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GPM6B inhibits tumor progression by targeting HPGD in lung adenocarcinoma

  • Authors:
    • Yonghuai Li
    • Xufeng Yao
    • Qian Chai
    • Xueyi Feng
    • Yuhao Ma
    • Guomeng Li
    • Hongbin Zhu
    • Lei Zhao
    • Qian Dai
  • View Affiliations / Copyright

    Affiliations: Department of Respiratory Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230012, P.R. China, School of Life Science, Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Respiratory Medicine, Chaohu Hospital of Anhui Medical University, Chaohu, Anhui 238000, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 253
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    Published online on: July 9, 2025
       https://doi.org/10.3892/mmr.2025.13618
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Abstract

Lung adenocarcinoma (LUAD) is the most prevalent form of lung cancer and the predominant cause of cancer-associated mortality. Given the low survival rate of patients with LUAD, there is a need to identify new therapeutic targets. Glycoprotein M6B (GPM6B) is a tumor‑associated gene in numerous types of malignancies; however, its specific role in LUAD remains largely unexplored. Integrated bioinformatics analyses of The Cancer Genome Atlas and Gene Expression Omnibus datasets, along with immunohistochemistry assays demonstrated that GPM6B was downregulated in LUAD compared with adjacent normal tissue. Elevated expression of GPM6B was associated with prolonged survival in patients with LUAD, suggesting that GPM6B serves as a prognostic biomarker in LUAD. Cell Counting Kit‑8 (CCK‑8) and Transwell assays demonstrated that exogenously expressed GPM6B significantly inhibited the proliferation and migration of the LUAD cell lines A549 and PC9. Notably, tumorigenesis assays conducted in nude mice demonstrated that the overexpression of GPM6B also suppressed tumor growth in vivo. Mechanistically, GPM6B may have inhibited the malignant behavior of LUAD cells by promoting the expression of 15‑hydroxyprostaglandin dehydrogenase and activating the p53 signaling pathway, as evidenced by transcriptome data analysis, western blotting and phenotypic assays. Furthermore, the qPCR results from LUAD cells treated with DNA methylation and histone deacetylase inhibitors indicated that low expression of GPM6B was associated with DNA methylation and histone deacetylation. Overall, the present study demonstrated that GPM6B may serve as a novel tumor suppressor and elucidated its potential mechanism in regulating the progression of LUAD.
View Figures

Figure 1

Association between GPM6B expression
and prognosis of patients with LUAD. (A) Survival curve for the
differential expression of GPM6B was analyzed using the
Kaplan-Meier plotter. (B) Nomogram based on clinicopathological
factors, including clinical N stage, sex, age, tumor stage and
GPM6B expression. Differential expression of GPM6B in LUAD tumor
and normal tissue based on the (C) Gene Expression Profiling
Interactive Analysis and (D) Gene Expression Omnibus datasets.
Differential expression of GPM6B based on (E) individual cancer
stage and (F) nodal metastasis status. (G) IHC analysis of GPM6B in
LUAD tissues and adjacent normal tissues. Scale bar, 100 µm.
*P<0.05, ***P<0.001, ****P<0.0001 vs. normal. HR, hazard
ratio; LUAD, lung adenocarcinoma; IHC, immunohistochemistry; GPM6B,
Glycoprotein M6B; TCGA The Cancer Genome Atlas.

Figure 2

GPM6B regulates the proliferation,
migration and invasion of LUAD cells. (A) Reverse
transcription-quantitative PCR analysis and (B) western blot
confirmation of GPM6B overexpression in LUAD cells A549 and PC9.
(C) CCK-8 and (D) Ki67 staining assays depicting the decreased
proliferation ability of GPM6B-overexpressing cells. (E) Transwell
assays were used to determine the migration and invasion of
GPM6B-overexpressing A549 and PC9 cells. (F) Wound healing assay
was used to monitor the migration ability of GPM6B-overexpressing
cells. **P<0.01, ***P<0.001, ****P<0.0001 vs. Control.
(A,C) LUAD, lung adenocarcinoma; GPM6B, Glycoprotein M6B.

Figure 3

GPM6B regulates HPGD expression. (A)
DEGs identified via transcriptome sequencing following GPM6B
overexpression. (B) Reverse transcription-quantitative PCR
validation of DEGs. (C) Western blot analysis of HPGD expression.
(D) OS plot of HPGD in LUAD. (E) Nomogram was used to predict the
OS probability of patients with LUAD at 1, 3 and 5 years. mRNA
expression levels of HPGD in LUAD and paired adjacent normal tissue
in (F) The Cancer Genome Atlas and (G) GSE10072 and GSE115002
datasets. (H) IHC analysis of HPGD in LUAD and adjacent normal
tissues. Scale bar, 100 µm. *P<0.05 vs. Normal; **P<0.01,
***P<0.01, ****P<0.0001 vs. Control. (G, H) HPGD, 15-hydroxy
prostaglandin dehydrogenase; DEG, differentially expressed gene;
OS, overall survival; LUAD, lung adenocarcinoma; IHC,
immunohistochemistry; ns, not significant.

Figure 4

Association between GPM6B and HPGD.
(A) Western blot showing the expression of GPM6B and HPGD in 293T
cells transfected with HA-tagged GPM6B plasmid. Association between
GPM6B and HPGD expression in (B) TCGA and (C) GSE10072 and
GSE115002 datasets. HPGD, 15-hydroxy prostaglandin dehydrogenase;
TGCA, The Cancer Genome Atlas; GPM6B, Glycoprotein M6B; IP,
Immunoprecipitation; TPM, Transcripts Per Million.

Figure 5

HPGD overexpression inhibits the
proliferation, migration and invasion of LUAD cells. (A) Reverse
transcription-quantitative PCR and (B) western blot confirmation of
HPGD overexpression efficiency in LUAD cells. (C) Cell Counting
Kit-8 and (D) Ki67 staining demonstrated reduced proliferation of
HPGD-overexpressing cells. (E) Transwell assays were used to
determine the migration and invasion of control and
HPGD-overexpressing LUAD cells. (F) Wound healing assay was used to
monitor the migration. **P<0.01, ***P<0.001, ****P<0.0001
vs. control. HPGD, 15-hydroxy prostaglandin dehydrogenase; LUAD,
lung adenocarcinoma.

Figure 6

GPM6B overexpression activates p53
signaling pathway. (A) GO, (B) KEGG and (C) Gene Set Enrichment
Analysis. (D) Western blot images revealed changes in the
expression of GPM6B, HPGD, P53, CCND1, Bcl2 and Bax.
****P<0.0001 vs. Control. (D) GO, Gene Ontology; KEGG, Kyoto
Encyclopedia of Genes and Genomes; GPM6B, Glycoprotein M6B; HPGD,
15-hydroxy prostaglandin dehydrogenase; CCND1, cyclin D1; NES,
normalized enrichment score.

Figure 7

Overexpression of GPM6B suppresses
LUAD tumor growth in vivo. (A) Subcutaneous tumors (circled
in red for visualization. (B) Xenograft tumors in each group. (C)
Changes in tumor volume. (D) Statistical histogram displaying the
weights of xenograft tumors. (E) Representative hematoxylin and
eosin staining. Scale bar, 20 µm. (F) Representative
immunohistochemistry analysis of Ki67. Scale bar, 100 µm.
*P<0.05, ****P<0.0001 vs. Control. LUAD, lung adenocarcinoma;
GPM6B, Glycoprotein M6B.

Figure 8

DNA methylation and histone
deacetylation inhibit expression of GPM6B. (A) Reverse
transcription-quantitative PCR analysis of GPM6B expression. (B)
DNA methylation at the GPM6B promoter region. (C) Enrichment of
H3K27ac at the GPM6B promoter region in IMR90 and A549 cells. The
effects of (D) DCA and (E) TSA were measured using Cell Counting
Kit-8 assay. The mRNA levels of GPM6B in control and (F) DCA or (G)
TSA-treated LUAD cells. +P<0.05,
++P<0.01, +++P<0.001 vs. NC,
****P<0.0001 vs. Normal, #P<0.05,
###P<0.001, ####P<0.0001 vs. 0 µM. ns,
not significant; EZH2, enhancer of zeste homolog 2; LUAD, lung
adenocarcinoma; TCGA, The Cancer Genome Atlas; DCA, decitabine;
TSA, trichostatin A; GPM6B, Glycoprotein M6B; NC, negative control;
si, small interfering.
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Copy and paste a formatted citation
Spandidos Publications style
Li Y, Yao X, Chai Q, Feng X, Ma Y, Li G, Zhu H, Zhao L and Dai Q: GPM6B inhibits tumor progression by targeting HPGD in lung adenocarcinoma. Mol Med Rep 32: 253, 2025.
APA
Li, Y., Yao, X., Chai, Q., Feng, X., Ma, Y., Li, G. ... Dai, Q. (2025). GPM6B inhibits tumor progression by targeting HPGD in lung adenocarcinoma. Molecular Medicine Reports, 32, 253. https://doi.org/10.3892/mmr.2025.13618
MLA
Li, Y., Yao, X., Chai, Q., Feng, X., Ma, Y., Li, G., Zhu, H., Zhao, L., Dai, Q."GPM6B inhibits tumor progression by targeting HPGD in lung adenocarcinoma". Molecular Medicine Reports 32.3 (2025): 253.
Chicago
Li, Y., Yao, X., Chai, Q., Feng, X., Ma, Y., Li, G., Zhu, H., Zhao, L., Dai, Q."GPM6B inhibits tumor progression by targeting HPGD in lung adenocarcinoma". Molecular Medicine Reports 32, no. 3 (2025): 253. https://doi.org/10.3892/mmr.2025.13618
Copy and paste a formatted citation
x
Spandidos Publications style
Li Y, Yao X, Chai Q, Feng X, Ma Y, Li G, Zhu H, Zhao L and Dai Q: GPM6B inhibits tumor progression by targeting HPGD in lung adenocarcinoma. Mol Med Rep 32: 253, 2025.
APA
Li, Y., Yao, X., Chai, Q., Feng, X., Ma, Y., Li, G. ... Dai, Q. (2025). GPM6B inhibits tumor progression by targeting HPGD in lung adenocarcinoma. Molecular Medicine Reports, 32, 253. https://doi.org/10.3892/mmr.2025.13618
MLA
Li, Y., Yao, X., Chai, Q., Feng, X., Ma, Y., Li, G., Zhu, H., Zhao, L., Dai, Q."GPM6B inhibits tumor progression by targeting HPGD in lung adenocarcinoma". Molecular Medicine Reports 32.3 (2025): 253.
Chicago
Li, Y., Yao, X., Chai, Q., Feng, X., Ma, Y., Li, G., Zhu, H., Zhao, L., Dai, Q."GPM6B inhibits tumor progression by targeting HPGD in lung adenocarcinoma". Molecular Medicine Reports 32, no. 3 (2025): 253. https://doi.org/10.3892/mmr.2025.13618
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