ArticleOncogene2015
Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 77 citations in OpenAlex.
- Regulatory mechanisms of LGR4 on cancer and cancer stem cell properties.Discover oncology · 2026Review
- RSPO4 exerts tumor suppression through antagonizing canonical and non-canonical Wnt signaling.International journal of biological sciences · 2026Article
- Hierarchical clustering defines hypermethylated RSPO2 as early-stage potential biomarker in colorectal cancer.Global medical genetics · 2025Article
- Anti-tumor activity of camptothecin analog conjugate of an RSPO4-based peptibody targeting LGR4/5/6 in preclinical models of colorectal cancer.British journal of cancer · 2025Article
- Therapeutic and Prognostic Potential of G Protein-Coupled Receptors in Lung Adenocarcinoma: Evidence From Transcriptome Data and In Vitro Experiments.The clinical respiratory journal · 2025Article
- LGR4 promotes proliferation and homing via activation of the NF‑κB signaling pathway in multiple myeloma.International journal of oncology · 2025Article
- The Use of Biologics for Targeting GPCRs in Metastatic Cancers.Biotech (Basel (Switzerland)) · 2025Review
- Toward precision oncology in LUAD: a prognostic model using single-cell sequencing and WGCNA based on a disulfidptosis relative gene signature.Frontiers in immunology · 2025Article
- The role of LGR4 in bone metabolism and tumor bone metastasis.Frontiers in endocrinology · 2025Review
- Why Is Wnt/β-Catenin Not Yet Targeted in Routine Cancer Care?Pharmaceuticals (Basel, Switzerland) · 2024Review
- Construction of an immune-related gene prognostic model with experimental validation and analysis of immune cell infiltration in lung adenocarcinoma.Oncology letters · 2024Article
- RSPO3 induced by Helicobacter pylori extracts promotes gastric cancer stem cell properties through the GNG7/β-catenin signaling pathway.Cancer medicine · 2024Article
- Rspo2-LGR4 exacerbates hepatocellular carcinoma progression via activation of Wnt/β-catenin signaling pathway.Gastroenterologia y hepatologia · 2024Article
- Molecular subtyping based on immune cell marker genes predicts prognosis and therapeutic response in patients with lung adenocarcinoma.BMC cancer · 2023Article
- Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma.Clinical epigenetics · 2023Article
- LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands.Scientific reports · 2023Article
- Computing microRNA-gene interaction networks in pan-cancer using miRDriver.Scientific reports · 2022Article
- The role of R-spondin proteins in cancer biology.Oncogene · 2021Review
- Drug Conjugates of Antagonistic R-Spondin 4 Mutant for Simultaneous Targeting of Leucine-Rich Repeat-Containing G Protein-Coupled Receptors 4/5/6 for Cancer Treatment.Journal of medicinal chemistry · 2021Article
- Role of IQGAP1 in Carcinogenesis.Cancers · 2021Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
The four R-spondins (RSPO1-4) and their three related receptors LGR4, 5 and 6 (LGR4-6) have emerged as a major ligand-receptor system with critical roles in development and stem cell survival through modulation of Wnt signaling. Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of human colorectal cancer. However, the exact roles and mechanisms of the RSPO-LGR system in oncogenesis remain largely unknown. We found that RSPO3 is aberrantly expressed at high levels in approximately half of Keap1-mutated lung adenocarcinomas (ADs). This high RSPO3 expression is driven by a combination of demethylation of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer. Patients with RSPO3-high tumors (~9%, 36/412) displayed much poorer survival than the rest of the cohort (median survival of 28 vs 163 months, log-rank test P<0.0001). Knockdown (KD) of RSPO3, LGR4 or their signaling mediator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to reduction in cell proliferation and migration in vitro, and KD of LGR4 or IQGAP1 resulted in decrease in tumor growth and metastasis in vivo. These findings suggest that aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1-deficient lung ADs.
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