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Jing Zhao:
Comparative transcriptome studies reveal mitochondrial role in lung cancer classification and mechanism in cancer-resistant species

Date: 02-12-2020    Supervisor: Karsten Kristiansen

The significant reduction in the cost of next generation sequencing makes it possible to introduce transcriptomics in cancer relative study. Cancer is a complicated disease triggered by genetic mutations. However, it is difficult to understand all the molecular network in the affected organisms. Transcriptome sequencing and analysis are powerful tools to sequence the entire messenger RNA (mRNA) and provide a comprehensive expression profile for a given tissues at a specific time. They are widely applied in cancer research. Here, the role of mitochondrial was identified in the classification and prognosis of human lung cancer, and the anti-cancer mechanism was worked out by comparing the expression differences between cancer-resistant and cancer-suspectable species in oncogenic insult experiments using comparative transcriptomics technology. 

Human lung cancer is a very prevalent disease, and mitochondria were speculated to be involved in the development and classification of tumors. By integrating and analysing the publicly available transcriptome sequencing data, the human lung cancer subtypes and their different prognosis were determined based on the mtDNA expression profile. Two known longevity but naturally cancer-resistant subterranean rodents, the naked mole-rat (short as NMR) and blind mole-rat (short as BMR), are receiving increasing attentions. To further understand the genes and pathways related to cancer resistant, a comprehensive oncogenic insult (using SV40 large T and Ras oncogene) study in the fibroblast cells from cancer-resistant species (NMR, BMR, and Human) and cancer-susceptible species (Mouse) were performed. By analysing the transcriptome data from these experiments, NMR cells are found to be more antagonistic to oncogene-induced transcriptional changes and many pathways including cell division, cell adhesion, extracellular matrix organization, metabolic process remained stable or changed to a less extent in NMR but significantly altered in cancer-suspectable mouse cells. Critical genes, such as Akt and Erk in the PI3K pathway, were down-regulated specifically in NMR cells, which could partly explain its cancer-resistant. This result could be confirmed by the observation of tumorigenesis in NMR when over-expressed Ras. Taken together, these studies in this thesis reveal the power of transcriptome in cancer relative research and the output provides multiple new insights into the mitochondrial function in human lung cancer stratification, and the underlying anti-cancer mechanisms in mammalian cancer-resistant species.