Neuropilin-1 predicts poor prognosis and promotes tumor metastasis through epithelial-mesenchymal transition in gastric cancer

Abstract

We aimed to determine whether Neuropilin-1 (NRP1) promotes gastric cancer (GC) metastasis by inducing epithelial-mesenchymal transition (EMT), and to clarify its regulatory mechanism. Using the data of GC patients in The Cancer Genome Atlas (TCGA) and Gene Tissue Expression (GTEx) databases, combined with the data of GC patients in our medical center, the effect of NRP1 on the prognosis of GC patients were analyzed. Then, we investigated the role of NRP1 in GC metastasis and its potential mechanism. The level of NRP1 was up-regulated in GC tissues and associated with poor prognosis of GC patients. The expression of NRP1 was closely related to maximum tumor diameter, invasion depth, lymphnode metastasis, distant metastasis, and advanced TNM stage, and was an independent prognostic factor for overall survival (OS) in GC patients. Besides, the results of in vitro indicated that NRP1 could induce EMT to promote the migration and invasion of GC cells by activating PI3K/Akt signaling pathway, and the HGF/c-Met axis was involved in this process. This study determined that NRP1 was a gene that promotes gastric cancer. NRP1 induced EMT to enhance the migration and invasion ability of GC cells by activating PI3K/Akt signaling pathway. NRP1 was an independent prognostic marker for OS in GC patients and expected to be a therapeutic target for GC patients.

Neuropilin-1 as a Potential Biomarker of Prognosis and Invasive-Related Parameters in Liver and Colorectal Cancer: A Systematic Review and Meta-Analysis of Human Studies

“…However, as observed in the present meta-analysis, no significant correlation between NRP1 expression and patient age, gender and pathology type was found [45]. Additional reports from studies conducted in different tumor types revealed that NRP1 overexpression was directly related to the presence of distant metastasis [40,47,48], advanced stages [47,48], invasion depth and lymph node metastasis in gastric cancer [40], osteosarcoma [47] and nasopharyngeal carcinoma [48], thus supporting results obtained in the present meta-analysis. Moreover, the liver is the main organ affected by CRC metastasis [4], and three out of the six CRC studies included in this meta-analysis were performed with patients suffering from mCRC [22,26,28].…”

“…Otherwise, results evaluating the differential expression of NRP1 between tumor and adjacent tissue revealed a significant correlation between NRP1 overexpression and HCC pathogenesis upon analyzing patient subgroups. Similar findings, describing increased NRP1 levels in tumor tissue collected from gastric cancer [40], cervical cancer [42], NSCLC [45], bladder cancer [46], osteosarcoma [47], nasopharyngeal carcinoma [48], and renal cell carcinoma [52] have been reported. Moreover, plasma NRP1 levels have been suggested as a valuable biomarker in breast cancer patients [44].…”

“…Moreover, the liver is the main organ affected by CRC metastasis [ 4 ], and three out of the six CRC studies included in this meta-analysis were performed with patients suffering from mCRC [ 22 , 26 , 28 ]. However, in preclinical models, similar results also demonstrated that NRP1 removal led to higher cell proliferation [ 42 ] and lower cell migration, invasion [ 40 , 42 , 53 ], epithelial-to-mesenchymal transition (EMT) [ 40 ] and angiogenesis [ 53 ] in cervical cancer [ 42 ], NSCLC [ 53 ] and gastric cancer [ 40 ]. Despite further studies needing to be accomplished to deeply elucidate the role of NRP1 in invasive-related mechanisms, this protein seems to have a crucial role in modulating invasive processes in different cancer types, including CRC and liver cancer.…”

“…The use of meta-analysis has shown to be a valuable tool for assessing the reliability of overexpressed proteins as tumor biomarkers by previous studies performed on CRC and liver cancer [ 36 , 37 , 38 ]. Although a number of investigations showing this potential correlation in other tumor types have been published [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], no previous study has evaluated the role of NRP1 as a prognostic biomarker in CRC and liver cancer patients through meta-analysis. The overexpression of NRP1 in tumor tissue has been correlated with worse prognosis in gastric cancer [ 39 , 40 ], cervical cancer [ 42 ], ovarian carcinoma [ 43 ], breast cancer [ 44 ], non-small cell lung cancer (NSCLC) [ 45 ], osteosarcoma [ 47 ], bladder cancer [ 46 ], glioma [ 49 ], nasopharyngeal carcinoma [ 48 ], and pancreatic ductal adenocarcinoma [ 41 ], among others.…”

“…Although a number of investigations showing this potential correlation in other tumor types have been published [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], no previous study has evaluated the role of NRP1 as a prognostic biomarker in CRC and liver cancer patients through meta-analysis. The overexpression of NRP1 in tumor tissue has been correlated with worse prognosis in gastric cancer [ 39 , 40 ], cervical cancer [ 42 ], ovarian carcinoma [ 43 ], breast cancer [ 44 ], non-small cell lung cancer (NSCLC) [ 45 ], osteosarcoma [ 47 ], bladder cancer [ 46 ], glioma [ 49 ], nasopharyngeal carcinoma [ 48 ], and pancreatic ductal adenocarcinoma [ 41 ], among others. Additionally, NRP1 was found to be negatively associated with PFS in gastric cancer [ 39 ], NSCLC [ 45 ], and nasopharyngeal carcinoma [ 48 ], and disease-free survival (DFS) in osteosarcoma [ 47 ].…”