Journal
ANNALS OF SURGICAL ONCOLOGY
Volume 29, Issue 11, Pages 7180-7189Publisher
SPRINGER
DOI: 10.1245/s10434-022-12039-5
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Funding
- Japan Society for the Promotion of Science (JSPS) KAKENHI [JP19K18080]
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Decreased ROBO4 expression is associated with malignant phenotypes and poor survival outcomes in pancreatic cancer.
Background The axon guidance gene family, SLIT/ROBO pathway, controls neural network formation, which correlates with the development of several cancers. Methods We found through analysis of the public database that ROBO4, one of the axon guidance molecules among the SLIT/ROBO family, is significantly downregulated in primary pancreatic cancer tissues compared with adjacent normal tissues. We carried out transfection experiments using three pancreatic cancer cell lines (MiaPaCa-2, BxPC-3, and SW1990) and one pancreatic duct epithelial cell line (HPDE6c7). A total of 51 clinical samples were then examined by immunohistochemical staining to find an association between ROBO4 expression at the protein level, clinical characteristics, and surgical outcomes. Results ROBO4 overexpression suppressed the invasion and migration abilities in MiaPaCa-2 and BxPC-3, while ROBO4 siRNA transfection to SW1990 and HPDE6c7 enhanced those activities. PCR-based profiling detected MMP-9 as a candidate downstream target of ROBO4, which was validated by decreased MMP-9 activity after the ROBO4 overexpression assay. High ROBO4 expression clinical samples had significantly better overall survival rather than low ROBO4 cases (P = 0.048). Conclusion These findings suggest that decreased ROBO4 expression activates malignant phenotypes in cancer cells and is correlated with poor survival outcomes in pancreatic cancer.
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