Nearly 90% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDACs). PDAC is an aggressive invasive malignancy with a dismal overall median survival rate. The ability of PDAC to metastasize in early stage is one of the major causes for cancer deaths. Thus, identification of novel molecules and pathways important for promoting pancreatic cancer metastasis will provide opportunities to develop targeted therapies. Our previous studies revealed that cellular retinoic acid binding protein (CRABP-II) is overexpressed in human PDAC pre-cancerous lesions, in PDAC tumors, and particularly in metastatic lymph nodes, while it is not detectable in normal pancreatic tissues or chronic pancreatitis. Our preliminary results further show that CRABP-II facilitates pancreatic cancer cell migration and invasion without alteration of cell proliferation. Gene expression microarray revealed that interleukin 8 (IL-8), and its downstream targets MMP-2/MMP-14, are all dramatically down-regulated by deletion of CRABP-II. Based on the observation of the interaction of CRABP-II with HuR, a RNA binding protein in PDAC cells, we hypothesis that CRABP-II promotes PDAC metastasis by interacting with posttranscriptional regulatory machinery, hence regulating expression of metastatic genes such as those in the IL-8/MMP-14/MMP-2 axis. In this proposal, we seek to further investigate the pathological significance of CRABP-II in PDAC metastasis and the molecular mechanisms underlying the role of CRABP-II to facilitate cancer metastasis. Successful completion of this study will uncover a novel function of CRABP-II in pancreatic cancer biology, which we believe is distinct from its well-known role as an RA-carrier to facilitate RAR activation. The findings from this study will also shed new insights to a novel pathway that regulates PDAC progress and invasiveness, and provide a unique therapeutic opportunity to curb PDAC metastasis.
Pancreatic cancer is an aggressive invasive malignancy with a dismal overall median survival rate. The ability of pancreatic cancer to metastasize is the primary reason for its notoriously dismal clinical outcome. This proposal aims to explore a novel molecular role of CRABP-II in the regulation of genes important for tumor metastasis by interacting with transcriptional regulatory machinery. Elucidating this novel oncogenic pathway will provide rationales for developing novel targeted therapeutics to curb pancreatic cancer metastasis.
