Regulatory networks in neural crest cell differentiation and cancer pathogenesis

Hongzi Liang, Purdue University

Abstract

Deregulation of mechanisms driving normal embryonic development is associated with diseases including cancer. Accordingly, discoveries from research of embryonic development may provide insight into understanding cancer pathogenesis, and vice versa. In my first study, I explored the molecular mechanism of cAMP-induced melanocyte differentiation from pluripotent neural crest (NC) cells at the expense of neuronal sympathoadrenal (SA) cells. The NC, known as the "fourth germ layer" specific to vertebrates, consists of cells with multiple differentiation potential. In primary cultures of NC cells, high intensity cAMP signaling promotes melanocyte differentiation while suppressing neuronal SA cell differentiation by an unknown mechanism. Employing primary cultures of avian NC cells and zebrafish as an animal model, my study demonstrates that in NC cells, cAMP-activated kinase HIPK2 downregulates co-repressor CtBP2 to induce concurrent expression of Mitf (melanocyte determining transcription factor) and REST (neuronal gene specific transcriptional repressor), leading to melanocyte promotion and neuronal SA cell suppression. The discovery that REST suppresses neuronal development led to the examination of its roles in the pathologic neuroendocrine differentiation (NED) associated with advanced prostate cancer (PCa). In my second study, I investigated the molecular mechanism for NED in advanced prostate cancer (PCa) and neuronal differentiation of NC cells. In advanced PCa, cancerous luminal epithelial cells transdifferentiate to neuroendocrine (NE)-like cells that secrete neuropeptide hormones. High serum levels of the secretory neuropeptides predict poor prognosis; however, the mechanism of NED remains unclear. By using human PCa cell lines, my study manifests that hypoxia-induced miR-106∼25 downregulates REST to allow expression of neuronal genes and miRNAs, resulting in NED and possible malignant tumor progression. This mechanism is further confirmed in the neuronal differentiation of NC cells. In conclusion, my research has identified regulatory pathways in pluripotent NC cell differentiation and NED of advanced PCa. By applying the finding that REST suppresses neuronal differentiation of NC cells, I discovered downregulation of REST is an essential step for NED in PCa; by applying the finding that hypoxia induces miR-106~25 to downregulate REST in PCa, I discovered the same mechanism is responsible for the neuronal differentiation of NC cells. Therefore, development and cancer are two sides of the same coin. Answers to one side may be found through the other.

Degree

Ph.D.

Advisors

Andrisani, Purdue University.

Subject Area

Molecular biology|Cellular biology|Developmental biology|Oncology

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