Epithelial to mesenchymal transition in urothelial cancer

• Project/Area Number: 18K16710
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Keio University
• Principal Investigator: DAIMON TATSUAKI 慶應義塾大学, 医学部(信濃町), 共同研究員 (40573275)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 尿路上皮癌 / 上皮間葉転換 / 低酸素

Outline of Final Research Achievements

We examined the protein expression of EPB4.1L5 and EMT related transcriptional factors by western blotting in human urothelial cell lines, UMUC-3, T24 and 5637. The protein expression accorded with a tendency of the invasion ability in order of UMUC-3>T24>5637. In the hypoxic state, although the expression of EMT-related transcription factor became higher, the protein expression of EPB4.1L5 became lower unexpectedly. In addition, there was no significant difference in the protein expression of EPB4.1L5 with or without the HIF-1α inhibitor.
Although the expression of EMT-related transcription factors like Snail were higher in the cisplatin-resistant T24 cell line compared with the original T24 cell line, there was no difference between the expression of the protein of the two cell lines.

Academic Significance and Societal Importance of the Research Achievements

浸潤、転移を有する難治性尿路上皮癌に対して集学的治療が行われるが、効果は限定的であり、新規治療戦略の確立が急務である。Arf6-AMAP1シグナル経路とその中心的な役割を果たすものとしてEPB4.1L5を介した上皮間葉転換の制御機構が近年新たに注目され、腫瘍の浸潤、転移、薬剤耐性との関連が報告されてきた。我々は尿路上皮がん患者においてEPB4.1L5の高発現症例で予後が悪いことを報告した。尿路上皮癌細胞株を用いて薬剤耐性と低酸素状態において検討したが、今回の検討においては、明らかなEPB41L5、Arf6-AMAP1シグナル経路の関与は認めなかった。