Laboratory of Molecular and Biochemical Research
We are now working on the following projects.
Stem cells possess two main attributes, namely, a self-renewal capacity and multipotency. Self-renewal refers to the ability of a cell to replicate itself without differentiating or losing multipotency. Multipotency is the ability to differentiate into more than one cell lineage. Stem cells repeat self-renewal and differentiation to produce tissues and organ in our body. Interestingly, stem-like cells exist also in the tumor tissues, and are called "cancer stem cells". It is thought that cancer stem cells produce tumor tissues and are responsible for cancer recurrence. However, the nature of cancer stem cells is still unknown.
We are now focusing our attention on the similarity between embryonic stem (ES) cells and cancer stem cells (Fig. 1). Both cells show similar properties, including tumor formation ability, high telomerase activity and indefinite growth. These stem cells display similarities also at a molecular level（Koide, 2014）. For example, STAT3 and Myc, which are involved in tumor growth, play an important role in ES cell self-renewal, while two critical factors for ES cell self-renewal, Oct3/4 and Sox2, participate in tumor growth. We have demonstrated that β-catenin and Etv4/5, which are implicated in tumor development and growth, regulate the self-renewal in ES cells（Takao et al., 2007; Kelly et al., 2011; Akagi et al., 2015）.
These similarities, as well as the genetic stability and the little genetic variation of ES cells, encouraged us to isolate a novel oncogene(s) from genes that are expressed in self-renewing ES cells. We have succeeded to identify an ES-specific transcription factor Zfp57 as a novel oncogene （Tada et al., 2015）（Fig. 2）. Furthermore, we found that Zfp57 is involved in the metastasis of colorectal cancer（Shoji et al., 2019）. We also found that an ES-specific transcription factor Nanog positively regulates Zfp57 expression （Yamaguchi et al., 2014; Shoji et al., 2019）.
We are currently examining the molecular mechanism of Zfp57-induced tumorigenesis, as well as searching for another ES-specific oncogene.
To utilize ES and iPS cells for regenerative medicine, we need to expand these cells efficiently to obtain sufficient amount of cells for transplantation. Previous studies demonstrated that ACTH, Shh and activin promote ES cell growth.
We are searching for such ES growth factors by taking the advantage of the similarity between ES and cancer stem cells. More specifically, we are exploring the possibility that tumor growth-promoting factors may enhance ES cell growth. In fact, we recently found that PDGF-C can promote the growth of ES cells（Kinjo et al., 2018）（Fig. 3）.
We are currently examining the molecular mechanism of PDGF-C-stimulated proliferation, as well as searching for another growth factor for ES cells.
- Akagi et al. (2015) ETS-related transcription factors ETV4 and ETV5 are involved in proliferation and induction of differentiation-associated genes in ES cells. J. Biol. Chem. 290, 22460-22473.
- Kelly et al. (2011) β-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism. Cell Stem Cell 8, 214-227.
- Kinjo et al. (2018) Platelet-derived growth factor-C functions as a growth factor in mouse embryonic stem cells and human fibrosarcoma cells. Cell. Mol. Biol. Lett. 23, 8.
- Koide (2014) Embryonic stem cells and oncogenes. in Pluripotent Stem Cell Biology - Advances in Mechanisms, Methods and Models (Craig S. Atwood & Sivan Vadakkadath Meethal eds.) pp 41-61, InTech.
- Shoji et al. (2019) The ES cell-specific transcription factor ZFP57 promotes liver metastasis of colorectal cancer. J. Surg. Res. 237, 22-29.
- Tada et al. (2015) The stem cell transcription factor ZFP57 induces IGF2 expression to promote anchorage-independent growth in cancer cells. Oncogene 34, 752-760.
- Takao et al. (2007) β-Catenin up-regulates Nanog expression through interaction with Oct-3/4 in embryonic stem cells. Biochem. Biophys. Res. Commun. 353, 699-705.
- Yamaguchi et al. (2014) Nanog positively regulates Zfp57 expression in mouse embryonic stem cells. Biochem. Biophys. Res. Commun. 453, 817–820.