Our research on transcription factors related to liver cancer and liver development has recently led in surprising new directions. We cloned Nkx2.8, a developmental homeobox transcription factor from human liver cancer and fetal liver, and made a knockout mouse, expecting to find altered liver development. Instead, the null mice have abnormal stem cell proliferations in the lung, ventral brain, and ventral spinal cord. Nkx2.8 is thus a negative regulator of these stem cells, and the marker gene that we inserted in place of Nkx2.8 provides a sensitive way to detect and isolate these cells. Most intriguing, the mice get progressive changes in their large airways that eventually lead to cancer. The similarity to human lung cancer has led to a pilot study of Nkx2.8 as a tumor suppressor of human cancer.

The stem cell and lung cancer research grew from projects that study (1) transcriptional regulators that control liver development and cell proliferation, (2) long-distance transcription controls that regulate a chromosomal locus, and (3) regulation of gene expression through a specific control language. This active research includes analysis of the domains of Nkx2.8, molecular reconstruction of enhancer-promoter interactions, chromatin structure, and combined molecular-bioinformatics analysis of gene control regions. A related project studies drugs and hormones that induce an alternate pathway of hepatocyte cell proliferation via nuclear receptor transcription factors. This form of proliferation is of particular interest because the drugs that activate it are powerful cancer promoters. Bioinformatics analysis of microarrays is a major part of the project—we are using arrays to define genes that activate the hepatocyte cell cycle and cause it to progress.

Our research already integrates transcriptional molecular biology, bioinformatics, and cancer biology, and we are exploring a new link to stem cell biology. 

Kajiyama Y, Tian J. and Locker J. Regulation of a-fetoprotein expression by Nkx2.8. Mol. Cell. Biol. 22:6122-6130, 2002.

Locker J., Ghosh D., Luc P.-V. and Zheng J. Definition and prediction of the full range transcription factor binding sites—the hepatocyte nuclear factor 1 dimeric site. Nucleic Acids Res. 30:3809-3817, 2002.

Locker J., Tian J., Carver R., Concas D., Cossu C., Ledda-Columbano G. M. and Columbano A. A common set of immediate-early response genes in liver regeneration and hyperplasia. Hepatology 38:314-325, 2003.

Locker J. (2004) A new way to look at liver cancer. Hepatology 40:521-523, 2004.

Columbano A., Ledda-Columbano G.M., Pibiri M., Cossu C., Menegazzi M., Moore, D.D., Huang, W., Tian, J., and Locker, J. Gadd45b is induced through a CAR-dependent TNF-independent pathway in liver hyperplasia. Hepatology, 2005, in press.