open access

https://doi.org/10.14943/doctoral.k13461

https://hdl.handle.net/2115/91638

EMTとがん悪性度：何が根本的事象なのか。

英語

2019-03-25

Hokkaido University

ⅳ,62p.

配架番号：2475

Despite global intellectual efforts that have continued for over half a century, cancer is still an incurable disease. There are two main reasons for this difficulty; treatment resistance and metastatic recurrence. Recent studies revealed that these two phenomena are not mutually exclusive but intimately related with one another by an epithelial-mesenchymal transition, or EMT. During EMT, tumour cells that are originally from the epithelium alter their epithelial characters into mesenchymal traits, which are characterised by high motility and the ability for anchorage-independent survival. Almost two decades ago, clinical trials were conducted using protease inhibitors, and these were expected to be able to prevent tumour invasive activity. However, all of these trials ended up in poor results. This was as cancer cells are able to move without matrix proteases, which is referred to as an amoeboid-type cell invasion. Mesenchymal-invasion and amoeboid-invasion are interchangeable in response to surroundings, where cancer cells are exposed. In this thesis, the relation between the Arf6-AMAP1-EPB41L5 pathway (Arf6-pathway) and amoeboid-invasion was investigated. The Arf6 pathway was found by Professor Sabe’s group, first in a malignant breast cancer, and has subsequently been shown to be involved in a variety of malignant tumours, including lung, head and neck, and renal cancer. This thesis further discovered that invasive breast cancer cells can exploit Arf6-pathway for their amoeboid motility. The next question that this study looks at would be the differences that exist between mesenchymal cells experienced EMT and bona fide mesenchymal cells. Substantial evidence is emerging that EMT sometimes links to cell stemness. Normal p53 has a critical role in suppressing tumour progression in many ways. p53 negotiates EMT by transcribing miR-200 family to suppress transcription factors, such as ZEB1 and ZEB2, which promote EMT. In this thesis, it has shown that p53 downregulates AMAP1, a core molecule of invasion machinery, via the miR-183 cluster. Thus far, it has been cleared that p53 cannot only target central proteins, such as transcription factors, but also implementation elements, including AMAP1. Those are mechanisms by which the epithelial cells employ p53, a reliable guardian, in order to prevent any aberrant motility. Professional mesenchymal cells, however, have high AMAP1 and low miR-183 cluster expressions, in spite of possessing a normal p53. This implies that bona fide mesenchymal cells may assign a different epigenetic status to cells that underwent EMT, at least in the sense of AMAP1 expression, even though both cells are phenotypically similar. These findings would thereby cast light on the complexity of the way in which cellular destiny would be decided. While it is indubitably important to elucidate the mechanisms of gene expression reprogramming during EMT, there is a need to investigate EMT from another viewpoint as well. One unique principle of life is to extract energy from its environment, viz. metabolism. This thesis therefore attempts to explore the way in which cells harness metabolism in order to endure EMT. The main power plant in the cell is mitochondrion. Mitochondria build up their networks for efficient energy generation, and thus have dynamic morphology. It has already shown that EMT induces mitochondria fission with OXPHOS enhanced, and there is apparently a general agreement that mitochondria fission usually impairs OXPHOS activities, thereby leading to the paradox. This thesis advocates a plausible interpretation of this discrepancy.

2019-03-25

甲第13461号

博士(医学)

(主査) 教授 廣瀬 哲郎, 教授 畠山 鎮次, 教授 秋田 弘俊, 教授 近藤 亨

医学研究科（医学専攻）

博士論文

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