RESUMO
The Notch signaling has an important role in multiple cellular processes and is related to carcinogenic process. To understand the potential molecular features of the crucial Notch pathway, a comprehensive multi-omics analysis is performed to explore its contributions in cancer, mainly including analysis of somatic mutation landscape, pan-cancer expression, ncRNA regulation and potential prognostic power. The screened 22 Notch core genes are relative stable in DNA variation. Dynamic expression patterns are associated with the Notch activity, which are mainly regulated by multiple ncRNAs via interactions of ncRNA:mRNA and ceRNA networks. The Notch pathway shows a potential prognostic ability through integrating multi-omics features as well as their targets, and it is correlated with immune infiltration and maybe available drug targets, implying the potential role in individualized treatment. Collectively, all of these findings contribute to exploring crucial role of the key pathway in cancer pathophysiology and gaining mechanistic insights into cross-talks among RNAs and biological pathways, which indicates the possible application of the well-conserved Notch signaling pathway in precision medicine.
RESUMO
Synthetic lethality is thought to play an important role in anticancer therapies. Herein, to understand the potential distributions and relationships between synthetic lethal interactions between genes, especially for pairs deriving from different sources, we performed an integrative analysis of genes at multiple molecular levels. Based on inter-species phylogenetic conservation of synthetic lethal interactions, gene pairs from yeast and humans were analyzed; a total of 37,588 candidate gene pairs containing 7,816 genes were collected. Of these, 49.74% of genes had 2-10 interactions, 22.93% were involved in hallmarks of cancer, and 21.61% were identified as core essential genes. Many genes were shown to have important biological roles via functional enrichment analysis, and 65 were identified as potentially crucial in the pathophysiology of cancer. Gene pairs with dysregulated expression patterns had higher prognostic values. Further screening based on mutation and expression levels showed that remaining gene pairs were mainly derived from human predicted or validated pairs, while most predicted pairs from yeast were filtered from analysis. Genes with synthetic lethality were further analyzed with their interactive microRNAs (miRNAs) at the isomiR level which have been widely studied as negatively regulatory molecules. The miRNA-mRNA interaction network revealed that many synthetic lethal genes contributed to the cell cycle (seven of 12 genes), cancer pathways (five of 12 genes), oocyte meiosis, the p53 signaling pathway, and hallmarks of cancer. Our study contributes to the understanding of synthetic lethal interactions and promotes the application of genetic interactions in further cancer precision medicine.
RESUMO
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide and is derived from an accumulation of genetic and epigenetic changes. This study explored potential prognostic markers in CRC via the construction and in-depth analysis of a competing endogenous RNA (ceRNA) network, which was generated through a three-step process. First, we screened candidate hub genes in CRC as the primary gene markers to survey their related regulatory non-coding RNAs, miRNAs. Second, the interacting miRNAs were used to search for associated lncRNAs. Thus, candidate RNAs were first constructed into ceRNA networks based on close associations with miRNAs. Further analysis at the isomiR level was also performed for each miRNA locus to understand the detailed expression patterns of the multiple variants. Finally, RNAs were performed an in-depth analysis of expression correlations, which contributed to further screening and validation of potential RNAs with close correlations to each other. Using this approach, nine hub genes, 13 related miRNAs, and 29 candidate lncRNAs were collected and used to construct the ceRNA network. Further in-depth analysis identified the MFAP5-miR-200b-3p-AC005154.6 axis as a potential prognostic marker in CRC. MFAP5 and miR-200b-3p have previously been reported to play important roles in tumorigenesis. These RNAs showed potential prognostic values, and the combination of them may have more sensitivity than using them alone. In conclusion, MFAP5, miR-200b-3p, and AC005154.6 may have potential prognostic value in CRC and may provide a prognostic reference for this patient population.
RESUMO
Cholangiocarcinoma (CCA), an aggressive tumor with poor prognosis, is a malignant cancer with increasing incidence and mortality rates. It is important to survey crucial genes in CCA to find and design potential drug targets, especially for those genes associated with cell proliferation that is a key biological process in tumorgenesis. Herein, we surveyed genes associated with cell proliferation via a comprehensive pan-cancer analysis. Candidate genes were further analyzed using multiple approaches, including cross-analysis from diverse molecular levels, examination of potential function and interactions, and additional experimental validation. We primarily screened 15 potential genes based on 11 validated genes, and these 26 genes were further examined to delineate their biological functions and potential roles in cancer treatment. Several of them were involved synthetically lethal genetic interactions, especially for RECQL4, TOP2A, MKI67 and ASPM, indicating their potential roles in drug design and cancer treatment. Further experimental validation indicated that some genes were significantly upregulated in several cancer cell lines, implying their important roles in tumorigenesis. Our study identifies some genes associated with cell proliferation, which may be potential future targets in molecular targeted therapy.
