Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Scientific Reports
  • View all journals
  • Search
  • My Account Login
  • Content Explore content
  • About the journal
  • Publish with us
  • Sign up for alerts
  • RSS feed
  1. nature
  2. scientific reports
  3. articles
  4. article
PLOD2 promotes proliferation, migration and invasion of colorectal cancer cells via PI3K-AKT-GSK3β signaling pathway
Download PDF
Download PDF
  • Article
  • Open access
  • Published: 10 February 2026

PLOD2 promotes proliferation, migration and invasion of colorectal cancer cells via PI3K-AKT-GSK3β signaling pathway

  • Hua Fang1 na1,
  • Jing Zheng1 na1,
  • Shutong Ren1 na1,
  • Danjing Chen1,
  • Yunli Wu2 &
  • …
  • Xian-E Peng1,2 

Scientific Reports , Article number:  (2026) Cite this article

  • 339 Accesses

  • 5 Altmetric

  • Metrics details

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer
  • Cell biology
  • Oncology

Abstract

Colorectal cancer (CRC) progression critically depends on the tumor microenvironment. PLOD2, an enzyme involved in collagen biosynthesis, is highly expressed in many cancers. While it promotes CRC growth via the USP15–AKT/mTOR pathway, its role in enhancing tumor cell migration and invasion remains unclear. Our study identified a significant upregulation of PLOD2 in colorectal cancer. This upregulation was closely associated with clinical stage, lymph node metastasis, and nerve invasion in CRC. Functional assays, including CCK-8, colony formation, wound healing, and Transwell migration and invasion assays, showed that PLOD2 overexpression enhanced CRC cell proliferation, migration, and invasion, while PLOD2 silencing exerted the opposite effects. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that PLOD2 may influence CRC progression via the PI3K-AKT signaling pathway. Co-immunoprecipitation assays demonstrated that PLOD2 was co-precipitated with PI3K, confirming their interaction. Additionally, rescue experiments showed that the PI3K inhibitor LY294002 and the agonist 740Y-P could reverse PLOD2-mediated effects on CRC cell proliferation, migration, and invasion. This study demonstrates that PLOD2 promotes the proliferation, migration, and invasion of CRC cells by interacting with PI3K to activate the PI3K-AKT-GSK3β signaling pathway.

Data availability

The genomic sequencing data and associated datasets analyzed in this study were obtained from publicly available repositories, including the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), UALCAN, and the European Genome-phenome Archive (EGA).

Abbreviations

CRC:

Colorectal cancer

PLOD2:

Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2

KEGG:

Kyoto encyclopedia of genes and genomes

ECM:

Extracellular matrix

EMT:

Epithelial–mesenchymal transition

DEGs:

Differentially expressed genes

GEO:

Gene expression omnibus

GO:

Gene ontology

TCGA:

The cancer genome atlas

IHC:

Immunohistochemistry

CO-IP:

Co- immunoprecipitation

References

  1. WHO. Global cancer burden growing, amidst mounting need for services. Lyon, France; Geneva, Switzerland; report of WHO Scientific Group (2024).

  2. Chatila, R. et al. Epidemiology and survival of colorectal cancer in lebanon: A sub-national retrospective analysis. Cancer Control 28, 10732748211041220 (2021).

    Google Scholar 

  3. Wang, S. et al. The implications for urological malignancies of non-coding RNAs in the the tumor microenvironment. Comput. Struct. Biotechnol. J. 23, 491–505 (2024).

    Google Scholar 

  4. Wang, K. et al. Extracellular matrix stiffness regulates colorectal cancer progression via HSF4. J. Exp. Clin. Cancer Res. 44(1), 30 (2025).

    Google Scholar 

  5. Bui, C. B. et al. Denatured collagen inhibits neuroblastoma tumor-sphere migration and growth via the LOX/LOXL2 - FAK signaling pathway. J. Therm. Biol. 115, 103624 (2023).

    Google Scholar 

  6. Lewinska, M. et al. Fibroblast-derived Lysyl oxidase increases oxidative phosphorylation and stemness in cholangiocarcinoma. Gastroenterology 166(5), 886-901.e7 (2024).

    Google Scholar 

  7. Yang, Z. et al. Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network. Mol. Cancer 22(1), 21 (2023).

    Google Scholar 

  8. Shayimu, P. et al. Serum nutritional predictive biomarkers and risk assessment for anastomotic leakage after laparoscopic surgery in rectal cancer patients. World J. Gastrointest. Surg. 16(10), 3142–54 (2024).

    Google Scholar 

  9. Wang, K. et al. Combined preoperative platelet-albumin ratio and cancer inflammation prognostic index predicts prognosis in colorectal cancer: A retrospective study. Sci. Rep. 15(1), 29500 (2025).

    Google Scholar 

  10. Chen, Y. et al. Integrative transcriptomic and single-cell analysis reveals IL27RA as a key immune regulator and therapeutic indicator in breast cancer. Discov. Oncol. 16(1), 977 (2025).

    Google Scholar 

  11. Li, H. H. et al. Hypoxia-induced translation of collagen-modifying enzymes PLOD2 and P4HA1 is dependent on RBM4 and eIF4E2 in human colon cancer HCT116 cells. Febs. J. 292(4), 881–98 (2025).

    Google Scholar 

  12. Fischer, A. G. et al. Matricellular protein CCN1 promotes collagen alignment and scar integrity after myocardial infarction. Matrix Biol. 133, 14–32 (2024).

    Google Scholar 

  13. Yue, W. et al. Procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 promotes collagen cross-linking and ECM stiffening to induce liver fibrosis. Biochim. Biophys. Acta. Mol. Basis Dis. 1870(5), 167205 (2024).

    Google Scholar 

  14. Xu, F. et al. Hypoxia and TGF-beta1 induced PLOD2 expression improve the migration and invasion of cervical cancer cells by promoting epithelial-to-mesenchymal transition (EMT) and focal adhesion formation. Cancer Cell Int. 17, 54 (2017).

    Google Scholar 

  15. Shi, Y. et al. Identification of Immune and Hypoxia risk classifier to estimate immune microenvironment and prognosis in cervical cancer. J. Oncol. 2022, 6906380 (2022).

    Google Scholar 

  16. Song, Y. et al. Hypoxia-induced PLOD2 promotes proliferation, migration and invasion via PI3K/Akt signaling in glioma. Oncotarget 8(26), 41947–62 (2017).

    Google Scholar 

  17. Du, H. et al. PLOD2 regulated by transcription factor FOXA1 promotes metastasis in NSCLC. Cell Death Dis. 8(10), e3143 (2017).

    Google Scholar 

  18. Gong, X., Wang, A. & Song, W. Clinicopathological significances of PLOD2, epithelial-mesenchymal transition markers, and cancer stem cells in patients with esophageal squamous cell carcinoma. Medicine (Baltimore) 101(34), e30112 (2022).

    Google Scholar 

  19. Tong, Y. et al. The PLOD2/succinate axis regulates the epithelial-mesenchymal plasticity and cancer cell stemness. Proc. Natl. Acad. Sci. U S A 120(20), e2214942120 (2023).

    Google Scholar 

  20. Xu, Q. et al. Pan-cancer analyses reveal oncogenic and immunological role of PLOD2. Front Genet 13, 864655 (2022).

    Google Scholar 

  21. Guo, C. et al. PPA1 promotes breast cancer proliferation and metastasis Through PI3K/AKT/GSK3β signaling pathway. Front. Cell Dev. Biol. 9, 730558 (2021).

    Google Scholar 

  22. Sun, W. et al. Long non-coding DANCR targets miR-185-5p to upregulate LIM and SH3 protein 1 promoting prostate cancer via the FAK/PI3K/AKT/GSK3β/snail pathway. J. Gene Med. 23(7), e3344 (2021).

    Google Scholar 

  23. Yuan, Y. et al. SHP2 promotes proliferation of breast cancer cells through regulating Cyclin D1 stability via the PI3K/AKT/GSK3β signaling pathway. Cancer Biol. Med. 17(3), 707–25 (2020).

    Google Scholar 

  24. Lan, J. et al. PLOD2 promotes colorectal cancer progression by stabilizing USP15 to activate the AKT/mTOR signaling pathway. Cancer Sci. 114(8), 3190–202 (2023).

    Google Scholar 

  25. Kanehisa, M. et al. KEGG: Biological systems database as a model of the real world. Nucl. Acid. Res. 53(D1), D672-d7 (2025).

    Google Scholar 

  26. Chandrashekar, D. S. et al. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia 25, 18–27 (2022).

    Google Scholar 

  27. ALMUTAIRI, B. O., ALMUTAIRI, M.H., ALREFAEI, A. F. et al. HSPB6 is depleted in colon cancer patients and its expression is induced by 5-aza-2’-deoxycytidine In Vitro. Medicina (Kaunas), 59(5) (2023).

  28. Chi, M. et al. TEAD4 functions as a prognostic biomarker and triggers EMT via PI3K/AKT pathway in bladder cancer. J. Exp. Clin. Cancer Res. 41(1), 175 (2022).

    Google Scholar 

  29. Liang, C., Jiang, Y. & Sun, L. Vitexin suppresses the proliferation, angiogenesis and stemness of endometrial cancer through the PI3K/AKT pathway. Pharm. Biol. 61(1), 581–9 (2023).

    Google Scholar 

  30. Chai, S. et al. Luteolin rescues postmenopausal osteoporosis elicited by OVX through alleviating osteoblast pyroptosis via activating PI3K-AKT signaling. Phytomedicine 128, 155516 (2024).

    Google Scholar 

  31. Wang, Z. et al. PLOD2 high expression associates with immune infiltration and facilitates cancer progression in osteosarcoma. Front. Oncol. 12, 980390 (2022).

    Google Scholar 

  32. Li, K. J. et al. Prognostic scoring system using inflammation- and nutrition-related biomarkers to predict prognosis in stage I-III colorectal cancer patients. World J. Gastroenterol. 31(14), 104588 (2025).

    Google Scholar 

  33. Fontana, F. et al. The PI3K/Akt pathway and glucose metabolism: A dangerous liaison in cancer. Int. J. Biol. Sci. 20(8), 3113–25 (2024).

    Google Scholar 

  34. Liu, Q. et al. ROR2 promotes cell cycle progression and cell proliferation through the PI3K/AKT signaling pathway in gastric cancer. Mol. Carcinog. 63(12), 2316–31 (2024).

    Google Scholar 

  35. Shafiek, M. S. et al. Vortioxetine ameliorates experimental autoimmune encephalomyelitis model of multiple sclerosis in mice via activation of PI3K/Akt/CREB/BDNF cascade and modulation of serotonergic pathway signaling. Eur. J. Pharmacol. 982, 176929 (2024).

    Google Scholar 

  36. Taheri, R. et al. The PI3K/Akt signaling axis and type 2 diabetes mellitus (T2DM): From mechanistic insights into possible therapeutic targets. Cell Biol. Int. 48(8), 1049–68 (2024).

    Google Scholar 

  37. Glaviano, A. et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol. Cancer 22(1), 138 (2023).

    Google Scholar 

  38. Maharati, A. & Moghbeli, M. PI3K/AKT signaling pathway as a critical regulator of epithelial-mesenchymal transition in colorectal tumor cells. Cell Commun. Sign. 21(1), 201 (2023).

    Google Scholar 

  39. Cui, G., Zhou, Y., Liao, W. et al. Inhibition of GSK3 and TSC2 mediates the oncogenic activity of AKT in hepatocellular carcinoma. Cancer Res. (2025).

  40. Feng, Q. et al. Phillygenin improves diabetic nephropathy by inhibiting inflammation and apoptosis via regulating TLR4/MyD88/NF-κB and PI3K/AKT/GSK3β signaling pathways. Phytomedicine 136, 156314 (2025).

    Google Scholar 

  41. Popov, S. V. et al. Regulation of autophagy of the heart in ischemia and reperfusion. Apoptosis 28(1–2), 55–80 (2023).

    Google Scholar 

  42. Deng, R. M. & Zhou, J. The role of PI3K/AKT signaling pathway in myocardial ischemia-reperfusion injury. Int. Immunopharmacol. 123, 110714 (2023).

    Google Scholar 

  43. Fu, C. et al. Rehmannioside A improves cognitive impairment and alleviates ferroptosis via activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway after ischemia. J. Ethnopharmacol. 289, 115021 (2022).

    Google Scholar 

  44. Yuan, Y., Long, H., Zhou, Z. et al. PI3K-AKT-targeting breast cancer treatments: Natural products and synthetic compounds. Biomolecules 13(1) (2023).

  45. Lu, Q. et al. Multiple myeloma: Signaling pathways and targeted therapy. Mol. Biomed 5(1), 25 (2024).

    Google Scholar 

  46. Alvarado-Ortiz, E. et al. Mutant p53 gain-of-function stimulates canonical Wnt signaling via PI3K/AKT pathway in colon cancer. J. Cell Commun. Sig. 17(4), 1389–403 (2023).

    Google Scholar 

  47. Sun, C. et al. The synergistic anti-colon cancer effect of aurora a inhibitors and AKT inhibitors through PI3K/AKT pathway. Anticancer. Agent. Med. Chem. 23(1), 87–93 (2023).

    Google Scholar 

  48. Wang, L. et al. PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages. J. Exp. Clin. Cancer Res. 41(1), 303 (2022).

    Google Scholar 

  49. Wang, C. et al. New insights into glycogen synthase kinase-3: A common target for neurodegenerative diseases. Biochem. Pharmacol. 218, 115923 (2023).

    Google Scholar 

  50. Kumari, S., Dhapola, R. & Reddy, D. H. Apoptosis in Alzheimer’s disease: Insight into the signaling pathways and therapeutic avenues. Apoptosis 28(7–8), 943–57 (2023).

    Google Scholar 

  51. Rana, A. K. et al. Glycogen synthase kinase-3: A putative target to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Cytokine Growth Factor Rev. 58, 92–101 (2021).

    Google Scholar 

  52. Long, S. et al. Extracellular matrix protein 1 regulates colorectal cancer cell proliferative, migratory, invasive and epithelial-mesenchymal transition activities through the PI3K/AKT/GSK3β/Snail signaling axis. Front. Oncol. 12, 889159 (2022).

    Google Scholar 

  53. Yao, M. et al. PP9, a steroidal saponin, induces G2/M arrest and apoptosis in human colorectal cancer cells by inhibiting the PI3K/Akt/GSK3β pathway. Chem. Biol. Interact. 331, 109246 (2020).

    Google Scholar 

  54. Zhang, W. J. et al. PI3K/Akt/GSK-3β signal pathway is involved in P2X7 receptor-induced proliferation and EMT of colorectal cancer cells. Eur. J. Pharmacol. 899, 174041 (2021).

    Google Scholar 

  55. Gao, S. et al. TUBB4A interacts with MYH9 to protect the nucleus during cell migration and promotes prostate cancer via GSK3β/β-catenin signalling. Nat. Commun. 13(1), 2792 (2022).

    Google Scholar 

  56. Li, Q. et al. RNF6 promotes colorectal cancer invasion and migration via the Wnt/β-catenin pathway by inhibiting GSK3β activity. Pathol. Res. Pract. 225, 153545 (2021).

    Google Scholar 

  57. Wang, H., Zhou, H., Ni, H., et al. COL11A1-driven epithelial-mesenchymal transition and stemness of pancreatic cancer cells induce cell migration and invasion by modulating the AKT/GSK-3β/Snail Pathway. Biomolecules 12(3) (2022).

  58. JI Y, LV J, SUN D, et al. Therapeutic strategies targeting Wnt/β‑catenin signaling for colorectal cancer (Review). Int. J. Mol. Med. 49(1) (2022).

  59. Li, J. et al. GNL3L exhibits pro-tumor activities via NF-κB pathway as a poor prognostic factor in acute myeloid leukemia. J. Cancer 15(13), 4072–80 (2024).

    Google Scholar 

Download references

Acknowledgements

We thank the Fujian Medical University Union Hospital for collecting the samples. We thank the School of Basic Medical Sciences of Fujian Medical University for providing the working platform.

Funding

This study was financially supported by the Natural Science Foundation of Fujian Province (No. 2023J01628 and No. 2023J06030).

Author information

Author notes

  1. Hua Fang, Jing Zheng and Shutong Ren are authors contributed equally to this work.

Authors and Affiliations

  1. Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, China

    Hua Fang, Jing Zheng, Shutong Ren, Danjing Chen & Xian-E Peng

  2. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China

    Yunli Wu & Xian-E Peng

Authors
  1. Hua Fang
    View author publications

    Search author on:PubMed Google Scholar

  2. Jing Zheng
    View author publications

    Search author on:PubMed Google Scholar

  3. Shutong Ren
    View author publications

    Search author on:PubMed Google Scholar

  4. Danjing Chen
    View author publications

    Search author on:PubMed Google Scholar

  5. Yunli Wu
    View author publications

    Search author on:PubMed Google Scholar

  6. Xian-E Peng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

H.F., J.Z. and S.R. conceived the study and conducted molecular evolution analysis and functional validation experiments and wrote the paper. D.C. were responsible for data collection assisted with manuscript revision. Y.W. administered the project and ensured its smooth execution. X.P. secured the funding for the research. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yunli Wu or Xian-E Peng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics

This study was approved by the Ethical Review Committee of Fujian Medical University, with approval No. 131. All procedures involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Supplementary Information.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fang, H., Zheng, J., Ren, S. et al. PLOD2 promotes proliferation, migration and invasion of colorectal cancer cells via PI3K-AKT-GSK3β signaling pathway. Sci Rep (2026). https://doi.org/10.1038/s41598-026-38593-6

Download citation

  • Received: 14 October 2025

  • Accepted: 30 January 2026

  • Published: 10 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-38593-6

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Keywords

  • PLOD2
  • Colorectal cancer
  • Malignant progression
  • Metastasis
  • PI3K-AKT- GSK3β
Download PDF

Advertisement

Explore content

  • Research articles
  • News & Comment
  • Collections
  • Subjects
  • Follow us on Facebook
  • Follow us on X
  • Sign up for alerts
  • RSS feed

About the journal

  • About Scientific Reports
  • Contact
  • Journal policies
  • Guide to referees
  • Calls for Papers
  • Editor's Choice
  • Journal highlights
  • Open Access Fees and Funding

Publish with us

  • For authors
  • Language editing services
  • Open access funding
  • Submit manuscript

Search

Advanced search

Quick links

  • Explore articles by subject
  • Find a job
  • Guide to authors
  • Editorial policies

Scientific Reports (Sci Rep)

ISSN 2045-2322 (online)

nature.com sitemap

About Nature Portfolio

  • About us
  • Press releases
  • Press office
  • Contact us

Discover content

  • Journals A-Z
  • Articles by subject
  • protocols.io
  • Nature Index

Publishing policies

  • Nature portfolio policies
  • Open access

Author & Researcher services

  • Reprints & permissions
  • Research data
  • Language editing
  • Scientific editing
  • Nature Masterclasses
  • Research Solutions

Libraries & institutions

  • Librarian service & tools
  • Librarian portal
  • Open research
  • Recommend to library

Advertising & partnerships

  • Advertising
  • Partnerships & Services
  • Media kits
  • Branded content

Professional development

  • Nature Awards
  • Nature Careers
  • Nature Conferences

Regional websites

  • Nature Africa
  • Nature China
  • Nature India
  • Nature Japan
  • Nature Middle East
  • Privacy Policy
  • Use of cookies
  • Legal notice
  • Accessibility statement
  • Terms & Conditions
  • Your US state privacy rights
Springer Nature

© 2026 Springer Nature Limited

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer