Tumor progression model for PC in which the pancreatic ductal epithelium progresses from normal to increased grades of pancreatic intraepithelial neoplasia (PanINs) merely to invasive cancer. Multiple alterations in genes that are important in PC progression have been identified, for example K-ras, INK4A, p53, and SMAD4/DPC4 [4], [5]. PC is characterized by near-universal mutations in K-ras and frequent deregulation of crucial embryonic signalling pathways, including the Hedgehog (HH) signaling pathway [6], [7]. A better understanding of the mechanisms underlying the development of PC might help to improve early diagnosis and potentially identify molecular therapeutic targets. The hedgehog (HH) signaling pathway was first identified in the embryonic development of Drosophila [8] and has been shown to be crucial for growth and patterning in the pancreas during embryonic development.

HH signaling regulates cell differentiation and organ formation during embryonic development , and is expressed in pancreatic epithelial cells [9], [10]. Constitutive activation of HH signaling is detected in a variety of human cancers, including pancreatic cancer [9]�C[13]. Given its misexpression in both metastatic pancreatic cancer cell lines and in precursor lesions (PanIN) [14], HH signal activation may be involved in both early and late pancreatic tumorigenesis. Of the three mammalian ligands in the HH family, Sonic (SHH), Desert (DHH), and Indian (IHH) Hedgehog [15], the former has been associated with both pancreatic organogenesis and pancreatic cancer.

HH signals are transmitted and modified by two transmembrane proteins, patched (PTCH) and smoothened (SMO), and by downstream transcription factors that are members of the glioma-associated oncogene (GLI) family (GLI1, 2, and 3). GLI2 and GLI3 have transactivation and repressive domains, whereas GLI1 likely functions only as a transactivator and transcriptional target of the HH pathway itself [16]�C[19]. The regenerating gene (Reg) family, a group of small secretory proteins, is involved in cell proliferation or differentiation in digestive organs [20], is upregulated in several gastrointestinal cancers, and functions as trophic or antiapoptotic factors [21]�C[23]. RegIV, a member of the regenerating gene family, is involved in digestive tract malignancies, including the stomach [24], colorectum [25], [26], and pancreas [27], [28], as well as in benign diseases such as ulcerative colitis [29].

RegIV overexpression in tumor cells has been associated with cell growth, survival, adhesion, and resistance to apoptosis. Recently, RegIV overexpression Drug_discovery was reported to be associated with the initiation and progression of pancreatic cancer, and was suggested as a promising tumor marker to screen early stage PC and target for adjuvant therapy in PC [28], [30].