Consensus transcriptome signature of perineural invasion in pancreatic carcinoma.
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.
Abiatari
Ivane
I
Department of General Surgery, Technische Universität München, Ismaningerstrasse 22, Munich, Germany.
DeOliveira
Tiago
T
Kerkadze
Vachtang
V
Schwager
Christian
C
Esposito
Irene
I
Giese
Nathalia A
NA
Huber
Peter
P
Bergman
Frank
F
Abdollahi
Amir
A
Friess
Helmut
H
Kleeff
Jörg
J
D000818:Animals; D023102:Anoikis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014630:Vagus Nerve / Q000502:physiology*; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
D020730:Guanine Nucleotide Dissociation Inhibitors; D015513:Oncogene Proteins; D025521:Tumor Suppressor Proteins; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; C502598:KIF14 protein, human; D016547:Kinesins