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. 2025 Jun 5:15:1582728.
doi: 10.3389/fonc.2025.1582728. eCollection 2025.

GPD1L downregulation in colorectal cancer: a novel obesity-related biomarker linking metabolic dysregulation to tumor progression

Feng Zhu  1   2 , Huiyuan Li  1   2 , Hongzhang Liu  1   2 , Yusheng Wang  1   2
Affiliations

GPD1L downregulation in colorectal cancer: a novel obesity-related biomarker linking metabolic dysregulation to tumor progression

Feng Zhu et al. Front Oncol. .

Abstract

Objective: To delineate the expression profile and tumor-suppressive function of the metabolism-associated gene GPD1L in colorectal carcinogenesis. Methods: Transcriptomic datasets from TCGA and GEO repositories (GSE74602, GSE113513, GSE164191) were computationally analyzed. Paired tumor/adjacent mucosal specimens (n=58) from CRC patients at Jincheng People's Hospital were analyzed alongside the NCM460 colon epithelial line and five CRC lines (SW620, HCT116, SW480, DLD-1, LOVO). Following GPD1L quantification via qPCR, selected cell models underwent pcDNA3.1-GPD1L transfection for functional characterization. Then Western blot analysis was used to explore its possible mechanism.

Results: Comparative analysis revealed a marked elevation of GPD1L expression in non-neoplastic tissues relative to tumor specimens (P<0.001). Transcriptional profiling further identified significant depletion of GPD1L mRNA levels across malignant cell lines versus the NCM460 epithelial reference (P<0.05), with HCT116/SW620 showing maximal downregulation. Ectopic GPD1L expression attenuated oncogenic phenotypes: proliferation decreased (P<0.001), while Transwell quantification revealed 46.0% (HCT116: 605.0 ± 9.2 vs 326.7 ± 8.50 cells/field) and 54.3% (SW620: 455.3 ± 17.2 vs 208.0 ± 14.0 cells/field) reductions in migratory capacity (both P<0.001). Invasion assays showed parallel inhibition (HCT116: 43.3% decrease, P<0.01; SW620: 54.8% decrease, P<0.001). After overexpression of GPD1L, the expression levels of HIF-1α and MMP9 were reduced (P<0.05).

Conclusion: GPD1L downregulation represents a hallmark of CRC progression, with affecting the expression of HIF-1α and MMP9 significantly impeding malignant behaviors, nominating it as a candidate tumor suppressor in colorectal neoplasia.

Keywords: GPD1L; bioinformatics; colorectal cancer; metabolism-associated gene; tumor suppressor genes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The expression differences of GPD1L in multiple datasets were analyzed. (a) Differential GPD1L expression profiling between malignant colorectal tissues (n=554) and non-cancerous controls (n=48), (b) Expression difference of GPD1L in 47 CRC tissues and donor-matched normal tissues (TCGA database), (c) Expression difference of GPD1L in 30 CRC tissues and donor-matched normal tissues (GSE74602), (d) Differences in the expression of GPD1L in 14 CRC tissues and donor-matched normal tissues (GSE113513), (e) Differences in the expression of GPD1L in whole blood genes between 62 healthy controls and 59 CRC patients (GSE164191), (***P<0.001).
Figure 2
Figure 2
The expression differences of GPD1L in clinical specimens and CRC cells. (a) Differences in the expression of GPD1L in 58 CRC patients and donor-matched normal tissues (***P<0.001), (b) Differences in the expression of GPD1L in normal colonic epithelial cell lines (NCM460) and five CRC cell lines (SW620, HCT1161, SCT116, DLD 480 and LOVO) (ns P>0.05, *P<0.05, **P<0.01, ***P<0.001).
Figure 3
Figure 3
Relationship between GPD1L expression level and clinicopathological features. (a) TCGA database, (b) Data from the center.
Figure 4
Figure 4
Patients with CRC with low GPD1L expression have a worse prognosis. (a) The relationship between GPD1L expression and overall survival in CRC patients in the TCGA database, (b) Univariate Cox regression analysis of GPD1L expression and clinicopathological features, (c) Multivariate Cox regression analysis of GPD1L expression and clinicopathological features.
Figure 5
Figure 5
Enrichment plots from the gene set enrichment analysis (GSEA). GSEA results showing differential enrichment of genes in KEGG with GPD1L expression.
Figure 6
Figure 6
Transfected with GPD1L overexpression plasmid. (a) Transfection efficiency at the mRNA level of GPD1L overexpression plasmid, (b) Transfection efficiency at the protein level of GPD1L overexpression plasmid in HCT116 cells, (c) Transfection efficiency at the protein level of GPD1L overexpression plasmid in SW620 cells (**P<0.01, ***P<0.001, ****P<0.0001).
Figure 7
Figure 7
Results of proliferation capacity analysis. (a) Changes in the proliferation capacity of HCT116 after GPD1L overexpression, (b) Changes in the proliferation capacity of SW620 (aP<0.05, bP<0.01, cP< 0.001).
Figure 8
Figure 8
Results of scratch wound closure analysis. (a) HCT116 migration ability decreased after GPD1L overexpression, (b) SW620 migration ability decreased after GPD1L overexpression (***P<0.001).
Figure 9
Figure 9
Transwell experimental results. (a) The migration and invasion ability of HCT116 decreased after overexpression of GPD1L, (b) The migration and invasion ability of SW620 decreased after overexpression of GPD1L (**P<0.01, ***P<0.001).
Figure 10
Figure 10
Genetic modulation of GPD1L overexpression altered HIF-1α stabilization and MMP9 transcriptional activity in CRC cell lines. (a) Effect of GPD1L overexpression on the expression levels of HIF-1α and MMP9 in HCT116 cells, (b) Effect of GPD1L overexpression on the expression levels of HIF-1α and MMP9 in SW620 cells (**P<0.01, ***P<0.001).
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