Lipolysis-stimulated lipoprotein receptor overexpression is a novel predictor of poor clinical prognosis and a potential therapeutic target in gastric cancer

Abstract

The prognosis of patients with advanced gastric cancer (GC) remains poor despite the recent advances in molecular targeted therapies, and the search for biomarkers that can predict prognosis and additional new agents with acceptable toxicity profiles are needed. Lipolysis-stimulated lipoprotein receptor (LSR) is a lipoprotein receptor that binds to triglyceride-rich lipoproteins and related to some malignancies. Herein, we examined the association between LSR expression and the prognosis of patients with GC, and investigated the antitumor effect of a previously developed anti-human LSR monoclonal antibody (#1–25). We first performed immunohistochemical analysis of LSR protein expression in GC and normal tissues, and then examined its association with the prognosis of 110 patients with GC. LSR was overexpressed in most of primary GC and metastatic tumors, but not in normal tissues. Patients with strong LSR expression (N = 80, 72.7%) had significantly poorer overall survival (OS) than those with weak expression (P = 0.017). Multivariate analysis identified strong LSR (as well as pT) as independent and significant prognostic factors for OS. Next, we demonstrated that very low density lipoprotein (VLDL) treatment increases cell proliferation in LSR-expressing GC cell lines in vitro; LSR inhibition using #1–25 inhibited VLDL-induced proliferation by suppressing JAK/STAT and PI3K signaling. In vivo, we demonstrated a marked antitumor effect of #1–25 in 2 distinct GC cell line xenograft mice models. Our findings suggest that LSR plays a key functional role in GC development, and that this antigen can be therapeutically targeted to improve GC treatment.

LSR Promotes Cell Proliferation and Invasion in Lung Cancer

“…LSR, a type I single-pass transmembrane protein, is primarily expressed in the liver, intestine, and other tissues [14]. Upregulated LSR was demonstrated in various cancers, including colon, bladder, breast, endometrial, and ovarian cancers [15]. Numerous studies imply that LSR probably participates in the development of multiple cancers [16].…”

The Roles of Tricellular Tight Junction Protein Angulin-1/Lipolysis-Stimulated Lipoprotein Receptor (LSR) in Endometriosis and Endometrioid-Endometrial Carcinoma

“…On the other hand, the expression of angulin-1/LSR in breast cancer is higher in invasive ductal carcinomas than in invasive lobular carcinomas [ 42 ]. Furthermore, high expression of angulin-1/LSR is a poor prognostic factor in epithelial ovarian cancer and gastric cancer [ 43 , 44 ].…”

Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple‐negative breast cancer

“…In gastric cancer, LISCH7 overexpression is proposed to be an independent prognostic factor of poor clinical outcome. 6 Likewise, in human colorectal cancer, elevated LISCH7 expression is tightly associated with disease progression. 29 By contrast, LISCH7 loss promotes cell invasiveness in human endometrial cancer.…”

“…Liver-specific bHLH-Zip transcription factor (LISCH7, also known as LSR) has been identified as a novel molecular constituent of tricellular contacts localized at most epithelial tissues. 4 Emerging evidence points to that LISCH7 may play an important role in the regulation of tight junction formation, 4 cell invasion and migration, 5 cell proliferation, 6 and drug response 7 in different types of malignancies. Of particular interest, in a previous study using a murine metastasis BCa model, Yang et al 8 observed that LISCH7 is one of the most upregulated metastasis-related genes.…”