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Lumican mediates HTB94 chondrosarcoma cell growth via an IGF?IR/Erk1/2 axis.

ABSTRACT: Chondrosarcoma is a malignant bone tumor characterized by the production of a modified cartilage?type extracellular matrix (ECM). In the present study, the expression levels of the small leucine?rich proteoglycans (SLRPs), decorin, biglycan and lumican, were examined in the HTB94 human chondrosarcoma cell line. HTB94 cells were found to express and secrete the 3 SLRP members. RT?qPCR and western blot analysis demonstrated that lumican was the most abundantly secreted SLRP, whereas decorin and biglycan expression levels were low. The utilization of short interfering RNA specific for the decorin, biglycan, and lumican genes resulted in the efficient downregulation of the respective mRNA levels (P?0.001). The growth of the HTB94 cells was stimulated by lumican (P?0.001), whereas their migration and adhesion were not affected (P=NS). By contrast, these cellular functions were not sensitive to a decrease in low endogenous levels of decorin and biglycan. Lumicandeficiency significantly inhibited both basal and insulin?like growth factor I (IGF?I)?induced HTB94 cell growth (P?0.001 andP?0.01, respectively). These effects were executed through the insulin?like growth factor I receptor (IGF?IR), whose activation was markedly attenuated (P?0.01) in lumican?deficient HTB94 cells. The downregulation of lumican induced the substantial inhibition of extracellular regulated kinase (ERK1/2) activation (P? 0.01), indicating that ERK1/2 is a necessary component of lumican/IGF?IR?mediated HTB94 cell proliferation. Moreover, the lumican?deficient cells exhibit increased mRNA levels of p53 (P?0.05), suggesting that lumican facilitates HTB94 cell growth through an IGF?IR/ERK1/2/p53 signaling cascade. On the whole, the findings of the present study demonstrate that endogenous lumican is a novel regulator of HTB94 cell growth.

SUBMITTER: Papoutsidakis A

PROVIDER: S-EPMC7384848 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Lumican mediates HTB94 chondrosarcoma cell growth via an IGF‑IR/Erk1/2 axis.

Papoutsidakis Antonis A Giatagana Eirini Maria EM Berdiaki Aikaterini A Spyridaki Ioanna I Spandidos Demetrios A DA Tsatsakis Aristidis A Tzanakakis George N GN Nikitovic Dragana D

International journal of oncology 20200706 3

Chondrosarcoma is a malignant bone tumor characterized by the production of a modified cartilage‑type extracellular matrix (ECM). In the present study, the expression levels of the small leucine‑rich proteoglycans (SLRPs), decorin, biglycan and lumican, were examined in the HTB94 human chondrosarcoma cell line. HTB94 cells were found to express and secrete the 3 SLRP members. RT‑qPCR and western blot analysis demonstrated that lumican was the most abundantly secreted SLRP, whereas decorin and bi ...[more]

PMID: 32705211

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Project description:Primary bone tumor, also known as osteosarcoma (OS), is the most common primary malignancy of bone in children and young adults. Current treatment protocols yield a 5-year survival rate of near 70% although approximately 80% of patients have metastatic disease at the time of diagnosis. However, long-term survival rates have remained virtually unchanged for nearly four decades, largely due to our limited understanding of the disease process. One major signaling pathway that has been implicated in human OS tumorigenesis is the insulin-like growth factor (IGF)/insulin-like growth factor-1 receptor (IGF1R) signaling axis. IGF1R is a heterotetrameric α2β2 receptor, in which the α subunits comprise the ligand binding site, whereas the β subunits are transmembrane proteins containing intracellular tyrosine kinase domains. Although numerous strategies have been devised to target IGF/IGF1R axis, most of them have failed in clinical trials due to the lack of specificity and/or limited efficacy. Here, we investigated whether a more effective and specific blockade of IGF1R activity in human OS cells can be accomplished by employing dominant-negative IGF1R (dnIGF1R) mutants. We engineered the recombinant adenoviruses expressing two IGF1R mutants derived from the α (aa 1-524) and β (aa 741-936) subunits, and found that either dnIGF1Rα and/or dnIGF1Rβ effectively inhibited cell migration, colony formation, and cell cycle progression of human OS cells, which could be reversed by exogenous IGF1. Furthermore, dnIGF1Rα and/or dnIGF1Rβ inhibited OS xenograft tumor growth in vivo, with the greatest inhibition of tumor growth shown by dnIGF1Rα. Mechanistically, the dnIGF1R mutants down-regulated the expression of PI3K/AKT and RAS/RAF/MAPK, BCL2, Cyclin D1 and most EMT regulators, while up-regulating pro-apoptotic genes in human OS cells. Collectively, these findings strongly suggest that the dnIGF1R mutants, especially dnIGF1Rα, may be further developed as novel anticancer agents that target IGF signaling axis with high specificity and efficacy.

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Lumican mediates HTB94 chondrosarcoma cell growth via an IGF?IR/Erk1/2 axis.

Publications

Lumican mediates HTB94 chondrosarcoma cell growth via an IGF‑IR/Erk1/2 axis.

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