Serum APN/CD13 as a novel diagnostic and prognostic biomarker of pancreatic cancer

Pang, Li; Zhang, Nan; Xia, Yan; Wang, Dawei; Wang, Guoqing

doi:10.18632/oncotarget.12835

Cited by 28 publications

(18 citation statements)

References 27 publications

(36 reference statements)

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“…In our study, NEP/CD10, ACE2 and APA activity was higher in renal cancer patients than in healthy controls. This result agrees with those described in pancreatic and colorectal cancer [ 48 , 49 ] but it is opposite to that demonstrated in breast cancer [ 47 ], which suggests that tumor-specific changes of angiotensin-regulating enzymes occur also in serum of cancer patients.…”

Section: Discussionsupporting

confidence: 90%

“…Angiotensin-regulating peptidases can be secreted to the extracellular space and appear in serum [ 44 ]. The comparative studies of peptidase profiles among cancer patients and control subjects have yielded significant results in several studies [ 47 – 49 ]. In our study, NEP/CD10, ACE2 and APA activity was higher in renal cancer patients than in healthy controls.…”

Section: Discussionmentioning

confidence: 99%

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Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients

et al. 2017

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The discovery of the intrarenal renin-angiotensin system (iRAS), which regulates angiogenesis, cell differentiation and proliferation, has opened new perspectives in the knowledge of kidney carcinogenesis. In this study we analyzed the immunohistochemical expression and fluorimetric activity of four key peptidases of iRAS in tumor tissue (n = 144) and serum samples (n = 128) from patients with renal neoplasms. Neutral endopeptidase (NEP/CD10), Angiotensin-converting enzyme-2 (ACE2), and aminopeptidase A (APA) were expressed in tumor cells whilst Angiotensin-converting enzyme (ACE) was expressed in the endothelial cells of intratumor blood vessels. The expression of ACE, ACE2 and NEP/CD10 was highest in clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). The expression of these enzymes correlated with CCRCC aggressiveness. In addition, NEP/CD10 correlated with 15-year overall survival. On the other hand, APA expression was decreased in CCRCC with higher grade and stage. The loss of expression of APA independently correlated with a worse 15-year overall survival. Serum activity of ACE2, NEP/CD10 and APA was significantly higher in renal tumor patients than in healthy subjects. Serum ACE activity was lower in high grade and metastatic CCRCC patients, and NEP/CD10 activity was negatively correlated with UISS (UCLA Integrated Staging System) and SSIGN (Mayo Clinic stage, size, grade and necrosis model) scores and with overall survival of CCRCC patients. These results suggest a metabolic imbalance of iRAS in renal tumors. This finding should be taken into account in the search of new diagnostic, prognostic and therapeutic tools for this disease.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients

et al. 2017

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“…The sensitivity against the false-positive rate (1 –specificity) was plotted. Optimal cutoff values were defined for serum MMP-2 according to the Youden index [ 23 ]. The cumulative survival rates were calculated in a survival curve using the Kaplan–Meier method and compared using the log-rank test.…”

Section: Methodsmentioning

confidence: 99%

Serum MMP-2 as a potential predictive marker for papillary thyroid carcinoma

Shi

et al. 2018

PLoS ONE

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ObjectiveThe prevalence of papillary thyroid carcinoma (PTC) is rising rapidly. However, there are no reliable serum biomarkers for PTC. This study aimed to investigate the validity of preoperative serum matrix metalloproteinase-2 (MMP-2) as a biomarker for predicting prognosis of PTC after total or partial thyroidectomy.MethodsMale patients with PTC or a benign thyroid nodule (BTN) and healthy controls (HCs) were retrospectively included. Receiver operating characteristic (ROC) curves were constructed to evaluate the performance of preoperative serum MMP-2 in diagnosing PTC, predicting lymph node metastasis (LNM), and predicting structurally persistent/recurrent disease (SPRD). Multivariate logistic regression and Cox regression were applied to identify independent risk factors for SPRD.ResultsThe preoperative serum MMP-2 concentration in the PTC group was higher than those in BTN and HC groups. The concentration of postoperative serum MMP-2 decreased in comparison with pre-operation. ROC curves showed that serum MMP-2 could differentially diagnose PTC from BTN at the cutoff value of 86.30 ng/ml with an area under the curve (AUC) of 0.905 and could predict central LNM (CLNM) at the cutoff value of 101.55 ng/ml with an AUC of 0.711. Serum MMP-2 ≥101.55 ng/ml, age ≥45 years, and advanced TNM stage were independent risk factors for CLNM. Patients with SPRD had a higher median MMP-2 level (149.22 ng/ml) than patients without SPRD (104.55 ng/ml). Serum MMP-2 at the cutoff value of 144.04 ng/ml could predict SPRD in PTC patients with an AUC of 0.803. Advanced TNM stage and serum MMP-2 ≥144.04 ng/ml were independent risk factors for SPRD. Patients with serum MMP-2 ≥144.04 ng/ml had a worse clinical outcome than those with MMP-2 <144.04 ng/ml.ConclusionPreoperative serum MMP-2 may serve as a biomarker for diagnosing PTC and a predictive indicator for LNM and SPRD in male patients with PTC.

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“…The inhibition of APN expression results in a significant decrease in the metastasis of T24 cell lines ( 4 ). High APN expression has been considered an indicator of metastasis and poor prognosis in bladder cancer, as well as in lung, pancreas and colon cancers ( 5 , 23 , 24 ). Moreover, a previous study revealed that ubenimex could inhibit metastasis and invasion of PC-3 cells and that this effect was related to the inhibition of APN activity ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

Ubenimex, an APN inhibitor, could serve as an anti‑tumor drug in RT112 and 5637 cells by operating in an Akt‑associated manner

Wang

Liu

et al. 2018

Mol Med Report

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Bladder cancer, a common urinary tract tumor, has high mortality and recurrence rates associated with metastasis. Aminopeptidase N (APN) expression and metastasis have been indicated to be associated with one another. Ubenimex may function as an APN inhibitor to inhibit the degradation of the extracellular matrix during tumorigenesis. Furthermore, APN has been widely used as an adjuvant therapy for the treatment of tumors; however, little information is available regarding the impact of ubenimex on patients. Autophagy is suggested to be important in the transformation and progression of cancer. Additionally, apoptosis, which leads to the rapid demolition of cellular organelles and structures, has also been suggested as an important factor. Thus, the present study investigated the role of ubenimex in inhibiting migration and invasion by downregulating APN expression levels to induce autophagic cell death and apoptosis in bladder cancer cells. RT112 and 5637 cell lines were treated with varying doses of ubenimex. Cell viability was measured by CCK8 colorimetry and flow cytometry. Using fluorescence microscopy, autophagic cell death was assessed using acridine orange/ethidium bromide staining. Furthermore, apoptotic cell death was assessed using flow cytometry and Trypan blue staining was used to evaluate the cell death rate. Protein expression was determined by western blot analysis. Matrigel invasion assays were exploited to assess the invasion capabilities of 5637 cells. Wound-healing migration assays and Matrigel migration assays were exploited to assess the migratory abilities of 5637 cells. Treatment with ubenimex was accompanied by decreased Akt expression, indicating that ubenimex may have similar functions to Akt inhibitors. Results also indicated that ubenimex inhibited cell migration and invasion in bladder cancer cells. Furthermore, ubenimex also induced autophagic cell death and apoptosis, which suggested that mixed programmed cell death occurred in ubenimex-treated bladder cancer cells. The results from the present study suggest that ubenimex may be a potential adjuvant therapy for the treatment of bladder cancer.

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Serum APN/CD13 as a novel diagnostic and prognostic biomarker of pancreatic cancer

Cited by 28 publications

References 27 publications

Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients

Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients

Serum MMP-2 as a potential predictive marker for papillary thyroid carcinoma

Ubenimex, an APN inhibitor, could serve as an anti‑tumor drug in RT112 and 5637 cells by operating in an Akt‑associated manner

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