RUNX1-BMP2 Promotes Vasculogenic Mimicry in Laryngeal Squamous Cell Carcinoma Via Activation of the PI3K-AKT Signaling Pathway

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2024 Apr 12

PMID 38610001

Authors

Qingwen Zhu

Xinyu Zhang

Fei Lu

Siyu Miao

Chunyang Zhang

Zhenzhen Liu

Zejun Gao

Meihao Qi

Xiaogang An

Panling Geng

Sufang Wang

Hongbo Ren

Fugen Han

Ruyue Zhang

Dingjun Zha

Affiliations

Soon will be listed here.

Abstract

Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck. Vasculogenic mimicry (VM) is crucial for tumor growth and metastasis and refers to the formation of fluid channels by invasive tumor cells rather than endothelial cells. However, the regulatory mechanisms underlying VM during the malignant progression of LSCC remain largely unknown.

Methods: Gene expression and clinical data for LSCC were obtained from the TCGA and Gene GEO (GSE27020) databases. A risk prediction model associated with VM was established using LASSO and Cox regression analyses. Based on their risk scores, patients with LSCC were categorized into high- and low-risk groups. The disparities in immune infiltration, tumor mutational burden (TMB), and functional enrichment between these two groups were examined. The core genes in LSCC were identified using the machine learning (SVM-RFE) and WGCNA algorithms. Subsequently, the involvement of bone morphogenetic protein 2 (BMP2) in VM and metastasis was investigated both in vitro and in vivo. To elucidate the downstream signaling pathways regulated by BMP2, western blotting was performed. Additionally, ChIP experiments were employed to identify the key transcription factors responsible for modulating the expression of BMP2.

Results: We established a new precise prognostic model for LSCC related to VM based on three genes: BMP2, EPO, and AGPS. The ROC curves from both TCGA and GSE27020 validation cohorts demonstrated precision survival prediction capabilities, with the nomogram showing some net clinical benefit. Multiple algorithm analyses indicated BMP2 as a potential core gene. Further experiments suggested that BMP2 promotes VM and metastasis in LSCC. The malignant progression of LSCC is promoted by BMP2 via the activation of the PI3K-AKT signaling pathway, with the high expression of BMP2 in LSCC resulting from its transcriptional activation by runt-related transcription factor 1 (RUNX1).

Conclusion: BMP2 predicts poor prognosis in LSCC, promotes LSCC VM and metastasis through the PI3K-AKT signaling pathway, and is transcriptionally regulated by RUNX1. BMP2 may be a novel, precise, diagnostic, and therapeutic biomarker of LSCC.

References

Lin P, Wang W, Sun B, Cai W, Li L, Lu H . Vasculogenic mimicry is a key prognostic factor for laryngeal squamous cell carcinoma: a new pattern of blood supply. Chin Med J (Engl). 2012; 125(19):3445-9. View

Li X, Xue Y, Liu X, Zheng J, Shen S, Yang C . ZRANB2/SNHG20/FOXK1 Axis regulates Vasculogenic mimicry formation in glioma. J Exp Clin Cancer Res. 2019; 38(1):68. PMC: 6371528. DOI: 10.1186/s13046-019-1073-7. View

Mann J, Smith J, Birkeland A, Bellile E, Swiecicki P, Mierzwa M . Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma. Cancer Immunol Immunother. 2018; 68(2):213-220. PMC: 6375747. DOI: 10.1007/s00262-018-2256-3. View

Zhang X, Feng H, Li Z, Li D, Liu S, Huang H . Application of weighted gene co-expression network analysis to identify key modules and hub genes in oral squamous cell carcinoma tumorigenesis. Onco Targets Ther. 2018; 11:6001-6021. PMC: 6157991. DOI: 10.2147/OTT.S171791. View

Treps L, Faure S, Clere N . Vasculogenic mimicry, a complex and devious process favoring tumorigenesis - Interest in making it a therapeutic target. Pharmacol Ther. 2021; 223:107805. DOI: 10.1016/j.pharmthera.2021.107805. View

Tian H, Zhao J, Brochmann E, Wang J, Murray S . Bone morphogenetic protein-2 and tumor growth: Diverse effects and possibilities for therapy. Cytokine Growth Factor Rev. 2017; 34:73-91. DOI: 10.1016/j.cytogfr.2017.01.002. View

Priya S, Nagare R, Sneha V, Sidhanth C, Bindhya S, Manasa P . Tumour angiogenesis-Origin of blood vessels. Int J Cancer. 2016; 139(4):729-35. DOI: 10.1002/ijc.30067. View

Gao H, Chakraborty G, Lee-Lim A, Mo Q, Decker M, Vonica A . The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell. 2012; 150(4):764-79. PMC: 3711709. DOI: 10.1016/j.cell.2012.06.035. View

Ten Dijke P, Fu J, Schaap P, Roelen B . Signal transduction of bone morphogenetic proteins in osteoblast differentiation. J Bone Joint Surg Am. 2003; 85-A Suppl 3:34-8. DOI: 10.2106/00004623-200300003-00007. View

10.

Lin T . RUNX1 and cancer. Biochim Biophys Acta Rev Cancer. 2022; 1877(3):188715. DOI: 10.1016/j.bbcan.2022.188715. View

11.

Feng X, Zheng Z, Wang Y, Song G, Wang L, Zhang Z . Elevated RUNX1 is a prognostic biomarker for human head and neck squamous cell carcinoma. Exp Biol Med (Maywood). 2020; 246(5):538-546. PMC: 7934153. DOI: 10.1177/1535370220969663. View

12.

Chen J, Chen S, Zhuo L, Zhu Y, Zheng H . Regulation of cancer stem cell properties, angiogenesis, and vasculogenic mimicry by miR-450a-5p/SOX2 axis in colorectal cancer. Cell Death Dis. 2020; 11(3):173. PMC: 7060320. DOI: 10.1038/s41419-020-2361-z. View

13.

Zhu Q, Zhang Q, Gu M, Zhang K, Xia T, Zhang S . upregulation suppresses autophagy and accelerates malignant phenotype in nasopharyngeal carcinoma. Autophagy. 2020; 17(7):1667-1683. PMC: 8354606. DOI: 10.1080/15548627.2020.1781368. View

14.

Hendrix M, Seftor E, Hess A, Seftor R . Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer. 2003; 3(6):411-21. DOI: 10.1038/nrc1092. View

15.

Martinez F, Gordon S . The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6:13. PMC: 3944738. DOI: 10.12703/P6-13. View

16.

Wu Y, Zhang Y, Zheng X, Dai F, Lu Y, Dai L . Circular RNA circCORO1C promotes laryngeal squamous cell carcinoma progression by modulating the let-7c-5p/PBX3 axis. Mol Cancer. 2020; 19(1):99. PMC: 7265647. DOI: 10.1186/s12943-020-01215-4. View

17.

Zhu Q, Zhang R, Lu F, Zhang X, Zhang D, Zhang Y . Cuproptosis-related LINC02454 as a biomarker for laryngeal squamous cell carcinoma based on a novel risk model and in vitro and in vivo analyses. J Cancer Res Clin Oncol. 2023; 149(16):15185-15206. DOI: 10.1007/s00432-023-05281-1. View

18.

Buijs J, Van Der Horst G, van den Hoogen C, Cheung H, de Rooij B, Kroon J . The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene. 2011; 31(17):2164-74. DOI: 10.1038/onc.2011.400. View

19.

Bieniasz M, Oszajca K, Eusebio M, Kordiak J, Bartkowiak J, Szemraj J . The positive correlation between gene expression of the two angiogenic factors: VEGF and BMP-2 in lung cancer patients. Lung Cancer. 2009; 66(3):319-26. DOI: 10.1016/j.lungcan.2009.02.020. View

20.

Gao J, Muroya R, Huang F, Nagata K, Shin M, Nagano R . Bone morphogenetic protein induces bone invasion of melanoma by epithelial-mesenchymal transition via the Smad1/5 signaling pathway. Lab Invest. 2021; 101(11):1475-1483. DOI: 10.1038/s41374-021-00661-y. View