Betaglycan Sustains HGF/Met Signaling in Lung Cancer and Endothelial Cells Promoting Cell Migration and Tumor Growth

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 May 17

PMID 38756586

Authors

Rodolfo Daniel Cervantes-Villagrana

Valentin Mendoza

Cynthia S Hinck

Rosa Luz de la Fuente-Leon

Andrew P Hinck

Guadalupe Reyes-Cruz

Jose Vazquez-Prado

Fernando Lopez-Casillas

Affiliations

Soon will be listed here.

Abstract

Persistent HGF/Met signaling drives tumor growth and dissemination. Proteoglycans within the tumor microenvironment might control HGF availability and signaling by affecting its accessibility to Met (HGF receptor), likely defining whether acute or sustained HGF/Met signaling cues take place. Given that betaglycan (BG, also known as type III TGFβ receptor or TGFBR3), a multi-faceted proteoglycan TGFβ co-receptor, can be found within the tumor microenvironment, we addressed its hypothetical role in oncogenic HGF signaling. We found that HGF/Met promotes lung cancer and endothelial cells migration via PI3K and mTOR. This effect was enhanced by recombinant soluble betaglycan (solBG) via a mechanism attributable to its glycosaminoglycan chains, as a mutant without them did not modulate HGF effects. Moreover, soluble betaglycan extended the effect of HGF-induced phosphorylation of Met, Akt, and Erk, and membrane recruitment of the RhoGEF P-Rex1. Data-mining analysis of lung cancer patient datasets revealed a significant correlation between high receptor, and expression and reduced patient survival. Soluble betaglycan showed biochemical interaction with HGF and, together, they increased tumor growth in immunocompetent mice. In conclusion, the oncogenic properties of the HGF/Met pathway are enhanced and sustained by GAG-containing soluble betaglycan.

References

Vilchis-Landeros M, Montiel J, Mendoza V, Mendoza-Hernandez G, Lopez-Casillas F . Recombinant soluble betaglycan is a potent and isoform-selective transforming growth factor-beta neutralizing agent. Biochem J. 2001; 355(Pt 1):215-22. PMC: 1221729. DOI: 10.1042/0264-6021:3550215. View

Qin J, Xie Y, Wang B, Hoshino M, Wolff D, Zhao J . Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis. Oncogene. 2009; 28(16):1853-63. PMC: 2672965. DOI: 10.1038/onc.2009.30. View

Rubin J, Day R, Breckenridge D, Atabey N, Taylor W, Stahl S . Dissociation of heparan sulfate and receptor binding domains of hepatocyte growth factor reveals that heparan sulfate-c-met interaction facilitates signaling. J Biol Chem. 2001; 276(35):32977-83. DOI: 10.1074/jbc.M105486200. View

Attwood M, Jonsson J, Rask-Andersen M, Schioth H . Soluble ligands as drug targets. Nat Rev Drug Discov. 2020; 19(10):695-710. DOI: 10.1038/s41573-020-0078-4. View

Gong Q, Wang Y, Zhu K, Bai X, Feng T, Sun G . CUL4B enhances the malignant phenotype of esophageal squamous cell carcinoma by suppressing TGFBR3 expression. Biochem Biophys Res Commun. 2023; 676:58-65. DOI: 10.1016/j.bbrc.2023.07.037. View

Zioncheck T, Richardson L, Liu J, Chang L, King K, Bennett G . Sulfated oligosaccharides promote hepatocyte growth factor association and govern its mitogenic activity. J Biol Chem. 1995; 270(28):16871-8. DOI: 10.1074/jbc.270.28.16871. View

Cao T, Pan J, Li X, He Y, Jiang Y, Chang Y . Isolation and Characterization of a Chinese Hamster Ovary Heparan Sulfate Cell Mutant Defective in Both Met Receptor Binding and Hepatocyte Growth Factor NK1/Met Signaling. Cell Physiol Biochem. 2018; 48(4):1480-1491. DOI: 10.1159/000492258. View

Huang P, Duda D, Jain R, Fukumura D . Histopathologic findings and establishment of novel tumor lines from spontaneous tumors in FVB/N mice. Comp Med. 2008; 58(3):253-63. PMC: 2693079. View

Zhang N, Li L, Luo J, Tan J, Hu W, Li Z . Inhibiting microRNA-424 in bone marrow mesenchymal stem cells-derived exosomes suppresses tumor growth in colorectal cancer by upregulating TGFBR3. Arch Biochem Biophys. 2021; 709:108965. DOI: 10.1016/j.abb.2021.108965. View

10.

Sosa M, Lopez-Haber C, Yang C, Wang H, Lemmon M, Busillo J . Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer. Mol Cell. 2010; 40(6):877-92. PMC: 3038344. DOI: 10.1016/j.molcel.2010.11.029. View

11.

Zhang X, Chen Y, Li Z, Han X, Liang Y . TGFBR3 is an independent unfavourable prognostic marker in oesophageal squamous cell cancer and is positively correlated with Ki-67. Int J Exp Pathol. 2020; 101(6):223-229. PMC: 7691215. DOI: 10.1111/iep.12380. View

12.

Kim S, Henen M, Hinck A . Structural biology of betaglycan and endoglin, membrane-bound co-receptors of the TGF-beta family. Exp Biol Med (Maywood). 2019; 244(17):1547-1558. PMC: 6920675. DOI: 10.1177/1535370219881160. View

13.

Cervantes-Villagrana R, Albores-Garcia D, Cervantes-Villagrana A, Garcia-Acevez S . Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies. Signal Transduct Target Ther. 2020; 5(1):99. PMC: 7303203. DOI: 10.1038/s41392-020-0205-z. View

14.

Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C . Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 2018; 17(1):45. PMC: 5817860. DOI: 10.1186/s12943-018-0796-y. View

15.

Fu J, Su X, Li Z, Deng L, Liu X, Feng X . HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene. 2021; 40(28):4625-4651. DOI: 10.1038/s41388-021-01863-w. View

16.

Cheifetz S, Hernandez H, Laiho M, Ten Dijke P, Iwata K, Massague J . Distinct transforming growth factor-beta (TGF-beta) receptor subsets as determinants of cellular responsiveness to three TGF-beta isoforms. J Biol Chem. 1990; 265(33):20533-8. View

17.

Bartolini B, Carava E, Caon I, Parnigoni A, Moretto P, Passi A . Heparan Sulfate in the Tumor Microenvironment. Adv Exp Med Biol. 2020; 1245:147-161. DOI: 10.1007/978-3-030-40146-7_7. View

18.

Srijakotre N, Liu H, Nobis M, Man J, Yip H, Papa A . PtdIns(3,4,5)P-dependent Rac exchanger 1 (P-Rex1) promotes mammary tumor initiation and metastasis. Proc Natl Acad Sci U S A. 2020; 117(45):28056-28067. PMC: 7668035. DOI: 10.1073/pnas.2006445117. View

19.

Jovanovic B, Beeler J, Pickup M, Chytil A, Gorska A, Ashby W . Transforming growth factor beta receptor type III is a tumor promoter in mesenchymal-stem like triple negative breast cancer. Breast Cancer Res. 2014; 16(4):R69. PMC: 4095685. DOI: 10.1186/bcr3684. View

20.

Chavez-Vargas L, Adame-Garcia S, Cervantes-Villagrana R, Castillo-Kauil A, Bruystens J, Fukuhara S . Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor: EFFECT ON PKA LOCALIZATION AND P-Rex1 SIGNALING. J Biol Chem. 2016; 291(12):6182-99. PMC: 4813559. DOI: 10.1074/jbc.M115.712216. View