An Essential NRP1-Mediated Role for Tagln2 in Gastric Cancer Angiogenesis

Abstract

Knowledge about the precise biological role and underlying mechanism of Tagln2 in tumor progression is relatively limited, especially in angiogenesis focused on tumor derived endothelial cells (ECs) has rarely been reported. Here, the function, molecular mechanism and potential clinical value of Tagln2 in gastric cancer (GC) angiogenesis were investigated. GC tissue microarrays were used to assess the expression of Tagln2 in ECs. The relationships between expression and clinicopathological features were analyzed to evaluate the clinical value of Tagln2. Gain- and loss-of-function approaches were performed in ECs to investigate the functions of Tagln2 in angiogenesis. A combination of angiogenesis antibody array, RNA-Seq analyses and a series of in vitro experiments were performed to reveal the proangiogenic mechanism mediated by NRP1. Immunohistochemistry performed on an independent tissue chip (n=75) revealed significant upregulation of Tagln2 in tumor-derived ECs which were specifically immunolabeled with CD34. Additionally, high Tagln2 levels correlated significantly with the presence of lymph node as well as distant metastases. Gain- and loss-of-function approaches highlighted the function of Tagln2 in promoting EC proliferation, motility, and capillary-like tube formation and in reducing apoptosis. Tagln2 upregulation led to significantly increased mRNA and protein levels of NRP1 and subsequently activated the NRP1/VEGFR2 and downstream MAPK signaling pathways. These data indicate the importance of Tagln2 in angiogenesis, as a potential therapeutic target, and as a candidate prognostic marker in GC.

An Integrated Analysis Identified TAGLN2 As an Oncogene Indicator Related to Prognosis and Immunity in Pan-Cancer

“…Our results were further reinforced by the IHC analysis from HPA. These results were in accordance with previous reports regarding colorectal cancer 8 , gastric cancer 30 , bladder cancer 34 , clear cell renal cell carcinoma 35 , glioma 36 , and breast cancer 37 . Meanwhile, in patients having BLCA, KICH, KIRC, LIHC, LUSC, PAAD, TGCT, and THCA, TAGLN2 expression was analyzed to be correlated with the advanced cancer stage.…”

“…TAGLN2, located on the human chromosome 1q23.2 region, is a member of the transgelins family and encodes a 199 amino acid protein. Studies on TAGLN2 in the context of tumor progression have garnered considerable interest due to its ability to modulate the tumor microenvironment and promote tumor angiogenesis 30 , 31 , invasion, and metastasis 32 , 33 . Nevertheless, the exact mechanism of TAGLN2 in cancers remains largely unknown and research into it is still in its early stages.…”

Systematic pan‐cancer analysis identified neuropilin 1 as an immunological and prognostic biomarker

“…Among the tumors from 33 different types of cancer investigated present in TCGA and the GTEX databases, NRP1 was highly expressed in 19 tumors and lowly expressed in 14 tumors. Some previous studies on NRP1 have shown that upregulation of TAGLN2 leads to a significant increase in the messenger RNA and protein levels of NRP1 in gastric cancer, 14 and activation of NRP1/ VEGFR2 and downstream MAPK signaling pathways promotes gastric cancer cell proliferation and motility. Meanwhile, in esophageal cancer studies, microRNA-124 inhibited cancer cell proliferation by negatively regulating NRP1.…”

Identification of Serum Biomarkers to Monitor Therapeutic Response in Intestinal-Type Gastric Cancer

“…Each of the markers we identified have previously been linked to human cancer, and thus are not limited in relevance to the murine model employed. Of these, Tagln2 has previously been linked to angiogenesis, proliferation, migration, and epithelial–mesenchymal transition in GC [ 25 , 26 ], while Mbl2 gene variants have been linked to risk of stomach cancer [ 27 ] and increased serum levels linked to pancreatic cancer [ 28 ]. In addition, Itih3 has previously been identified as a predictor of GC in mice and patients [ 29 ], while F12 is a prognostic marker for thyroid cancer [ 30 ].…”