Differential Machinery of Pluripotency Regulation in Stem Cells in Embryonic Stage and Somatic Cancers and Its Clinical Implications in Human Diseases---Crosstalk among Niche Growth Factor/Cytokine Signaling, Extracellular Matrix, and Epigenetic Netw (I)

Pluripotency regulation is critical for early embryogenesis and cancer development. In early embryogenesis, embryonic stem cells and embryonic germ cells are two cell origins under pluripotency regulation. Embryonic germ cells involve in germ cell development, particularly for pluripotent primordial germ cells (PGCs). Defects in early PGC cell were in specificity and competence from epiblasts to genital ridges lead to infertility and/or extragonadal germ cell tumors, such as testicular germ cell tumors (TGCTs). The TGCTs are histologically classified into seminomas and non-seminomas. Pluripotent stem cells in TGCTs include seminomas (which are generally transformed from PGCs) and the embryonal carcinoma (EC) in non-seminomas. In clinic, pluripotent seminomas and ECs of TGCTs are able to differentiate into other tumor types (e.g., teratomas, yolk sac tumors, and choriocarcinomas), and the differentiated TGCTs are more malignant and display higher resistance to chemotherapy. For embryonic stem cells, the pluripotency contributes to three somatic germ layer formations. Down-regulation of the pluripotency-related gene levels in embryonic stem cells leads to differentiation into somatic cells. Recently, re-expression of pluripotency-related genes in somatic cancers, so called cancer stemness, has been highly associated with drug resistance, early tumor relapse, and poor prognosis which challenge the cancer therapy currently. However, differential mechanism involving pluripotency regulation of cells in embryonic- and somatic lineage still remains largely unknown. Understanding the underlying mechanism will benefit the research in stem cell biology as well as the drug development targeting on cancer stemness in human diseases. The external niche signaling and internal epigenetic networks will be critical for pluripotency regulation between PGCs and somatic cancers (Appendix II-SP3, Fig. 8). This pre-proposal will extend our previous findings (Appendix II-SP3, Figs. 1-10) on pluripotent mouse germline stem cells and somatic cancers to further identify how the niche signaling (in particular for endocrinal growth factor and inflammatory cytokines), ECM, and epigenetic networks regulates the pluripotency of cells in embryonic stage (embryonic germline stem cells) and somatic lineage, and its implications in human disease. Three specific aims will be addressed as listed: Aim 1: To identify how niche insulin-like growth factor I receptor (IGF-IR) signaling cooperates with extracellular matrix (laminin and integrin a6 CD49f) and epigenetic regulators (microRNA and DNMT) to regulate the self-renewal proliferation and OCT4 expression in embryonic pluripotent mouse and human pluripotent germ cells and tumors (using mouse pluripotent AP+GSCs, human ES-derived PGCs, and seminomas/embryonal carcinomas). (The 1st and 2nd years) Aim 2: To identify how niche growth factor/cytokine signaling (IL-6/IGF-IR) cooperates with extracellular matrix (laminin and integrin a6 CD49f) in regulating epigenetic regulators (microRNA and DNMT) by which to mediate the re-expression of pluripotency-related genes (OCT4 and NANOG) in somatic cancers (using hepatocellular carcinomas (HCC) and renal cell carcinoma)(The 1st and 2nd years) Aim 3: To identify the IL-6/IGF-IR-stimulated specific differential genetic/epigenetic regulatory machinery for HIF-2a-mediated OCT4 expression in cells of embryonic stage and somatic cancers and its clinical implication on drug resistance and early recurrence of human disease (targeting on HCC) (The 2nd and 3rd years)