Functions and Regulations of Phospho Residues of Stress-Induced Phosphoprotein 1 (Stip1) in Ovarian Cancer

Ovarian cancer remains the leading cause of female cancer death in Taiwan as well as worldwide. The data of post-genomic era has shed some light in the understanding of the molecular mechanisms of the tumorigenesis of ovarian cancer. Stress-induced phosphoprotein 1 (STIP1) is a co-chaperone of heat shock protein (HSP) 70/HSP90, chaperones of diverse cellular functions. STIP1 is overexpressed in various cancers including ovarian, hepatocellular, colon, melanoma, and pancreatic tumors. Our group has investigated extensively on the role of STIP1 in cancer cells. We first found that STIP1 was overexpressed in ovarian cancer, and served as a biomarker for the detection of this disease (US patent No: 7851230). We further showed that STIP1 activated the ALK2-SMAD pathway that promoted cell proliferation. STIP1 was also revealed to play an important role in maintaining the stability of JAK2, in the oncogenic IL6-JAK2-STAT3 pathway. We then dissected the domains of STIP1 with less clear function, i.e. DP2 domain of C-terminal, and found that a Peptide 520 (520-543 amino acids in the C-terminal) has inhibitory effects on cancer cell growth and tumor in mice model. US Patent (No: 9145449) on the application of Peptide 520 is released on Sept. 29, 2015. Nevertheless, there are gaps in our understanding of STIP1 and its role in the tumorigenesis of ovarian cancer. Whether the mutations in exons and promoter regions of STIP1 regulates its upregulation in cancer is unknown. We hypothesized that the identification of upstream kinases of STIP1 will help understand the regulation of the STIP1 signaling pathway. In addition, we would like to understand which phosphorylation sites of STIP1 are important for its functions as a phosphoprotein. In the 3-year project, we aim to achieve: 1. To discover how STIP1 is upregulated in cancer cells. 2. To identify the upstream regulators of STIP1 in the cells. 3. To elucidate the functions of phospho residues in STIP1.

Project ID:PC10507-0268
External Project ID:MOST105-2314-B182-056