LECT 2 Antagonizes FOXM1 Signaling via Inhibiting MET to Retard PDAC Progression.

Xin Li,Chenjing Wang,Yunshan Wang,Yu Cao,Ting Li,Ye Tao,Xin Jiang,Pingping Lin

doi:10.3389/fcell.2021.661122

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with minimally effective treatments, highlighting the importance of developing novel biomarkers and therapeutic targets. Here, we disclosed the mechanisms that leukocyte cell-derived chemotaxin-2 (LECT2) modulates PDAC development using in vitro and in vivo models. LECT2 is downregulated in metastatic PDACs compared with the primary tumor, and its expression is correlated with multiple clinical pathologic features and prognosis. The absence promotes multiple malignant behaviors, including cell proliferation, epithelial-mesenchymal transition, migration, and invasion. In vivo studies showed that LECT2 overexpression inhibits tumor growth and lung metastasis. Mechanistically, LECT2 inhibits FOXM1 signaling by targeting HGF/MET to retard PDAC progression, revealing LECT2 as a promising biomarker and therapeutic target for PDAC in the future.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer worldwide
Accumulated evidence showed that the clinical implications of leukocyte cell-derived chemotaxin-2 (LECT2) in various malignancies, the molecular mechanisms of LECT2 in PDAC progression remain mostly unclear
We showed that LECT2 serves as a tumor suppressor in PDAC progression as follows: (1) LECT2 is downregulated in metastatic PDACs compared with the primary tumor, and its expression is negatively correlated metastasis in vitro and in vivo

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer worldwide. Despite the progress in surgical techniques and medical treatment, the overall prognosis is still weak, as the 5-year relative survival rate is only 9% (Siegel et al, 2020). It is typically diagnosed at a distant stage resulting in limited treatment options, and the available therapies are mostly unsuccessful due to frequent recurrence and metastasis. In this case, there is an urgent need to identify new biomarkers or therapeutic targets to improve the diagnosis and prognosis of this malignancy. It has been reported to have a batch of other functions in many pathological conditions, including arthritis (Okumura et al, 2008), cancer (Chen et al, 2014; Okabe et al, 2014), immune modulation (Ando et al, 2012; Lu et al, 2013), liver fibrosis (Xu et al, 2019), neuronal development (Koshimizu and Ohtomi, 2010), glucose metabolism and metabolic syndrome (Lan et al, 2014; Hwang et al, 2015)

Methods

Results

Conclusion