Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
liver cancer, cirrhosis, cellular signaling, the MAPK pathway, targeted therapy
To understand the mechanistic regulation underlying tumorigenesis of normal cells is a long-term interest of my scientific research. Recently, taken hepatocytes as the experimental system, my lab has initiated studies on cell lineage conversion, specifically focusing on induction of functional hepatocyte-like cells from cells of non-hepatic origin. Striving to understand these two seemingly different phenomena, we slowly find ourselves in querying the essential scientific question: How is cell identity maintained through preventing the conversion of terminally differentiated cells to other cell types, including transdifferentiation to different lineages and transformation to tumor cells? We wish that with the efforts to address this question we would eventually contribute to the development of novel therapies for liver diseases and cancers.
1. The mechanism of tumorigenic transformation of hepatocytess
Epidemiological studies of human liver cancers indicate that genetic and epigenetic alterations are accumulated in a multi-stage manner. Advances in understanding molecular aberrations in malignant liver cancers have led to the development of efficient targeted therapies. On the other hand, preventive therapeutic approaches have been proposed to intervene at the initial phase of liver tumorigenesis (Nature Cell Biology, 2012). The critical step for developing effective preventive therapies is to identify targetable molecules and pathways responsible for liver cancer initiation.
2. Generating hepatocyte-like cells via transdifferentiation
We have previously shown that mouse fibroblasts are directly converted into induced hepatocyte-like (iHep) cells by Foxa3, Gata4 and Hnf1a expression and p19Arf inactivation (Nature, 2011). We are now working on converting non-hepatic human cells into hepatocytes by defined transcription factors, which could be used for generation of potential sources of hepatocytes for disease modeling, transplantation, and tissue engineering independent of donor organs.
3. Cell identity maintenance ¨C linking the tumorigenesis and lineage conversion
During the generation of iHep cells, we observed an extensive cell death, senescence and proliferation arrest in wild-type fibroblasts upon overexpression of the 3 hepatic transcription factors. Cell fate conversion is a dramatic process that is extremely rare in nature. It is conceivable that cells with defined identity should be preserved to maintain the physiological function of a given tissue. It is interesting that the p19Arf/p53 pathway is found to suppress both tumorigenesis and cell fate conversion. We speculate that the p19Arf/p53 pathway may be employed by normal cells as a common mechanism to maintain the cell identity.
- Huang, P., Zhang, L., Gao, Y., He, Z., Yao, D., Wu, Z., Cen, J., Chen, X., Liu, C., Hu, Y., Lai, D., Hu, Z., Chen, L., Zhang, Y., Ma, X., Pan, G., Wang, X., Hui, L. (2014). Direct reprogramming of human fibroblasts to functional and expandable hepatocyte-like cells. Cell stem cell 14: 370¨C384.
- Li, D., Cen, J., Chen, X., Conway, E.M., Ji, Y., and Hui, L. (2013). Hepatic loss of survivin impairs postnatal liver development and promotes expansion of hepatic progenitor cells in mice. Hepatology 58:2109-2121
- Ji, S., Zhang, L., and Hui, L. (2013). Cell fate conversion: direct induction of hepatocyte-like cells from fibroblasts. Journal of cellular biochemistry 114, 256-265. (Review)
- Min, L., Ji, Y., Bakiri, L., Qiu, Z., Cen, J., Chen, X., Chen, L., Scheuch, H., Zheng, H., Qin, L., Zatloukal, K., Hui, L.*, Wagner, E.F.* (2012). Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nature cell biology 14, 1203-1211. (*: Co-corresponding authors)
- Schultze, S.M., Mairhofer, A., Li, D., Cen, J., Beug, H., Wagner, E.F., and Hui, L. (2012). p38alpha controls erythroblast enucleation and Rb signaling in stress erythropoiesis. Cell research 22, 539-550.
- Huang, P., He, Z., Ji, S., Sun, H., Xiang, D., Liu, C., Hu, Y., Wang, X., and Hui, L. (2011). Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475, 386-389.
- Min, L., He, B., and Hui, L. (2011). Mitogen-activated protein kinases in hepatocellular carcinoma development. Seminars in cancer biology 21, 10-20. (Review)
- Huang, P., Han, J., and Hui, L. (2010). MAPK signaling in inflammation-associated cancer development. Protein & cell 1, 218-226. (Review)
- Hui, L., Zatloukal, K., Scheuch, H., Stepniak, E., and Wagner, E.F. (2008). Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. The Journal of clinical investigation 118, 3943-3953.
- Hui, L., Bakiri, L., Stepniak, E., and Wagner, E.F. (2007). p38alpha: a suppressor of cell proliferation and tumorigenesis. Cell Cycle 6, 2429-2433.
- Hui, L., Bakiri, L., Mairhorfer, A., Schweifer, N., Haslinger, C., Kenner, L., Komnenovic, V., Scheuch, H., Beug, H., and Wagner, E.F. (2007). p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nature genetics 39, 741-749.
- Hui, L., Zhang, X., Wu, X., Lin, Z., Wang, Q., Li, Y., and Hu, G. (2004). Identification of alternatively spliced mRNA variants related to cancers by genome-wide ESTs alignment. Oncogene 23, 3013-3023.
- Xu, L.*, Hui, L.*, Wang, S., Gong, J., Jin, Y., Wang, Y., Ji, Y., Wu, X., Han, Z., and Hu, G. (2001). Expression profiling suggested a regulatory role of liver-enriched transcription factors in human hepatocellular carcinoma. Cancer research 61, 3176-3181. (*: Co-first authors)
Education Background & Academic Experience
From 2008: Principle Investigator. Shanghai Institute of Biochemistry and Cell Biology (SIBCB), Shanghai, China.
2003-2008: Postdoctoral Fellow. Institute of Molecular Pathology (IMP), Vienna, Austria.
1998-2003: PhD. Shanghai Institute of Biochemistry and Cell Biology (SIBCB), Shanghai, China.
1992-1997: BS. University of Science and Technology of China (USTC), Hefei, China.