Kakehashi Anna, Suzuki Shugo, Nishidoi Yusaku, Hagihara Atsushi, Ikenaga Hiroko, Shiota Masayuki, Qiu Guiyu, Noura Ikue, Kuwae Yuko, Vachiraarunwong Arpamas, Fujioka Masaki, Gi Min, Kawada Norifumi, Wanibuchi Hideki
Department of Molecular Pathology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-ku, Osaka 545-8585, Japan.
Cancers (Basel). 2025 Jul 1;17(13):2212. doi: 10.3390/cancers17132212.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death and tumors with an extremely poor prognosis. In the present study, novel biomarker candidates useful for the early diagnosis and prognosis of human invasive PDAC were investigated. Biomarker candidates were first selected based on the proteomic/bioinformatic and clinico-pathological analyses of 10 and 100 patients with PDAC, respectively, operated at Osaka Metropolitan University Hospital (Exp. 1). Next, the expression and secretion of the target protein and its EV mRNA were investigated in pancreatic cancer cells in vitro and in a Balb/c nude mouse model. In addition, the protein and EV mRNA levels of candidate molecules were measured in the blood serum of 36 PDAC and 10 IPMN patients, and diagnostic significance was assessed (Exp. 2). A significant elevation of peroxiredoxin 3 (PRX3), a mitochondrial matrix protein, was found in PDAC via LC-Ms/Ms analysis. In Exp. 1, PRX3 overexpression was found in PDAC and PanIN lesions and was associated with a tumor infiltrative growth pattern (INFc) and poor overall 1-year patient survival. The prognostic value was significantly improved when PRX3 was combined with serum SPan-1 and DUPAN-2 markers in survival analyses. Furthermore, the PRX3 protein and its extracellular vesicle (EV: exosome and oncosome)-incorporated mRNA were secreted at detectable levels from PANC-1, MIAPaCa-2, and SW1990 cells into the blood of Balb/c nude mice bearing tumors. The overexpression of PRX3 was positively correlated with that of cancer stem cell marker CD44 variant 9 (CD44v9), P-Nrf2, and FOXO3a, as well as the generation of reactive oxygen species. In Exp. 2, a significant increase in PRX3 protein and EV mRNA was detected in the blood serum of PDAC subjects compared to IPMN patients and healthy controls. Significantly higher PRX3 protein levels were found in the IPMN group. The elevation of PRX3 EV mRNA was significantly associated with poor patient survival. These results indicate that PRX3 may become a novel early biomarker for PDAC diagnosis and prognosis.
胰腺导管腺癌（PDAC）是癌症死亡的主要原因之一，其肿瘤预后极差。在本研究中，对可用于人类侵袭性PDAC早期诊断和预后的新型生物标志物候选物进行了研究。首先分别基于大阪市立大学医院接受手术的10例和100例PDAC患者的蛋白质组学/生物信息学及临床病理分析来选择生物标志物候选物（实验1）。接下来，在体外胰腺癌细胞和Balb/c裸鼠模型中研究了靶蛋白及其细胞外囊泡（EV）mRNA的表达和分泌情况。此外，在36例PDAC患者和10例胰腺导管内乳头状黏液性肿瘤（IPMN）患者的血清中检测了候选分子的蛋白质和EV mRNA水平，并评估了其诊断意义（实验2）。通过液相色谱-串联质谱（LC-Ms/Ms）分析发现，线粒体基质蛋白过氧化物还原酶3（PRX3）在PDAC中显著升高。在实验1中，发现PRX3在PDAC和胰腺上皮内瘤变（PanIN）病变中过表达，且与肿瘤浸润性生长模式（INFc）及患者1年总生存率低相关。在生存分析中，当PRX3与血清糖链抗原1（SPan-1）和胰腺癌相关抗原2（DUPAN-2）标志物联合使用时，预后价值显著提高。此外，PRX3蛋白及其包含在细胞外囊泡（EV：外泌体和肿瘤小体）中的mRNA以可检测的水平从PANC-1、MIAPaCa-2和SW1990细胞分泌到荷瘤Balb/c裸鼠的血液中。PRX3的过表达与癌症干细胞标志物CD44变体9（CD44v9）、磷酸化核因子E2相关因子2（P-Nrf2）和叉头框蛋白O3a（FOXO3a）的过表达以及活性氧的产生呈正相关。在实验2中，与IPMN患者和健康对照相比，PDAC患者血清中PRX3蛋白和EV mRNA显著增加。在IPMN组中发现PRX3蛋白水平显著更高。PRX3 EV mRNA的升高与患者生存不良显著相关。这些结果表明，PRX3可能成为PDAC诊断和预后的新型早期生物标志物。
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