Secreted Protein Acidic and Rich in Cysteine (SPARC) Enhances Cell Proliferation, Migration, and Epithelial Mesenchymal Transition, and SPARC Expression is Associated with Tumor Grade in Head and Neck Cancer

Chang, Chih‐Hau; Yen, Meng‐Chi; Liao, Ssu-Hui; Hsu, Yu‐Ling; Lai, Chung-Sheng; Chang, Kao-Ping; Hsu, Ya‐Ling

doi:10.3390/ijms18071556

Cited by 44 publications

(36 citation statements)

References 37 publications

(45 reference statements)

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“…Our data showed that SPARC overexpression induced an EMT phenotype in A549 and H1299 cells, while knockdown of SPARC in A549 cells shown a contrary result. The positive relationship between SPARC and EMT was illustrated in melanoma cells and head and neck cancer . Previous studies have shown that SPARC regulates the interplay between myeloid‐derived suppressor cells and extracellular matrix to induce the induction of EMT in tumor cells .…”

Section: Discussionmentioning

confidence: 93%

SPARC acts as a mediator of TGF‐β1 in promoting epithelial‐to‐mesenchymal transition in A549 and H1299 lung cancer cells

et al. 2018

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Migration and metastasis of tumor cells greatly contributes to the failure of cancer treatment. Recently, the extracellular protein secreted protein acidic and rich in cysteine (SPARC) has been reported closely related to tumorigenesis. Some articles have suggested that SPARC promoted metastasis in several highly metastatic tumors. However, there are also some studies shown that SPARC acted as an antitumor factor. SPARC-induced epithelial-tomesenchymal transition (EMT) in melanoma cells and promoted EMT in hepatocellular carcinoma. Therefore, the role of SPARC in tumorigenesis and its relationship with EMT is still unclear. In this study, we investigated the expression change of SPARC in A549 and H1299 lung cancer cells undergoing EMT process. Our study indicated that SPARC was upregulated in A549 and H1299 cells EMT process. We further investigated the function of SPARC on proliferation, migration, and EMT process of A549 and H1299 cells. Overexpression of SPARC promoted the migration and EMT of A549 and H1299 cells. Knockdown SPARC inhibited the EMT of A549 cells. Overexpression of SPARC induced the increased expression of p-Akt and P-ERK. Furthermore, exogenous SPARC peptide promoted transforming growth factor (TGF)-β1-induced EMT of A549 and H1299 cells. SPARC knockdown partially eliminated TGF-β1 function in inducing EMT of A549 cells. SPARC follistatin-like functional domain reduced the expression of E-cadherin, but had no effect on the expression of p-Akt and p-ERK. In conclusion, we elucidated that SPARC contributes to tumorigenesis by promoting migration and EMT of A549 and H1299 lung cancer cells. These results will provide some new suggestion for lung cancer treatment. © 2018 BioFactors, 44(5):453-464, 2018Abbreviations: A549, A human lung adenocarinoma epithelial cell line; Akt, A serine/threonine-specific protein kinase; BSA, bovine serum albumin; CCK-8, cell counting kit-8; DMEM, Dulbecco's modified Eagle's Medium; EC, extracellular calcium-binding domain; EDTA, ethylenediaminetetraacetic acid; EGFP, enhancer green fluorescent protein; EGF, epidermal growth factor; EMT, epithelial-to-mesenchymal transition; ERK, extracellular signal-regulated kinases; FBS, fetal bovine serum; FS, follistatin-like functional domain; Fyn, Fyn proto-oncogene, Src family tyrosine kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; H1299, A human non-small cell lung carcinoma cell line; ILK, integrin-linked kinase; MDM2, mouse double minute 2 homolog; NF-κB, nuclear factor kappa B subunit 1; Nab-PTX, nanoparticle albumin bound paclitaxel; NSCLC, nonsmall cell lung cancer; NT, N terminal acidic domain; PBS, phosphate-buffered saline; PARP, poly (ADP-ribose) polymerase 1; PMSF, phenylmethane sulfonyl fluoride; RIPA, radioimmunoprecipitation assay buffer; SDS, sodium dodecyl sulfate; SPARC, secreted protein acidic and rich in cysteine; TGF-β, transforming growth factor; TBST, a mixture of tris-buffered saline and Tween 20 Additional Supporting Information may be found in the online version of this article.

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Section: Discussionmentioning

confidence: 93%

SPARC acts as a mediator of TGF‐β1 in promoting epithelial‐to‐mesenchymal transition in A549 and H1299 lung cancer cells

et al. 2018

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“…Consistent with this result, we found that HOXC6 is a master regulator of many genes, which have documented pro-tumorigenic functions. In our studies, we identified several genes, including CEACAM6, SPARC, WNT6, CST1, MMP2, and KRT13, which have been extensively studied and demonstrated to be involved in the regulation of tumor growth, migration and invasion, cell cycle, and apoptosis (Chang et al 2018;Choi et al 2009;Dai et al 2017;Kuo et al 2014;Rizeq et al 2018;Wang et al 2018;Yusuf et al 2014;. In other types of cancers, HOXC6 has also been shown to have the capacity to regulate these cancerrelated genes.…”

Section: Manuscript To Be Reviewedmentioning

confidence: 87%

Peer Review #1 of "Evidence for an oncogenic role of HOXC6 in human non-small cell lung cancer (v0.2)"

2019

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Background: Identification of specific biomarkers is important for the diagnosis and treatment of nonsmall cell lung cancer (NSCLC). HOXC6 is a homeodomain-containing transcription factor that is highly expressed in several human cancers; however, its role in NSCLC remains unknown. Methods: The expression and protein levels of HOXC6 were assessed in NSCLC tissue samples by Quantitative real-time PCR (qRT-PCR) and immunohistochemistry, respectively. HOXC6 was transfected into the NSCLC cell lines A549 and PC9, and used to investigate its effect on proliferation, migration, and invasion using CFSE, wound healing, and Matrigel invasion assays. Next-generation sequencing was also used to identify downstream targets of HOXC6 and to gain insights into the molecular mechanisms underlying its biological function. Results: HOXC6 expression was significantly increased in 66.6% (20/30) of NSCLC tumor samples in comparison to normal controls. HOXC6 promoted proliferation, migration, and invasion of NSCLC cells in vitro. RNA-seq analysis demonstrated the upregulation of 310 and 112 genes in A549-HOXC6 and PC9-HOXC6 cells, respectively, and the downregulation of 665 and 385 genes in A549-HOXC6 and PC9-HOXC6 cells, respectively. HOXC6 was also found to regulate the expression of genes such as CEACAM6, SPARC, WNT6, CST1, MMP2, and KRT13, which have documented pro-tumorigenic functions. Discussion: HOXC6 is highly expressed in NSCLC, and it may enhance lung cancer progression by regulating the expression of pro-tumorigenic genes involved in proliferation, migration, and invasion. Our study highlighted the oncogenic potential of HOXC6, and suggests that it may be a novel biomarker for the diagnosis and treatment of NSCLC.

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“…More importantly, SPARC silencing significantly mitigated the VEGF-stimulated Collagen-I and MMP9 expression in HTFs and attenuated the VEGF-stimulated proliferation and wound healing of HTFs. Previous studies have shown that SPARC can modulate MMP activity in U87MG glioma cells 17 and altered MMP activity can affect the ECM remodeling and fibroblast proliferation and migration 18-19. Moreover,SPARC can promote cell adhesion 20 and SPARC deficiency inhibits cell migration in various types of cells [21][22] . It is possible that SPARC modulates MMP activity and wound healing,contributing to the progression of fibrosis 23 .…”

Section: Discussionmentioning

confidence: 99%

Secreted protein, acidic and rich in cysteine is crucial for the vascular endothelial growth factor-stimulated fibrotic process in human Tenon’s fibroblasts

Xiang¹,

Luo²,

Chen³

et al. 2019

Preprint

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Background Aberrant post-surgical scarring is responsible for failure of glaucoma filtration surgery (GFS) and is attributed to strong fibrotic process of human Tenon’s fibroblasts (HTFs). Vascular endothelial growth factor (VEGF) and secreted protein, acidic and rich in cysteine (SPARC) contribute to angiogenesis and fibrosis. However, whether SPARC can regulate the VEGF-mediated fibrotic process in HTFs has not been clarified. This study aimed to examine how SPARC and VEGF crosstalk to regulate the expression of Collagen-I and matrix metalloproteinase 9 (MMP9) as well as the ERK signalling in HTFs.Methods Human Tenon's capsule tissues were cultured for preparation of HTFs, which were characterized by immunofluorescence. The effects of VEGF treatment on SPARC, Collagen-I and MMP9 expression and ERK phosphorylation were determined by Western blot, quantitative RT-PCR and immunofluorescence. The proliferation and wound healing induced by VEGF were examined in HTFs and SPARC-silenced HTFs.Results Following successful passages, immunofluorescent assays indicated that HTFs at passages 3-9 displayed unique characters of fibroblasts with Vimentin, but not keratin, expression. Treatment with VEGF significantly up-regulated SPARC, Collagen-I and MMP9 expression and ERK phosphorylation, and promoted the proliferation and wound healing of HTFs. The stimulatory effects of VEGF were significantly mitigated by SPARC silencing in HTFs.Conclusions Our data provided novel evidence that SPARC was crucial for the VEGF-stimulated fibrotic process in HTFs and may be a novel target for anti-fibrotic therapies post GFS.

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Secreted Protein Acidic and Rich in Cysteine (SPARC) Enhances Cell Proliferation, Migration, and Epithelial Mesenchymal Transition, and SPARC Expression is Associated with Tumor Grade in Head and Neck Cancer

Cited by 44 publications

References 37 publications

SPARC acts as a mediator of TGF‐β1 in promoting epithelial‐to‐mesenchymal transition in A549 and H1299 lung cancer cells

SPARC acts as a mediator of TGF‐β1 in promoting epithelial‐to‐mesenchymal transition in A549 and H1299 lung cancer cells

Peer Review #1 of "Evidence for an oncogenic role of HOXC6 in human non-small cell lung cancer (v0.2)"

Secreted protein, acidic and rich in cysteine is crucial for the vascular endothelial growth factor-stimulated fibrotic process in human Tenon’s fibroblasts

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