IGFBP1 Promotes the Proliferation and Migration of Lung Adenocarcinoma Cells Through the PPARα Pathway

Overview

Journal Transl Oncol

Specialty Oncology

Date 2024 Aug 21

PMID 39167955

Authors

Yunyun Li

Xuelian Yang

Tao Han

Jiawei Zhou

Yafeng Liu

Jianqiang Guo

Ziqin Liu

Ying Bai

Yingru Xing

Xuansheng Ding

Jing Wu

Dong Hu

Affiliations

Soon will be listed here.

Abstract

Background: The immune status is closely linked to cancer progression, metastasis, and prognosis. Lipid metabolism, crucial for reshaping immune status, plays a key role in regulating the advancement of lung adenocarcinoma (LUAD) and deserves further investigation.

Methods: This study classifies LUAD patients into different immune subtypes based on lipid metabolism-related genes and compares the clinical characteristics among these subtypes. Single-multi COX analysis screens out key genes related to prognosis, and a risk feature and prognostic model are constructed. Cell cloning, scratch, transwell, western blotting and flow cytometry cell cycle analysis to detect the function of key genes. A subcutaneous tumor animal model is used to investigate the in vivo function and molecular mechanisms of key genes.

Results: LUAD patients are classified into three immune subtypes, among which C3 subtype has lower immune status and higher frequency of gene mutations, and show lower immunoreactivity in immunotherapy. COX analysis identified a prognostic model for four lipid metabolism factors (IGFBP1, NR0B2, PPARA, and POMC). IGFBP1, a core gene in this model, is highly expressed in the C3 subtype. Functionally, knocking down IGFBP1 significantly inhibits tumor cell cloning, scratch, and migration abilities, and downregulates the expression of cell cycle and EMT-related proteins. Knocking down IGFBP1 significantly inhibits tumor burden (P < 0.05). Mechanistically, knocking down IGFBP1 inhibits the activation of PPARα to regulate tumor cell growth.

Conclusions: This study found that lipid metabolism genes are closely related to LUAD, and IGFBP1 may be a key gene in regulating tumor growth and development.

References

Zhao M, Ma J, Li M, Zhang Y, Jiang B, Zhao X . Cytochrome P450 Enzymes and Drug Metabolism in Humans. Int J Mol Sci. 2021; 22(23). PMC: 8657965. DOI: 10.3390/ijms222312808. View

Fitzgerald R, Antoniou A, Fruk L, Rosenfeld N . The future of early cancer detection. Nat Med. 2022; 28(4):666-677. DOI: 10.1038/s41591-022-01746-x. View

Wang D, Ye Q, Gu H, Chen Z . The role of lipid metabolism in tumor immune microenvironment and potential therapeutic strategies. Front Oncol. 2022; 12:984560. PMC: 9510836. DOI: 10.3389/fonc.2022.984560. View

Feitelson M, Arzumanyan A, Kulathinal R, Blain S, Holcombe R, Mahajna J . Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol. 2015; 35 Suppl:S25-S54. PMC: 4898971. DOI: 10.1016/j.semcancer.2015.02.006. View

Tang Y, Qiao G, Xu E, Xuan Y, Liao M, Yin G . Biomarkers for early diagnosis, prognosis, prediction, and recurrence monitoring of non-small cell lung cancer. Onco Targets Ther. 2017; 10:4527-4534. PMC: 5602468. DOI: 10.2147/OTT.S142149. View

Popay T, Wang J, Adams C, Howard G, Codreanu S, Sherrod S . MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor-1. Elife. 2021; 10. PMC: 7793627. DOI: 10.7554/eLife.60191. View

Liu Q, Jiang J, Zhang X, Zhang M, Fu Y . Comprehensive Analysis of IGFBPs as Biomarkers in Gastric Cancer. Front Oncol. 2021; 11:723131. PMC: 8567138. DOI: 10.3389/fonc.2021.723131. View

Jin M, Jin W . The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct Target Ther. 2020; 5(1):166. PMC: 7447642. DOI: 10.1038/s41392-020-00280-x. View

Ding L, Cao J, Lin W, Chen H, Xiong X, Ao H . The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer. Int J Mol Sci. 2020; 21(6). PMC: 7139603. DOI: 10.3390/ijms21061960. View

10.

Casciano J, Perry C, Cohen-Nowak A, Miller K, Vande Voorde J, Zhang Q . MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer. Br J Cancer. 2020; 122(6):868-884. PMC: 7078291. DOI: 10.1038/s41416-019-0711-3. View

11.

Lin Y, Weng X, Huang B, Guo H, Xu Y, Peng Y . IGFBP-1 in cancer: expression, molecular mechanisms, and potential clinical implications. Am J Transl Res. 2021; 13(3):813-832. PMC: 8014352. View

12.

Prendeville H, Lynch L . Diet, lipids, and antitumor immunity. Cell Mol Immunol. 2022; 19(3):432-444. PMC: 8891265. DOI: 10.1038/s41423-021-00781-x. View

13.

Lin Y, Wang Y, Li P . PPARα: An emerging target of metabolic syndrome, neurodegenerative and cardiovascular diseases. Front Endocrinol (Lausanne). 2023; 13:1074911. PMC: 9800994. DOI: 10.3389/fendo.2022.1074911. View

14.

Chen J, Dhahbi J . Lung adenocarcinoma and lung squamous cell carcinoma cancer classification, biomarker identification, and gene expression analysis using overlapping feature selection methods. Sci Rep. 2021; 11(1):13323. PMC: 8233431. DOI: 10.1038/s41598-021-92725-8. View

15.

Vasseur S, Guillaumond F . Lipids in cancer: a global view of the contribution of lipid pathways to metastatic formation and treatment resistance. Oncogenesis. 2022; 11(1):46. PMC: 9363460. DOI: 10.1038/s41389-022-00420-8. View

16.

Godoy L, Chen J, Ma W, Lally J, Toomey K, Rajappa P . Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer: current status and perspectives. Biomark Res. 2023; 11(1):7. PMC: 9847175. DOI: 10.1186/s40364-022-00444-7. View

17.

Sinha N, Sinha S, Valero C, Schaffer A, Aldape K, Litchfield K . Immune Determinants of the Association between Tumor Mutational Burden and Immunotherapy Response across Cancer Types. Cancer Res. 2022; 82(11):2076-2083. PMC: 9177633. DOI: 10.1158/0008-5472.CAN-21-2542. View

18.

Chen S, Cao G, Wei W, Yida L, Xiaobo H, Lei Y . Prediction and identification of immune genes related to the prognosis of patients with colon adenocarcinoma and its mechanisms. World J Surg Oncol. 2020; 18(1):146. PMC: 7325073. DOI: 10.1186/s12957-020-01921-9. View

19.

Wojtowicz S, Strosznajder A, Jezyna M, Strosznajder J . The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer's Disease and Other Neurodegenerative Disorders. Neurochem Res. 2020; 45(5):972-988. PMC: 7162839. DOI: 10.1007/s11064-020-02993-5. View

20.

Simioni C, Conti I, Varano G, Brenna C, Costanzi E, Neri L . The Complexity of the Tumor Microenvironment and Its Role in Acute Lymphoblastic Leukemia: Implications for Therapies. Front Oncol. 2021; 11:673506. PMC: 8131840. DOI: 10.3389/fonc.2021.673506. View