Pilot Project: Understanding the Mechanism of Sulfiredoxin-induced Colorectal Cancer Cell Invasion and Metastasis

The long-term goal of our research is to understand the molecular basis of human colorectal cancer pathogenesis and to identify molecular targets that can be used to develop novel strategies for cancer prevention and treatment. Sulfiredoxin (Srx) is the master enzyme that reduces the hyperoxidized inactive form of Peroxiredoxins (Prxs). In contrast to the well-documented biochemical function of Srx in redox regulation,however, the biological significance of Srx expression in huma cancer has not been well understood. In a preliminary study we have demonstrated that Srx is highly expressed in human colorectal cancer but not in normal colon epithelium or benign tumors. The levels of Srx expression in colorectal adenocarcinoma are positively correlated with their TNM stages, i.e., significant high levels of Srx expression are observed in stage II or above, which are characterized by indications of invading to subserosa or metastases. Moreover, Srx is found to be preferentially expressed in human colorectal cancer cell lines but not in cells derived from normal colon epithelium. Furthermore, we have also demonstrated that Srx is required for the matrigel invasion of poorly-differentiated colorectal cancer cells by loss-of-function experiments, whereas ectopic expression of Srx in well-differentiated colorectal tumor cells promotes cell invasion by gain-of-function experiments. Based on these findings, we hypothesized that Srx promotes invasion and metastasis of human colorectal cancer cells, and targeting Srx or Srx-mediated signaling may provide novel strategies for colorectal cancer prevention and treatment. To test this hypothesis, the first specific aim is to investigate whether Srx contributes to distant metastases in vivo by orthotopic implantation of human colorectal cancer cells into mouse colon. The second aim is to explore the molecular mechanism of Srx-mediated Epithelial-Mesenchymal Transition (EMT) and its role in promoting colorectal cancer cell invasion and metastasis. The third aim is to explore Srx-associated gene expression changes and to identify essential regulator(s) that mediates these changes in response to Srx expression in human colorectal cancer cells. Series of experiments using advanced biochemistry and molecular biology techniques as well as cell culture and mouse models are proposed and will be accomplished by a talented group of graduate students and postdoctoral fellows under the guidance of the principal investigator. Accomplishment of these aims will generate significant amounts of data not only critical for an external grant application, but are also essential for the mechanistic understanding of the molecular basis of human colorectal cancer pathogenesis and future translational studies, which may eventually contribute to the development of novel strategies for cancer prevention and treatment.