Pancreatic regenerating protein (regⅠ) and regⅠreceptor mRNA are upregulated in rat pancreas after induction of acute pancreatitis

AIM: Pancreatic regenerating protein (regI) stimulates pancreatic regeneration after pancreatectomy and is mitogenic to ductal and β-cells. This suggests that regIand its receptor may play a role in recovery after pancreatic injury. We hypothesized that regIand its receptor are induced in acute pancreatitis. METHODS: Acute pancreatitis was induced in male Wistar rats by retrograde injection of 3% sodium taurocholate into the pancreatic duct. Pancreata and serum were collected 12, 24, and 36 hours after injection and from normal controls (4 rats/group). RegIreceptor mRNA, serum regIprotein, and tissue regIprotein levels were determined by Northern analysis, enzyme-linked immunosorbent assay (ELISA), and Western analysis, respectively. Immunohistochemistry was used to localize changes in regIand its receptor. RESULTS: Serum amylase levels and histology confirmed necrotizing pancreatitis in taurocholate treated rats. There was no statistically significant change in serum regIconcentrations from controls. However, Western blot demonstrated increased tissue levels of regIat 24 and 36 h. This increase was localized primarily to the acinar cells and the ductal cells by immunohistochemistry. Northern blot demonstrated a significant increase in regIreceptor mRNA expression with pancreatitis. Immunohistochemistry localized this increase to the ductal cells, islets, and acinar cells. CONCLUSION: Acute pancreatitis results in increased tissue regIprotein levels localized to the acinar and ductal cells, and a parallel threefold induction of regIreceptor in the ductal cells, islets, and acinar cells. These changes suggest that induction of regIand its receptor may be important for recovery from acute pancreatitis

Reg4 and its downstream transcriptional activator CD44ICD in stage II and III colorectal cancer

Reg4 is highly expressed in gastrointestinal malignancies and acts as a mitogenic and pro-invasive factor. Our recent works suggest that Reg4 binds with CD44 and induces its proteolytic cleavage to release intra-cytoplasmic domain of CD44 (CD44ICD). The goal of this study is to demonstrate clinical significance of the Reg4-CD44/CD44ICD pathway in stage II/III colon cancer and its association with clinical parameters of aggression. We constructed a tissue microarray (TMA) of 93 stage II/III matched colon adenocarcinoma patients, 23 with recurrent disease. The TMA was immunohistochemically stained for Reg4, CD44, and CD44ICD proteins and analyzed to identify associations with tumor characteristics, recurrence and overall survival. The TMA data analysis showed a significant correlation between Reg4 and CD44 (

RNA Binding Protein CUGBP2/CELF2 Mediates Curcumin-Induced Mitotic Catastrophe of Pancreatic Cancer Cells

Curcumin inhibits the growth of pancreatic cancer tumor xenografts in nude mice; however, the mechanism of action is not well understood. It is becoming increasingly clear that RNA binding proteins regulate posttranscriptional gene expression and play a critical role in RNA stability and translation. Here, we have determined that curcumin modulates the expression of RNA binding protein CUGBP2 to inhibit pancreatic cancer growth.In this study, we show that curcumin treated tumor xenografts have a significant reduction in tumor volume and angiogenesis. Curcumin inhibited the proliferation, while inducing G2-M arrest and apoptosis resulting in mitotic catastrophe of various pancreatic cancer cells. This was further confirmed by increased phosphorylation of checkpoint kinase 2 (Chk2) protein coupled with higher levels of nuclear cyclin B1 and Cdc-2. Curcumin increased the expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) mRNA, but protein levels were lower. Furthermore, curcumin increased the expression of RNA binding proteins CUGBP2/CELF2 and TIA-1. CUGBP2 binding to COX-2 and VEGF mRNA was also enhanced, thereby increasing mRNA stability, the half-life changing from 30 min to 8 h. On the other hand, silencer-mediated knockdown of CUGBP2 partially restored the expression of COX-2 and VEGF even with curcumin treatment. COX-2 and VEGF mRNA levels were reduced to control levels, while proteins levels were higher.Curcumin inhibits pancreatic tumor growth through mitotic catastrophe by increasing the expression of RNA binding protein CUGBP2, thereby inhibiting the translation of COX-2 and VEGF mRNA. These data suggest that translation inhibition is a novel mechanism of action for curcumin during the therapeutic intervention of pancreatic cancers