Previous research
Transcription factor and signaling pathway crosstalk in regulation of immune cell development and cancer
Transcriptional regulation of signaling pathway blood cell development
Platelets and red blood cells are derived from the megakaryocytic and erythroid cell lineages, respectively. Development of these cell lineages are known to be tightly controlled by a repertoire of cytokines. We demonstrated that the homeobox transcription factor DLX4 induces IL1beta-mediated NFkB signaling. By doing so, this protein promotes megakaryocytic differentiation while inhibiting erythroid differentiation. This suggests that transcription factors might play a role in blood development via modulating cytokine signaling loops (Trinh, et al, 2015, J Cell Sci).
(Trinh et al, 2015, J Cell Sci)
Transcription factor and molecular pathways in drug response and metastasis
We discovered high expression of the homeobox transcription factor DLX4 in a subset of breast cancer patients that are insensitive to doxorubicin and demonstrated that DLX4 expression renders cancers cells insensitive to this drug. Mechanistically, we demonstrated that the homeobox gene modulates the responsiveness of tumor cells to Topoisomerase II-targeting drugs by stimulating non homologous end-joining DNA break repair This finding might explain why some breast and ovarian cancer patients do not respond well to common targeted chemo drugs such as doxorubicin and etoposide (Trinh et al, 2013, Cancer Res).
In another study investigating ovarian cancer cell metastasis, we revealed that the oncogenic transcription factor promotes interaction between ovarian cancer cells and mesothelial cells leading to an increase in the numbers of tumor implants on the peritoneum. We showed that this oncoprotein exerts its effects by inducing expression of the cell surface molecule CD44 via the NF-kB signaling (Haria, Trinh, et al, 2015, Am J Pathol, equal contribution).
(Trinh et al, 2013, Cancer Res)
Transcriptional regulation of signaling pathway in cancer cell growth
The homeobox transcription factor DLX4 is absent from most normal adult tissues but is expressed in a wide variety of malignancies. In a study focused on the understanding of growth regulation in cancer, we discovered that the oncogenic transcription factor promotes tumor growth by counteracting TGF-β-mediated growth inhibition. It sequesters the common mediator Smad4 from binding to the receptor-regulated SMADs. This could explain, in part, the resistance of tumors to the anti-proliferative effect of TGF-β (Trinh et al., Oncogene, 2011).
(Trinh et al, 2009, Oncogene)
Transcriptional regulation of inflammatory signaling pathway in cancer angiogenesis
We demonstrated that homeobox transcription factor DLX4 induces production of the vascular endothelial growth factor VEGF in tumor cells leading to stimulation of endothelial cell growth and angiogenesis. DLX4 induces iNOS expression, in part, by interacting with, and stimulating, STAT1 activity, resulting in augmentation of iNOS-mediated cancer angiogenesis (Trinh et al. 2015, Mol Cancer). These findings raise the possibility that transcription factors might promote angiogenesis not only by directly regulating the transcription of angiogenic factors, but also by modulating intracellular signaling and environmental cues.
(Trinh et al. 2015, Mol Cancer)