Ruiying Zhao, MD, PhD

Areas of Interest

Research Interests

Crosstalk between p53 network and RNA regulation during tumor pathogenesis

Tremendous research has showed the vital role of tumor suppressor p53 at different stages of cancer development. As the central player to maintain cellular homeostasis, p53 regulates its target genes in response to various stimulations. Any change in p53 status could lead to undesired cell fate. Therefore, the fine tune control of p53 signaling is important and worth to explore. Even more, these factors as well as regulation steps could be useful point for developing therapeutic methods.

As a subunit of nuclear pore complex (NPC), the nuclear porin protein NUP98 has an established role in regulating macromolecule trafficking and mRNA export, our recent study interestingly showed that NUP98 itself is involved in p53 signaling through post posttranscriptional regulation on selected p53 target genes most notably p21, and may function as a tumor suppressor in Hepatocellular carcinoma (HCC). Mechanistically NUP98 is associated with the 3’UTR of the p21 gene and thereby stabilizes p21 mRNA. The selectively expression of p21 directs the entry of cell cycle arrest instead of apoptosis. Thus, p21 and some other p53 target genes’ mRNA levels are associated with the expression of NUP98 have been identified in human HCC samples. Hepatocellular carcinoma (HCC) is the fifth most common cancer disease worldwide and the third most common cause of cancer death. HCC is most common in Asia and its prevalence is rapidly increasing in Western countries including US. Chronic infection with HBV is the leading cause of HCC. Although treatment options have improved in the past 30 years, prognosis remains dismal for many patients due to unclear molecular mechanisms of HBV-mediated HCC. The HBV genome contains four overlapping genes including X, P, S/preS, and C/preC. The X gene, encoding a 17 kDa protein named HBX, is the most frequently integrated viral gene found in HCC and is suggested to play a vital role in HBV-mediated HCC development. Interestingly, we discovered that HBX protein has a negative impact on NUP98, then regulates the expression of several HCC related genes, such as IGFBP3. To understand the link between the p53/NUP98 axis and HBX may provide a fundamental molecular mechanism to illuminate HCC pathogenesis.

On the other hand, NUP98 chimeric mutants were often found in AML/CML due to the chromosomal translocation. NUP98-HOXA9 is the first NUP98 associated fusion protein has been identified from leukemia patient in 1996. AML, which is one of the major subtypes of leukemia, accounts for approximately 18% of childhood cancer diagnoses. As AML is a differentiation-defect disease, NUP98 fusion proteins likely inhibit hematopoietic differentiation. To elucidate how NUP98-HOXA9 contributes to the development and/or maintenance of leukemia stem cells (LSCs, the cell type capable of initiating and maintaining the leukemic clonal hierarchy) and how NUP98-HOXA9 is involved in dysregulation of p53, engineered NUP98-HOXA9 human ES lines are proposed. The NUP98-HOXA9 fusion has been endogenously expressed in human ESCs by CRISPR/Cas9 genome editing, differentiate the cells to hematopoietic lineages and study their pathological alterations and potential tumorigenic potential. Since current cancer cell lines are only isolated after many steps of tumor evolution these lines are not optimal for studying the biological function of chromosomal translocations during tumor development and progression of NUP98-HOXA9 in AML. The NUP98-HOXA9 hESC model not only can be used for studying NUP98-HOXA9-associated AML, but will also advance information for other AMLs with NUP98 fusions such as NUP98-HOXA11, NUP98-HOXA13, NUP98-HOXC11, NUP98-HOXC13, NUP98-NSD1, and others. This model will provide a valuable resource for the leukemia scientific research community. Also, identification of an LSC population in NUP98-HOXA9-associated AML could enable future therapies for AML patients.