Evidence map›Paper›PMID 41250196›Full record

ArticleJournal of translational medicine2025

HOXA9 drives lymphatic metastasis by activating the c-MYC-glycolysis-lactate axis in gastric cancer.

Tailiang Lu, Guodong Shen, Tao Huang, Xinyuan Mao, Junting He, Yanfeng Hu

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Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

6 authors.

Tailiang Lu *Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Guodong Shen *Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Tao Huang *Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Xinyuan MaoDepartment of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Junting HeDepartment of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Yanfeng HuDepartment of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. banby@smu.edu.cn.ORCID 0000-0001-5608-3587

Funding

National Natural Science Foundation of China 62027901, 82272062, 91959129, U21A20386, and 32271448
6 · The paper itself

Abstract

backgroundThe molecular mechanisms underlying lymph node metastasis (LNM) in gastric cancer (GC) remain poorly understood. This study investigated HOXA9’s role in driving LNM via metabolic reprogramming.

methodsIntegrated analysis of gastric cancer RNA sequencing data and clinical specimens was performed. Functional validation involved HOXA9 overexpression and knockdown in AGS and HGC-27 cell lines, c-MYC silencing by siRNA, and glycolytic inhibition using 2-deoxyglucose (2-DG, 2.5 mM). In vitro assays evaluated proliferation (CCK-8), apoptosis (Annexin V/PI), migration/invasion (Transwell), lymphangiogenesis (HLEC tubulogenesis), and metabolism (Seahorse analyser). In vivo, effects were evaluated using a popliteal LNM mouse model (n = 6/group) and administered exogenous lactate (20 mM) to restore levels.

resultsHOXA9 was significantly upregulated in LNM-positive GC tissues (1.3-fold, p = 0.0006) and predicted poor survival (HR = 1.57, p = 1.7 × 10⁻⁵). HOXA9 overexpression enhanced GC cell proliferation (2.5-fold, p < 0.0001), invasion (1.6-fold, p = 0.0002), and migration (2.0-fold, p < 0.0001), while suppressing apoptosis. Mechanistically, HOXA9 directly bound the c-MYC promoter, thereby upregulating glycolytic enzymes (HIF-1α, HK2, GLUT1, PDK1, LDHA) and increasing lactate secretion (1.7-fold, p = 0.005). The resultant lactate-rich microenvironment stimulated lymphangiogenesis (1.4-fold, p < 0.01) and endothelial cell migration (1.8-fold, p < 0.001). These effects were significantly reversed by c-MYC knockdown or 2-DG treatment, with 2-DG reducing lymphangiogenesis by 37.56% (p < 0.0001). In vivo, HOXA9 knockdown reduced LNM burden (66% reduction in node volume, 83% lower metastasis rate), and this effect was markedly rescued by lactate supplementation.

conclusionsHOXA9 promotes GC LNM by activating the c-MYC-glycolysis-lactate axis, which remodels the lymphatic niche. This axis represents a targetable pathway for GC therapy.

Indexed as

GlycolysisHomeodomain ProteinsLactic AcidLymphatic MetastasisProto-Oncogene Proteins c-mycStomach NeoplasmsAnimalsApoptosisCell Line, TumorCell MovementCell ProliferationFemaleGene Expression Regulation, NeoplasticHumansLymphangiogenesisMetabolic Reprogramminghomeobox protein HOXA9Homeodomain ProteinsLactic AcidProto-Oncogene Proteins c-mycGastric cancerGlycolysisHOXA9LymphangiogenesisLymph node metastasis

Identifiers

PMID41250196
PMCPMC12625457

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.