VSIG2 hinders gastric cancer progression by suppressing ANXA2-mediated NF-κB pathway activation

Abstract

As the fifth most common cancer and the third leading cause of cancer death worldwide, gastric cancer (GC) has long been a serious global health challenge. The purpose of this study was to explore the expression of V-set and immunoglobulin domain containing 2 (VSIG2) in GC and to elucidate its role in GC progression and related mechanisms. Western blot analysis, qRT-PCR and immunohistochemical (IHC) staining are used to detect the expression of VSIG2 in GC cells and tissues. Kaplan-Meier survival curve analysis is performed. The effects of VSIG2 on biological effects related to GC progression in vitro are detected by CCK-8, EdU, Transwell and wound healing assays and in vivo by a nude mouse subcutaneous tumor model and a liver metastasis model. Mechanistically, co-immunoprecipitation, immunofluorescence and ubiquitination experiments are used to explore the regulatory effect of VSIG2 on ANXA2 and the regulatory effect between FBXW10 and ANXA2. VSIG2 is abnormally expressed at low levels in patients with GC and is associated with patient prognosis. Low VSIG2 expression is closely related to tumor size, lymph node metastasis, TNM stage and vascular invasion in GC patients. Functionally, in vitro and in vivo experiments reveal that VSIG2 could inhibit the growth, proliferation and metastasis of GC. Mechanistically, VSIG2 and ANXA2 interact directly in GCs and co-localize at the cell membrane. Further exploration reveals that highly expressed VSIG2 competes with FBXW10 for binding to ANXA2 and relies on FBXW10-mediated K63 polyubiquitination of ANXA2 to induce membrane localization of ANXA2 and further inactivate NF-κB, thereby suppressing GC progression. In summary, VSIG2 is expressed at abnormally low levels in patients with GC, and its low expression is associated with poor patient prognosis. VSIG2 can inhibit the proliferation and migration of GC via the ANXA2/NF-κB pathway. This study elucidates a new mechanism by which VSIG2 inhibits GC progression, which may provide a new perspective for the diagnosis and treatment of GC patients.

1. Introduction

Gastric cancer is the fifth most common malignant tumor in the world and the third leading cause of cancer-related death. In 2020, there were 1.09 million new cases and 769,000 deaths worldwide, of which more than 60% occurred in East Asia [1]. Helicobacter pylori (H. pylori) chronic infection accounts for approximately 78% of all cases and is classified by the WHO as a class I carcinogenic factor. It is expected that 11.9 million gastric cancer cases will be attributed to H. pylori infection in the cohort born from 2008 to 2017 [2]. Although endoscopic screening, radical surgery and perioperative FLOT regimens have significantly improved the prognosis of patients with resectable disease, the 5-year survival rate of patients with advanced or metastatic gastric cancer is still less than 20% [3]. Molecular mapping studies (TCGA & ACRG) have revealed four subtypes, namely, EBV-positive, microsatellite instability, chromosome instability, and genomic stability, providing a precise framework for the targeting and immunotherapy of HER2, claudin 18.2, VEGFR2, and PD-1/PD-L1. However, tumor microenvironment-mediated immune escape and targeted drug resistance are still the biggest challenges [4]. Therefore, in-depth analysis of the molecular network of gastric cancer development and the development of new joint strategies are urgently needed to improve the survival rate of patients.

V-set and immunoglobulin domain-containing 2 (VSIG2) is an emerging B7-like immune checkpoint whose expression topography has quietly shifted from a “thymocyte relic” to a decisive regulator of tumor–immune crosstalk [5]. First cloned as the Xenopus cortical thymocyte marker CTXL, human VSIG2 maps to 11q24.2 and encodes a 283-aa type-I glycoprotein that pairs a membrane-distal IgV with a juxtamembrane IgC2 domain [6]. Transcriptomic atlases now reveal that VSIG2 is not confined to the thymus but is highly enriched in gastric and colonic epithelia, renal tubules, and critically tumour-associated macrophages and B cells [7]. Functionally, VSIG2 behaves as a Janus-faced rheostat: in pancreatic ductal adenocarcinoma, VSIG2 partners with LAMTOR2 to hyperactivate mTOR, fuelling glycolytic reprogramming and aggressive invasion; conversely, in colorectal cancer, VSIG2 loss is linked to reduced M1 macrophage and B-cell infiltration, dampened antigen presentation, and shortened survival [8,9]. Single-cell interrogations further revealed that VSIG2 expression inversely correlates with cytotoxic CD8⁺ T-cell programs and synergizes with tumour-derived lactate to enforce an immunosuppressive niche [10]. However, whether VSIG2 plays a critical role in GC progression and is a tractable target for next-generation precision immunotherapy remain to be probed.