Although pancreatic cancer accounts for only 2% of all malignancies, it is one of the most aggressive and lethal cancers known today, with a 5-year survival of less than 5%. It is the fourth most common cause of cancer-related death in the western countries. Patients with pancreatic cancer typically have poor prognosis partly because the cancer usually causes no symptoms early on and it is already metastatic at the time of diagnosis. The treatment options for pancreatic cancer include surgery, radiation and chemotherapy. 1) Currently, gemcitabine was chosen the first-line therapeutic drug to treat pancreatic cancer. However, the one-year survival of pancreatic cancer patients treated with gemcitabine was only about 18%. One of the major reasons for the poor therapeutic effects on pancreatic cancer was its high resistance to gemcitabine.2) Dozens of studies had been focused on the mechanisms of intrinsic or acquired gemcitabine resistance in pancreatic cancer. Among them, Annexin A2 (ANXA2), a member of the annexin family, was once identified to be involved in antiapoptotic effects on pancreatic cancer cells through its ligand progastrin.3) The annexin family members were calcium-dependent phospholipid-binding proteins. They played important roles in the regulation of cell growth and signal transduction pathways. ANXA2 was involved in diverse cellular processes such as cell motility, linkage of membrane-associated protein complexes to the actin cytoskeleton, endocytosis, fibrinolysis, ion channel formation and cell matrix interactions.4) ANXA2 had been proposed to function inside the cell in sorting of endosomes and outside the cell in anticoagulant reactions. 5,6) Additionally, enhanced expression of ANXA2 in human pancreatic carcinoma cells and primary pancreatic cancers was observed. 7) ANXA2 overexpression predicted an rapid recurrence after surgery in pancreatic cancer patients undergoing gemcitabine-adjuvant chemotherapy. 8)Ligands for ANXA2 were varied. The alternatively spliced segment of tenascin-C (TNfnA-D) was proved to be a receptor for ANXA2 with high affinity. 9) Tenascin-C (TN-C) was an important component of the provisional extracellular matrix (ECM) that characterized solid tumors. TN-C was a hexameric glycoprotein with a molecular weight of 210-400 kDa and was reported transiently present during ECM remodeling, embryo maturation, inflammation and neoplasias.10) Each subunit of TN-C contained a TA domain that formed a coiled-coil at the N-terminus, 14烯1/2 epidermal growth factor (EGF)-like domains, 8-15 fibronectin type III-like (FNIII) repeats (depending on alternative RNA splicing) and a fibrinogen-like domain (FBG). The universal FNIII domains (FNIII repeats 1-5 and FNIII repeats 6-8) were present in all TN-C variants. The largest TN-C variant also contains nine alternatively spliced domains (FNIII repeats A1-D, TNfnA-D, Fig. 1A) which were missing in the shortest splice variant. A small-molecular-weight variant of TN-C without TNfnA-D domains existed constitutively in normal tissues, whereas ...
GRP is a multi-functional peptide, which acts as a stress mediator as well as a growth factor linking stressor to cancer progression. GRP and its high-affinity receptor are useful targets for the diagnosis and treatment of cancers.
Abstract. Gastrin-releasing peptide (GRP) plays an important role in regulating tumor growth and migration. However, little is known about its role in human hepatocellular carcinoma (HCC) cells. This study explored the effect of GRP on the growth of HCC HepG2 cells and the underlying mechanisms. Expression of GRP and its cognate receptor (GRPR) were detected by immunocytochemisty, reverse transcription-PCR and Western blotting and compared between two human HCC cell lines (HepG2 and MHCC97H) and a normal hepatic cell line (HL-7702). The effects of GRP on cell proliferation and signaling pathways were examined by Western blotting, MTT assay and flow cytometry. Both GRP and GRPR were overexpressed in HepG2 and MHCC97H cells. GRP activated MAPK/ERK1/2 in HepG2 cells, leading to enhanced proliferation, reduced apoptosis and accelerated cell cycle progression. The effect of GRP on ERK1/2 was effectively attenuated by the GRPR antagonist PD176252 or MEK inhibitor U0126, but not by the TNF-路 protease inhibitor TAPI-1 or the EGFR tyrosine kinase inhibitor PD153035. The effect of GRP on the growth of HepG2 cells was significantly attenuated by PD176252 or U0126. GRP serves as a mitogen for HepG2 and MHCC97H cells. GRP promotes the growth of HepG2 cells through interaction with GRPR co-expressed in tumor cells, and subsequently activates MAPK/ERK1/2 via EGFRindependent mechanisms.
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