Identification of HSPG2 As a Bladder Pro-tumor Protein Through NID1/AKT Signaling

Overview

Journal Cancer Cell Int

Publisher Biomed Central

Date 2024 Oct 23

PMID 39438949

Authors

Cong Li

Pengwei Luo

Fengzhu Guo

Xu Jia

Min Shen

Ting Zhang

Shusen Wang

Ting Du

Affiliations

Soon will be listed here.

Abstract

Purpose: Heparan sulfate proteoglycans (HSPGs) are complex molecules found on the cell membrane and within the extracellular matrix, increasingly recognized for their role in tumor progression. This study aimed to investigate the involvement of Heparan sulfate proteoglycan 2 (HSPG2) in the progression of bladder cancer.

Methods: We identified HSPG2 as a promoter of bladder tumor progression using single-cell RNA sequencing and transcriptome analysis of sequencing data from seven patient samples obtained from the Gene Expression Omnibus (GEO) database (GSE135337). Transcript profiles of 28 normal tissues and 407 bladder tumor tissues were analyzed for HSPG2 expression and survival outcomes using the Sanger tools and cBioPortal databases. HSPG2-overexpressing T24 and Biu-87 cell lines were generated, and cell proliferation and migration were assessed using CCK-8 and Transwell assays. Western blotting and immunostaining were performed to evaluate the activation of Nidogen-1 (NID1)/protein kinase B (AKT) signaling. Mouse models with patient-derived tumor organoids (HSPG2 and HSPG2) were established to assess anticancer effects.

Results: Our results demonstrated a marked upregulation of HSPG2 in malignant bladder tumors, which correlated significantly with poor patient prognosis. HSPG2 overexpression consistently enhanced bladder tumor cell proliferation and conferred chemotherapy resistance, as shown in both in vitro and in vivo experiments. Mechanistically, HSPG2 upregulated NID1 expression, leading to the activation of the AKT pro-survival signaling pathway and promoting sustained tumor growth in bladder cancer.

Conclusion: This study highlights the critical pro-tumor role of HSPG2/NID1/AKT signaling in bladder cancer and suggests its potential as a therapeutic target in clinical treatment.

References

Nagarajan A, Malvi P, Wajapeyee N . Heparan Sulfate and Heparan Sulfate Proteoglycans in Cancer Initiation and Progression. Front Endocrinol (Lausanne). 2018; 9:483. PMC: 6118229. DOI: 10.3389/fendo.2018.00483. View

Kalscheuer S, Khanna V, Kim H, Li S, Sachdev D, DeCarlo A . Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer. Sci Rep. 2019; 9(1):12492. PMC: 6713791. DOI: 10.1038/s41598-019-48993-6. View

Hammond E, Khurana A, Shridhar V, Dredge K . The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics. Front Oncol. 2014; 4:195. PMC: 4109498. DOI: 10.3389/fonc.2014.00195. View

Tian X, Sun J, Li C, Zhang K . COL4A1 promotes the proliferation and migration of oral squamous cell carcinoma cells by binding to NID1. Exp Ther Med. 2023; 25(4):176. PMC: 10061039. DOI: 10.3892/etm.2023.11875. View

Li L, Zhang Y, Li N, Feng L, Yao H, Zhang R . Nidogen-1: a candidate biomarker for ovarian serous cancer. Jpn J Clin Oncol. 2014; 45(2):176-82. DOI: 10.1093/jjco/hyu187. View

Mayer I, Arteaga C . The PI3K/AKT Pathway as a Target for Cancer Treatment. Annu Rev Med. 2015; 67:11-28. DOI: 10.1146/annurev-med-062913-051343. View

Han N, Li X, Wang Y, Li H, Zhang C, Zhao X . HIF-1α induced NID1 expression promotes pulmonary metastases via the PI3K-AKT pathway in salivary gland adenoid cystic carcinoma. Oral Oncol. 2022; 131:105940. DOI: 10.1016/j.oraloncology.2022.105940. View

Urooj T, Wasim B, Mushtaq S, Haider G, Shah S, Ghani R . Increased NID1 Expression among Breast Cancer Lung Metastatic Women; A Comparative Analysis between Naive and Treated Cases. Recent Pat Anticancer Drug Discov. 2020; 15(1):59-69. DOI: 10.2174/1574892815666200302115438. View

Onyeisi J, Ferreira B, Nader H, Lopes C . Heparan sulfate proteoglycans as targets for cancer therapy: a review. Cancer Biol Ther. 2020; 21(12):1087-1094. PMC: 7746240. DOI: 10.1080/15384047.2020.1838034. View

10.

Lenis A, Lec P, Chamie K, Mshs M . Bladder Cancer: A Review. JAMA. 2020; 324(19):1980-1991. DOI: 10.1001/jama.2020.17598. View

11.

Xue C, Li G, Lu J, Li L . Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal Transduct Target Ther. 2021; 6(1):400. PMC: 8611092. DOI: 10.1038/s41392-021-00788-w. View

12.

Kamat A, Hahn N, Efstathiou J, Lerner S, Malmstrom P, Choi W . Bladder cancer. Lancet. 2016; 388(10061):2796-2810. DOI: 10.1016/S0140-6736(16)30512-8. View

13.

Rokavec M, Jaeckel S, Hermeking H . Nidogen-1/NID1 Function and Regulation during Progression and Metastasis of Colorectal Cancer. Cancers (Basel). 2023; 15(22). PMC: 10670298. DOI: 10.3390/cancers15225316. View

14.

Sever R, Brugge J . Signal transduction in cancer. Cold Spring Harb Perspect Med. 2015; 5(4). PMC: 4382731. DOI: 10.1101/cshperspect.a006098. View

15.

Seidl C . Targets for Therapy of Bladder Cancer. Semin Nucl Med. 2020; 50(2):162-170. DOI: 10.1053/j.semnuclmed.2020.02.006. View

16.

Mercier F . Fractones: extracellular matrix niche controlling stem cell fate and growth factor activity in the brain in health and disease. Cell Mol Life Sci. 2016; 73(24):4661-4674. PMC: 11108427. DOI: 10.1007/s00018-016-2314-y. View

17.

Rokavec M, Bouznad N, Hermeking H . Paracrine Induction of Epithelial-Mesenchymal Transition Between Colorectal Cancer Cells and its Suppression by a p53/miR-192/215/NID1 Axis. Cell Mol Gastroenterol Hepatol. 2019; 7(4):783-802. PMC: 6468198. DOI: 10.1016/j.jcmgh.2019.02.003. View

18.

Raman K, Kuberan B . Chemical Tumor Biology of Heparan Sulfate Proteoglycans. Curr Chem Biol. 2010; 4(1):20-31. PMC: 2892923. DOI: 10.2174/187231310790226206. View

19.

de Mello L, Ribeiro Carneiro T, Araujo A, Alves C, Galante P, Buzatto V . Identification of NID1 as a novel candidate susceptibility gene for familial non-medullary thyroid carcinoma using whole-exome sequencing. Endocr Connect. 2021; 11(1). PMC: 8859953. DOI: 10.1530/EC-21-0406. View

20.

Vaes N, Schonkeren S, Rademakers G, Holland A, Koch A, Gijbels M . Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2. EMBO Rep. 2021; 22(6):e51913. PMC: 8183412. DOI: 10.15252/embr.202051913. View