Mien-Chie Hung, PhD, Oral History Interview, February 20, 2014

Major Topics Covered: Personal and educational background; witty and humorous personal stories Experiences of a Chinese immigrant and foreign graduate student The working strategies, inspirations, and commitment of a basic/translational scientist Research: signaling pathways and genes, Department of Molecular and Cellular Oncology: history, evolution, personal vision for Research culture at MD Anderson Vice President of Basic Research The Institute for Basic Science Effective leadership and mentoring Training young scientistshttps://openworks.mdanderson.org/mchv_interviewsessions/1151/thumbnail.jp

Mien-Chie Hung, PhD, Oral History Interview, April 21, 2014

Major Topics Covered: Personal and educational background; witty and humorous personal stories Experiences of a Chinese immigrant and foreign graduate student The working strategies, inspirations, and commitment of a basic/translational scientist Research: signaling pathways and genes, Department of Molecular and Cellular Oncology: history, evolution, personal vision for Research culture at MD Anderson Vice President of Basic Research The Institute for Basic Science Effective leadership and mentoring Training young scientistshttps://openworks.mdanderson.org/mchv_interviewsessions/1153/thumbnail.jp

Mien-Chie Hung, PhD, Oral History Interview, March 7, 2014

Major Topics Covered: Personal and educational background; witty and humorous personal stories Experiences of a Chinese immigrant and foreign graduate student The working strategies, inspirations, and commitment of a basic/translational scientist Research: signaling pathways and genes, Department of Molecular and Cellular Oncology: history, evolution, personal vision for Research culture at MD Anderson Vice President of Basic Research The Institute for Basic Science Effective leadership and mentoring Training young scientistshttps://openworks.mdanderson.org/mchv_interviewsessions/1152/thumbnail.jp

Regulation of Ubiquitination-Mediated Protein Degradation by Survival Kinases in Cancer

The ubiquitin–proteasome system is essential for multiple physiological processes via selective degradation of target proteins and has been shown to plays a critical role in human cancer. Activation of oncogenic factors and inhibition of tumor suppressors have been shown to be essential for cancer development, and protein ubiquitination has been linked to the regulation of oncogenic factors and tumor suppressors. Three kinases, AKT, extracellular signal-regulated kinase, and IκB kinase, we refer to as oncokinases, are activated in multiple human cancers. We and others have identified several key downstream targets that are commonly regulated by these oncokinases, some of which are regulated directly or indirectly via ubiquitin-mediated proteasome degradation, including FOXO3, β-catenin, myeloid cell leukemia-1, and Snail. In this review, we summarize these findings from our and other groups and discuss potential future studies and applications in the clinic

Nanoparticle Delivery of miR-34a Eradicates Long-Term-Cultured Breast Cancer Stem Cells via Targeting C22ORF28 Directly

Rationale: Cancer stem cells (CSCs) have been implicated as the seeds of therapeutic resistance and metastasis, due to their unique abilities of self-renew, wide differentiation potentials and resistance to most conventional therapies. It is a proactive strategy for cancer therapy to eradicate CSCs. Methods: Tumor tissue-derived breast CSCs (BCSC), including XM322 and XM607, were isolated by fluorescence-activated cell sorting (FACS); while cell line-derived BCSC, including MDA-MB-231.SC and MCF-7.SC, were purified by magnetic-activated cell sorting (MACS). Analyses of microRNA and mRNA expression array profiles were performed in multiple breast cell lines. The mentioned nanoparticles were constructed following the standard molecular cloning protocol. Tissue microarray analysis has been used to study 217 cases of clinical breast cancer specimens. Results: Here, we have successfully established four long-term maintenance BCSC that retain their tumor-initiating biological properties. Our analyses of microarray and qRT-PCR explored that miR-34a is the most pronounced microRNA for investigation of BCSC. We establish hTERT promoter-driven VISA delivery of miR-34a (TV-miR-34a) plasmid that can induce high throughput of miR-34a expression in BCSC. TV-miR-34a significantly inhibited the tumor-initiating properties of long-term-cultured BCSC in vitro and reduced the proliferation of BCSC in vivo by an efficient and safe way. TV-miR-34a synergizes with docetaxel, a standard therapy for invasive breast cancer, to act as a BCSC inhibitor. Further mechanistic investigation indicates that TV-miR-34a directly prevents C22ORF28 accumulation, which abrogates clonogenicity and tumor growth and correlates with low miR-34 and high C22ORF28 levels in breast cancer patients. Conclusion: Taken together, we generated four long-term maintenance BCSC derived from either clinical specimens or cell lines, which would be greatly beneficial to the research progress in breast cancer patients. We further developed the non-viral TV-miR-34a plasmid, which has a great potential to be applied as a clinical application for breast cancer therapy

Enhanced MDM2 Oncoprotein Expression in Soft Tissue Sarcoma: Several Possible Regulatory Mechanisms

Purpose. MDM2 is an oncogene whose protein product may promote tumorigenesis by blocking wild-type p53 tumor suppressor mediated G 0/G1 cell cycle arrest, thereby inhibiting repair of damaged DNA prior to cell division. While MDM2 DNA amplification is frequently observed in human sarcoma, the mechanisms linking this amplification to MDM2 oncoprotein over-production as well as its functional significance have not been well characterized in patients with soft tissue sarcoma

Interaction of Proliferation Cell Nuclear Antigen (PCNA) with c-Abl in Cell Proliferation and Response to DNA Damages in Breast Cancer

Cell proliferation in primary and metastatic tumors is a fundamental characteristic of advanced breast cancer. Further understanding of the mechanism underlying enhanced cell growth will be important in identifying novel prognostic markers and therapeutic targets. Here we demonstrated that tyrosine phosphorylation of the proliferating cell nuclear antigen (PCNA) is a critical event in growth regulation of breast cancer cells. We found that phosphorylation of PCNA at tyrosine 211 (Y211) enhanced its association with the non-receptor tyrosine kinase c-Abl. We further demonstrated that c-Abl facilitates chromatin association of PCNA and is required for nuclear foci formation of PCNA in cells stressed by DNA damage as well as in unperturbed cells. Targeting Y211 phosphorylation of PCNA with a cell-permeable peptide inhibited the phosphorylation and reduced the PCNA-Abl interaction. These results show that PCNA signal transduction has an important impact on the growth regulation of breast cancer cells

GSK-3β Targets Cdc25A for Ubiquitin-Mediated Proteolysis, and GSK-3β Inactivation Correlates with Cdc25A Overproduction in Human Cancers

SummaryThe Cdc25A phosphatase positively regulates cell-cycle transitions, is degraded by the proteosome throughout interphase and in response to stress, and is overproduced in human cancers. The kinases targeting Cdc25A for proteolysis during early cell-cycle phases have not been identified, and mechanistic insight into the cause of Cdc25A overproduction in human cancers is lacking. Here, we demonstrate that glycogen synthase kinase-3β (GSK-3β) phosphorylates Cdc25A to promote its proteolysis in early cell-cycle phases. Phosphorylation by GSK-3β requires priming of Cdc25A, and this can be catalyzed by polo-like kinase 3 (Plk-3). Importantly, a strong correlation between Cdc25A overproduction and GSK-3β inactivation was observed in human tumor tissues, indicating that GSK-3β inactivation may account for Cdc25A overproduction in a subset of human tumors