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Proteomic analysis of solid pseudopapillary tumor of the pancreas reveals dysfunction of the endoplasmic reticulum protein processing pathway.

ABSTRACT: Solid pseudopapillary tumor of the pancreas (SPTP) is a low-grade malignant tumor with a favorable prognosis after surgery. Many previous studies have focused on clinical features or pathological biomarkers of the disease, but a better understanding of the molecular mechanisms underlying SPTP may help guide future therapeutic strategies. Here, we used isobaric tags for relative and absolute quantitation (iTRAQ) technology integrated with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to identify differentially expressed proteins in SPTP specimens. A total of 1171 proteins with a threshold of a 1.5-fold change and a p value ? 0.05 between SPTP tissue and matched normal pancreas tissue were identified for bioinformatics analysis. Mass spectrometry results were then further confirmed by assessing six representative proteins (ACADL, EPHX2, MSI2, DKK4, JUP, and DAD1) in individual specimens with immunohistochemistry. Upon mapping of the differentially expressed proteins to the Kyoto Encyclopedia of Genes and Genomes pathways database, we found several new cell-adhesion molecules that could be used as pathologic biomarkers. Furthermore, we observed that many endoplasmic reticulum-associated proteins were altered, suggesting that endoplasmic reticulum stress may play an important role in SPTP tumorigenesis. Seven proteins (ERO1LB, TRIM1, GRP94, BIP, SEC61B, P4HB, and PDIA4) in this pathway were further validated by immunohistochemistry, and six of them (except SEC61B) coincided to the LC-MS/MS results. This first comprehensive analysis of the SPTP proteome confirms proteins that have been implicated in earlier reports and reveals novel candidates and pathways that could be investigated further for clinical applications.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC4188989 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Project description:ObjectiveSolid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor. This study aims to examine the clinicopathological features and surgical treatments of SPN and compare the clinical behavior and prognosis between men and women with SPN.MethodsWe collected the population data of patients with SPN diagnosed between 2004 and 2017 from the SEER database. The Kaplan-Meier method was used to analyze overall survival (OS) and disease-specific survival (DSS), and log-rank tests were used to evaluate the differences between subgroups. Univariate and multivariate Cox regression analyses were performed to screen out prognostic risk factors of SPN.ResultsA total of 378 patients with SPN were included, with 246 (65.1%) female patients. 1-, 3-, and 5-year overall survival rates were 98.9%, 95.7%, and 93.7%, respectively. Survival analysis revealed that regardless of stage, patients with SPN who underwent surgical interventions still had a significantly better prognosis than those without surgical interventions (P < .001). The patients with lymphatic dissection had a significantly better prognosis than those without lymphatic dissection (P < .001). Moreover, compared with female patients, male patients had significantly poorer OS and DSS (P < .001). Female SPN showed a bimodal age-frequency distribution with early-onset incidence at 28 years and late-onset peak incidence at 62 years, while male SPN presented a unimodal distribution with peak incidence at approximately age 64 years. In female patients, the tumor size in premenopausal females (<65 years old) was significantly larger than that in postmenopausal females (≥65 years old) (P < .001). Clinicopathological characteristic profiles were different not only between male SPN and premenopausal female SPN but also between premenopausal and postmenopausal female SPN.ConclusionSPN presents indolent behavior and predominantly occurs in young women. Regardless of stage, surgical intervention is recommended. Moreover, our study is the first large enough study to demonstrate sex-related discrepancies in SPN. Thus, different treatment strategies should be designed for patients of different sexes at different ages and hormone therapy is a promising approach for SPN.

Project description:Solid pseudopapillary neoplasm (SPN) of pancreas is a rare pancreatic neoplasm with a low metastatic potential. Up to 10% of patients with localized disease at presentation will develop systemic metastases, usually in the peritoneum or the liver. Due to the rarity of SPNs and the overall excellent prognosis, reliable prognostic factors to predict malignant biological behavior remain undetermined. Therefore, we aimed to define clinical, histological, and microRNA patterns that are associated with metastatic disease. We conducted a retrospective single center study on all patients operated for SPN of pancreas between 1995 and 2018. Clinical and pathological data were collected, and expression patterns of 2,578 human microRNAs were analyzed using microRNA array (Affimetrix 4.1) in normal pancreases (NPs), localized tumors (LTs), and metastatic tumors (MTs). The diagnosis of SPN was confirmed in 35 patients who included 28 females and 3 males, with a mean age of 33.8 ± 13.9 years. The only clinical factor associated with metastases was tumor size (mean tumor size 5.20 ± 3.78 in LT vs. 8.13± 1.03 in MT, p < 0.012). Microscopic features of malignancy were not associated with metastases, nor were immunohistochemical stains, including the proliferative index KI67. Higher expressions of miR-184, miR-10a, and miR-887, and lower expressions of miR-375, miR-217, and miR-200c were observed in metastatic tissues on microarray, and validated by real-time polymerase chain reaction. Hierarchal clustering demonstrated that the microRNA expression pattern of MTs was significantly different from that of LTs. The only clinical factor associated with metastases of SPN of pancreas was tumor size. Histological features and immunohistological staining were not predictive of metastases. A panel of six microRNAs was differentially expressed in MTs, and these findings could potentially be used to predict tumor behavior. Validation of these results is needed in larger series.

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Proteomic analysis of solid pseudopapillary tumor of the pancreas reveals dysfunction of the endoplasmic reticulum protein processing pathway.

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