Yan Xu, Ph.D. | Research | Publications

Research

My main research interests deal with understanding, at the molecular level, the mechanism of development of ovarian, breast, prostate, and other malignancies.  Theses include developing effective diagnostic and prognostic biomarkers for these diseases and novel therapeutic targets and methods to treat them.

We have pioneered research in the role of signaling lipid molecules in ovarian cancer and identified the first receptors for SPC and LPC :

We have identified the first lipid growth factor in ovarian cancer cells—We have purified and identified a factor in ascites from ovarian cancer patients and have termed it ovarian cancer activating factor, or OCAF.  The most striking feature of this factor is that it is not a peptide factor, but a lipid molecule.  OCAF is composed of several species of lysophosphatidic acid (LPA).  OCAF/LPA is sufficient to induce proliferation of ovarian and breast cancer cells as assayed by [3H]thymidine incorporation, MTT dye reduction or colony formation.

We have first demonstrated that LPA is a potential marker for the early detection of ovarian cancer—We have found that LPA levels are significantly elevated in plasma from patients with ovarian and other gynecological cancers, but not from patients with breast cancer or leukemia compared with normal healthy controls.  Particularly, LPA levels were also elevated in plasma from patients with early stage ovarian cancer where levels of CA 125, the most commonly used ovarian cancer marker, are often not elevated.  Moreover, LPA was not detected in plasma from patients with benign gynecological disease, where CA 125 levels are often elevated.  Therefore, LPA may represent a more sensitive and specific marker than CA 125 for the early detection of ovarian and other gynecological carcinomas.

We have developed a highly effective method to analyze lysophospholipids in body fluids and shown that certain bioactive lysophospholipids are elevated in blood, ascites, and peritoneal washings from patients with ovarian cancer—Recently, we have developed an electrospray ionization mass spectrometry (ESI-MS)-based assay for detection and quantification of LPA and closely related lysophospholipids.  This method can reproducibly detect various lipid species simultaneously with high sensitivity.  Using this method, we detected alkyl-LPAs and alkenyl-LPAs for the first time in human body fluids (ascites from patients with ovarian cancer).  We also detected SPC and other lysolipids in ovarian cancer ascites.  Most importantly, these bioactive lysolipids are elevated in blood and ascitic fluids from patients with ovarian cancer, but not in normal healthy controls or patients with non-malignant diseases.  These findings suggest that these lipid molecules are likely to be pathologically relevant to ovarian cancer.

We have investigated the role and signaling mechanisms of S1P, SPC, LPA, and other lysophospholipids in ovarian cancer development.  In addition, we have successfully employed the Clontech PCR-select cDNA subtraction kit and Affymetrix GeneChip in identification of genes up- or down regulated by LPA, S1P, and SPC.

Identification of the first receptors for SPC and LPC - Lysophospholipids and other small bioactive molecules function through G protein coupled receptors (GPCRs).  There is increasing evidence that abnormalities in the structure and function of GPCRs are responsible for many diseases, including cancers.  Molecular cloning and characterization of novel GPCRs will contribute to a better understanding of the normal functioning and signaling mechanisms of these receptors, as well as the role that these receptors play in cancer.  GPCRs hold enormous promise for therapeutic drug discovery, since about 50% of all existing pharmacenticals are targeted towards GPCRs.  In an effort to identify GPCRs in ovarian cancer cells, we have cloned a novel G protein coupled receptor gene (ovarian cancer G protein coupled receptor 1, or OGR1) from HEY ovarian cancer cells by degenerate oligonucleotide PCR amplification.  We have shown that SPC is a high-affinity ligand for OGR1 through calcium mobilization, ligand binding, receptor internalization, MAP kinase, and cell proliferation assays.  We have also identified an OGR1-related GPCR, GPR4, as not only another high affinity receptor for SPC, but also a receptor for LPC, albeit with a lower affinity. 

We will continue to: 1) investigate the role and signaling mechanisms of LPA, LPC, and SPC and their receptors in cancer and other diseases; 2) determine the structure-function relationship of the OGR1-subfamily receptors and establish molecular models of these receptors for drug development; and 3) determine the physiological and pathological roles and functions of OGR1-subfamily receptors using mouse knockout models.