Hu Dingyuan, Ansari Daniel, Zhou Qimin, Sasor Agata, Said Hilmersson Katarzyna, Andersson Roland
a Department of Gastroenterology , The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University , Wenzhou , China.
b Department of Surgery, Clinical Sciences , Lund University and Skåne University Hospital , Lund , Sweden.
Scand J Gastroenterol. 2019 Feb;54(2):246-251. doi: 10.1080/00365521.2019.1574360. Epub 2019 Mar 17.
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.
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.
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).
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.
胰腺癌中的肿瘤微环境在疾病发展和进展中具有多方面作用。脯氨酰4-羟化酶α2亚基（P4HA2）和蛋白酶3（PRTN3）参与肿瘤微环境中胶原蛋白的合成与降解，在我们之前的质谱研究中已被确定为胰腺癌预后生物标志物候选物。本研究旨在验证P4HA2和PRTN3在更大患者队列中的预后性能。
采用组织芯片和免疫组化方法评估140例行手术切除的胰腺癌患者中P4HA2和PRTN3的表达。使用Kaplan-Meier法和Cox比例风险回归模型分别或联合探讨P4HA2和PRTN3与临床病理因素及生存的相关性。
大多数肿瘤P4HA2呈阳性（133/140，95%），而77例肿瘤（55%）PRTN3呈阳性。在单变量或多变量分析中，P4HA2和PRTN3的表达水平与无病生存期或总生存期均无单独相关性。然而，低P4HA2和高PRTN3表达与较短的无病生存期（中位时间7.0个月对13.4个月，校正风险比3.24，95%置信区间：1.13 - 9.25，p = 0.028）和总生存期（中位时间8.5个月对25.8个月，校正风险比8.14，95%置信区间：3.41 - 19.44，p < 0.001）相关。
我们的数据表明，低P4HA2和高PRTN3表达与胰腺癌患者的不良生存相关，表明胶原蛋白沉积参与肿瘤抑制过程。PRTN3在肿瘤中的表达增强了靶向PR1免疫疗法在胰腺癌中的治疗潜力。
