ABSTRACT
Perineural invasion of tumor cells is a characteristic feature of human pancreatic cancer. Unrevealing the molecular mechanisms that enable cancer cells to invade and grow along nerves is important for the development of novel therapeutic strategies in this disease. We have previously identified transcriptional changes in highly nerve invasive pancreatic cancer cells. Here we further analyzed one of the identified deregulated genes, MAPRE2, a microtubule-associated protein. MAPRE2 expression was significantly increased in high versus less nerve invasive pancreatic cancer cells, and changes of MAPRE2 expression resulted in altered actin distribution in these cells. MAPRE2 was predominately expressed in normal pancreatic acinar cells but absent in ductal cells. In pancreatic cancer, there was strong cytoplasmic and occasionally nuclear expression of MAPRE2 in the cancer cells themselves. Increased MAPRE2 mRNA levels in bulk pancreatic cancer tissues tended to be associated with reduced postoperative survival of pancreatic cancer patients. In conclusion, MAPRE2 is highly expressed in pancreatic cancer cells, and seems to be involved in perineural invasion. Therefore, targeting this microtubule-associated protein might be a promising approach in the therapy of pancreatic cancer.
Subject(s)
Biomarkers, Tumor/analysis , Microtubule-Associated Proteins/biosynthesis , Neoplasm Invasiveness/genetics , Pancreatic Neoplasms/pathology , Peripheral Nerves/pathology , Aged , Blotting, Western , Cell Line, Tumor , Female , Fluorescent Antibody Technique , Gene Expression , Gene Expression Profiling , Humans , Immunohistochemistry , Male , Microtubule-Associated Proteins/genetics , Pancreatic Neoplasms/metabolism , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Perineural invasion, the growth of tumor cells along nerves, is a key feature of pancreatic cancer. The cardinal symptom of pancreatic cancer, abdominal pain often radiating to the back, as well as the high frequency of local tumor recurrence following resection are both attributed to the unique ability of pancreatic tumor cells to invade the neuronal system. The molecular mechanisms underlying the neuroaffinity of pancreatic tumors are not completely understood. In this study, we developed a novel method to monitor ex vivo perineural invasion into surgically resected rat vagal nerves by different human pancreatic tumor cell lines. Genome-wide transcriptional analyses were employed to identify the consensus set of genes differentially regulated in all highly nerve-invasive (nerve invasion passage 3) versus less invasive (nerve invasion passage 0) pancreatic tumor cells. The critical involvement of kinesin family member 14 (KIF14) and Rho-GDP dissociation inhibitor beta (ARHGDIbeta) in perineural invasion was confirmed on RNA and protein levels in human pancreatic tumor specimens. We found significant up-regulation of KIF14 and ARHGDIbeta mRNA levels in patients with pancreatic cancer, and both proteins were differentially expressed in tumor cells invading the perineural niche of pancreatic cancer patients as detected by immunohistochemistry. Moreover, functional knockdown of KIF14 and ARHGDIbeta using small interfering RNA resulted in altered basal and/or perineural invasion of pancreatic tumor cells. Our work provides novel insights into the molecular determinants of perineural invasion in pancreatic cancer. The established nerve invasion model and the consensus signature of perineural invasion could be instrumental in the identification of novel therapeutic targets of pancreatic cancer as exemplified by KIF14 and ARHGDIbeta.
