Low P4HA2 and high PRTN3 expression predicts poor survival in patients with pancreatic cancer

Background: The tumor microenvironment in pancreatic cancer has a multifaceted role in disease development and progression. Prolyl 4-hydroxylase subunit alpha 2 (P4HA2) and proteinase 3 (PRTN3) are involved in the synthesis and degradation of collagen in the tumor microenvironment and have been identified as prognostic biomarker candidates for pancreatic cancer in our previous mass spectrometric study. This study aimed at validating prognostic performance of P4HA2 and PRTN3 in a larger cohort of patients.Methods: The expression of P4HA2 and PRTN3 was evaluated with tissue microarrays and immunohistochemistry in 140 patients with pancreatic cancer who underwent surgical resection. Kaplan-Meier and Cox proportional hazards regression modeling were used to explore the association of P4HA2 and PRTN3, either separately or combined, with clinicopathological factors and survival.Results: Most tumors were positive for P4HA2 (133/140, 95%), whereas 77 tumors (55%) were positive for PRTN3. Expression levels of P4HA2 and PRTN3 did not separately correlate with disease-free or overall survival, in either uni- or multivariable analysis. However, a low P4HA2 and high PRTN3 expression correlated with shorter disease-free survival (median 7.0 vs. 13.4 months, adjusted HR 3.24, 95% CI: 1.13-9.25, p=.028) and overall survival (median 8.5 vs. 25.8 months, adjusted HR 8.14, 95% CI: 3.41-19.44, p<.001).Conclusion: Our data show that a low P4HA2 and high PRTN3 expression correlates with poor survival in patients with pancreatic cancer, indicating the involvement of collagen deposition in the restraint of the tumor. The tumoral expression of PRTN3 reinforces the therapeutic potential of PR1-targeting immunotherapy in pancreatic cancer.