TFCP2L1 which facilitates the survival and differentiation of bladder cancer stem cells inhibits ID2

Published in ‘Experimental and Molecular Medicine' (Impact Factor=12.178), a sister journal of 'Nature'

▲ (from the left) Professor Dong-Myung Shin, Professor Jaekyoung Son, and Professor Bumsik Hong

Advanced bladder cancer is known to be an intractable disease because it has high recurrence and resistance to chemotherapy. A research team at Asan Medical Center (AMC) discovered a mechanism that blocks cancer proliferation, unraveling new clues to advanced bladder cancer treatment.

A team led by Professor Dong-Myung Shin and Professor Jaekyoung Son of the Department of Biomedical Science, University of Ulsan College of Medicine, and Professor Bumsik Hong of the Department of Urology, Asan Medical Center recently revealed that ID2 protein is a target factor inhibited by TFCP2L1 protein, which is involved in the survival and stemness features of bladder cancer stem cells.

The research findings were published in the June, 2022 issue of ‘Experimental and Molecular Medicine' (Impact Factor=12.178), a sister journal of 'Nature' and a renowned academic journal in the field of biochemistry and molecular biology.

Bladder cancer is the fourth most common cancer among men in developed countries. The incidence of bladder cancer is increasing in South Korea as well due to westernized dietary habits, environmental pollution, and aging. In particular, lifelong follow-up and treatment are needed for bladder cancer due to high recurrence after treatment. Of all cancers, it is a cancer for which a patient spends the most in his or her lifetime, and therefore developing an effective treatment for bladder cancer is desperately needed.

In order to verify whether ID2 activation inhibits the stemness features (proliferation, self-renewal and invasive activity) of bladder cells induced through overexpression of TFCP2L1, the research team overexpressed TFCP2L1 and ID2 simultaneously in HT1197 and HT1376 cells that are subtypes of muscle-invasive bladder carcinoma.

As a result, it was observed in both cells that the stemness feature of bladder cancer cells, which was increased due to overexpressed TFCP2L1, was inhibited by overexpression of ID2.

The research team further examined two bladder cancer cohort studies registered on the Cancer Genome Atlas, a public data protal for cancer big data, and analyzed the expression of CDK1 protein, which activates TFCP2L1, and ID2, which inhibits the function of TFCP2L1. It was confirmed as a result that CDK1 and ID2 showed an inverse correlation, and a clinical basis was obtained for bladder cancer treatment through CDK1 inhibition and ID2 activation.

Accordingly, the research team sought to secure an in vivo basis for the treatment of bladder cancer based on the regulation of TFCP2L1-ID2 signaling system and designed a treatment method of using RO-3306 drug, which phosphorylates TFCP2L1 protein and specifically inhibits CKD1 protein, in combination with apigenin, a small molecule that promotes ID2 activation.

Later, when a combination of RO-3306 and apigenin was injected into an orthotopic xenograft animal model of bladder cancer, it was confirmed that the invasive power and tumor-sphere formation of bladder cancer cells HT1197 and HT1376 were suppressed. When 21 days passed after the transplantation of bladder cells, the two drugs were mixed and processed for 6 days. As a result, bladder size and weight were significantly reduced, and the malignancy of bladder cancer was reduced as well, seen from a histological examination.

Professor Dong-Myung Shin of the Department of Biomedical Science, University of Ulsan College of Medicine, said, “This study is of great significance demonstrating the roles and clinical benefits of ID2 as a direct target of the CDK1-TFCP2L1 pathway to suppress stemness feature of bladder cancer cells. I hope that an effective treatment for advanced bladder cancer will be developed based on the research findings so that many bladder cancer patients who have suffered from frequent recurrence and repeated treatment can enjoy a quality life.”

This research was supported by the National Research Foundation of Korea on Basic Science Research Program (Mid-Career Researcher Program and Sejong Science Fellowship) and Advanced Research Center Program.