Legumain: A biomarker for diagnosis and prognosis of human ovarian cancer

Abstract

Legumain is a member of the asparaginyl endopeptidase family that is over-expressed in response to hypoxic stress on mammary adenocarcinoma, colorectal cancer, proliferating endothelial cells, and tumor-associated macrophages (TAMs). Here, we demonstrate that elevated expression of legumain in ovarian cancer by a proteomic approach using isobaric tags for relative and absolute quantification (iTRAQ) followed by liquid chromatography-mass spectrometry (LC-MS/MS). To investigate the relationship between legumain expression and ovarian cancer development, we tested legumain expression in malignant human ovarian tumors (n = 60), borderline ovarian tumors (n = 20), benign ovarian tumors (n = 20), and normal ovary samples (n = 20) using immunohistochemical assay (IHC). A correlation between legumain expression, and clinocopathologic and biological variables was also established. Importantly, increased legumain expression was validated by real-time PCR and Western blots, correlated positively with an increased malignancy of ovarian tumors (P < 0.01). In fact, patients with strong legumain expression had a worse prognosis (P = 0.03). In addition, results of in vitro experiments revealed that over-expression of legumain correlates with increased cell migration and invasion of ovarian cancer cells. Although legumain's functional role and clinical utility remain to be established, our results indicated that a sensitive assay for early expression of legumain may serve as both a potential biomarker and a molecular target for treatment of ovarian cancer.

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

“…We showed that VDAC1 is cleaved by AEP (EC 3.4.22.34), a cysteine protease mainly located in endolysosomes. AEP plays important roles in regulation of the immune system (45) and in cancer (46,47) and has recently been shown to cleave the protein tau in Alzheimer's disease (48,49). In addition, its expression and activity are regulated by TP53 (50), and it cleaves peptide bonds carboxy terminal to asparagine (51).…”

Legumain Protein as a Potential Predictive Biomarker for Asian Patients with Breast Carcinoma

“…Mei Wu, Guang-Rui Shao*, Fei-Xue Zhang, Wen-Xiu Wu, Ping Xu, Zheng-Min Ruan that legumain positively expressed in many types of human solid tumors, such as colon caner, prostate cancer and breast cancers (Lewen et al, 2008;Wang et al, 2012). However, the legumain always expresses with low level or even no expression in normal tissue.…”

The Nf-κb Inhibitor Imd-0354 Targets Human Non-Small Cell Lung Cancer Stem Cells and Combined with Chemotherapy Reduces Multidrug Resistance

“…To overcome this problem, a targeted nanoparticle (tNP) delivery method has been previously developed in our laboratory that allows for safe in vivo Dox delivery to the TME with little or no toxic side effects [27]. Such nanoparticles specifically target cells expressing legumain in their plasma membranes, which is a common property of the TME, especially under hypoxic conditions [27,31,33,41]. However, before a combination therapy of IMD-0354 plus Dox could be critically tested in animal models, legumain expression and tNP drug delivery had to be assessed in vitro.…”

“…Legumain is the only mammalian asparaginyl endopeptidase, which is overexpressed on tumorassociated macrophages and on tumor cells under hypoxic stress [28][29][30][31]. Interestingly, legumain expression increased cell migration and invasion in vitro, and correlated with poor prognosis and malignancy [32][33][34]. Furthermore, legumain activated prodrugs suppressed tumor growth and metastasis without toxicity [35].…”