztm rat strain. Furthermore, studies on human cell lines, patient cancer tissues, and the use of human cancer genome analysis indicate that DND1 may possess either tumor-suppressive or -promoting functions in a variety of somatic cancers. Here we review the involvement of DND1 in cancers, including what appears to be its emerging role in somatic cancers.

Deficiency of Splicing Factor 1 (SF1) Reduces Intestinal Polyp Incidence in ApcMin/+ Mice.

BACKGROUND: Splicing factor 1 (SF1) is a conserved alternative splicing factor expressed in many different mammalian cell types. The genetically modified Sf1+/- (or Sf1ß-geo/+) mice express reduced levels of SF1 protein in mouse tissues, including in cells of the intestines. Mutational inactivation of human adenomatous polyposis coli (APC) gene deregulates the Wnt signaling pathway and is a frequent genetic event in colon cancers. Mice with a point mutation in the Apc gene (ApcMin/+) also develop numerous intestinal polyps at a young age. Our aim was to determine the effect of reduced SF1 levels on polyp development due to the strong driver ApcMin/+ mutation. METHODS: We utilized mice genetically deficient for expression of SF1 to assess how SF1 levels affect intestinal tumorigenesis. We crossed ApcMin/+ to Sf1+/- mice to generate a cohort of heterozygous mutant ApcMin/+;Sf1+/- mice and compared intestinal polyp development in these mice to that in a control cohort of sibling ApcMin/+ mice. We compared total polyp numbers, sizes of polyps and gender differences in polyp numbers between ApcMin/+;Sf1+/- and ApcMin/+ mice. RESULTS: Our results showed that ApcMin/+ mice with lower SF1 expression developed 25-30% fewer intestinal polyps compared to their ApcMin/+ siblings with normal SF1 levels. Interestingly, this difference was most significant for females (ApcMin/+;Sf1+/- and ApcMin/+ females developed 39 and 55 median number of polyps, respectively). Furthermore, the difference in polyp numbers between ApcMin/+;Sf1+/- and ApcMin/+ mice was significant for smaller polyps with a size of 2 mm or less, whereas both groups developed similar numbers of larger polyps. CONCLUSIONS: Our results suggest that lower SF1 levels likely inhibit the rate of initiation of polyp development due to ApcMin/+ driver mutation in the mouse intestine. Thus, therapeutic lowering of SF1 levels in the intestine could attenuate intestinal polyp development.