ABSTRACT Tumor‐associated macrophages (TAMs) and the complement system play pivotal roles in reshaping the chronic inflammatory microenvironment and driving malignant transformation. Although C1QA+ TAMs have been identified in multiple tumor types, their role in gastric cancer (GC) remains unexplored. Single‐cell RNA sequencing (scRNA‐seq) was performed on paired tumor tissues and adjacent tissues from three treatment‐naïve patients to map macrophage heterogeneities. To evaluate the clinical and translational value of C1q, immunohistochemistry (IHC) was conducted on 100 GC samples, and C1q concentrations were measured via ELISA in plasma from a multi‐center cohort of 240 patients and 100 GC tissue. Additionally, the effects of C1q‐mediated THP‐1‐derived macrophages on the malignant behaviors of GC cells were investigated using in vitro migration. Transcriptomic analysis of 56,151 single cells successfully identified a distinct pro‐inflammatory subset: C1QA+ TAMs. IHC staining demonstrated that C1q and CD163 were highly co‐expressed in compromised tissues, and their elevated expression significantly correlated with poor patient prognosis. Multi‐center plasma analysis revealed that elevated circulating C1q levels robustly enhanced clinical diagnostic accuracy. In vitro functional assays confirmed that C1q significantly primed M2 macrophage polarization, thereby accelerating the migration of GC cells. We first identified and functionally validated the C1QA+ TAM subset as a key driver of microenvironmental remodeling. C1q serves as a crucial mediator of macrophage polarization and holds strong promise as a novel, non‐invasive biomarker for the early diagnosis.
Saisai Gong, Yu-Peng Zhao, Sheng Yang et al.· Cancer Science· 0 citations
INTRODUCTION
Methyl-N'-nitro-N-nitrosoguanidine (MNNG) is an environmental carcinogen that induces Gastric Cancer (GC). N7-methylguanosine (m7G) is a prevalent RNA modification closely linked to cancer onset and progression. However, the role of m7G in regulating gene expression during MNNG-induced gastric carcinogenesis remains unclear. This study aims to investigate the role of m7G modification in MNNG-induced GC and to identify potential downstream regulatory genes.
METHODS
Cell proliferation and migration were evaluated using CCK-8 and scratch assays in Malignant transformed cells (MC) and GC cells with different METTL1 expression levels. The m7G MeRIP-seq and whole-transcriptome sequencing were integrated to screen potential genes regulated by m7G modification in MC-30 cells. GO and KEGG analyses were performed for gene function. Candidate gene expression was screened and validated in MC and GC cells by RT-qPCR. Finally, we validated SLC2A3 by analyzing gene expression using the TCGA STAD cohort and 24 pairs of clinical GC samples.
RESULTS
METTL1 knockdown significantly inhibited proliferation and migration by about 25% (p < 0.001). Sequencing analysis identified SLC2A3 as a key METTL1 downstream target, with significantly altered m7G modification levels (fold change > 2, p < 0.05) and enrichment in cancer-related pathways. Clinically, SLC2A3 expression was significantly up-regulated in GC tissues versus normal controls (FC = 2.52, p < 0.001) and was significantly associated with tumor stage and prognosis in GC patients (p < 0.05).
CONCLUSION
Our study revealed that m7G methyltransferase METTL1 plays an oncogenic role in MNNG-induced gastric carcinogenesis. SLC2A3 is a key downstream target of METTL1, which is associated with clinical progression in GC patients. These findings may provide evidence for developing prognostic biomarkers for GC.
Jia-Xian Li, Jiabei Jian, Wen-Zheng Yuan et al.· Current Medicinal Chemistry· 0 citations
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