The Role and Mechanism of SPARC in Renal Cancer Metastasis

Abstract

Background: Aberrant expression of transforming growth factorβ1 (TGF-β1) is associated with renal cell carcinoma (RCC) progression by inducing cancer metastasis. However, the downstream effector(s) in TGF-β signaling pathway that is involved in RCC progression is not fully characterized. Methods: SPARC was identified as a potential downstream target gene in TGF-β-induced cell invasion by applying microarray analysis, qRT-PCR and Western blot. In vitro and in vivo assays were subsequently performed to validate the role of SPARC in RCC. SPARC expression profile in RCC tissues and its correlation with clinical data were also examined. Findings: We demonstrate that elevated SPARC is associated with metastatic RCC; SPARC gene expression can be induced by TGF-β1 via Snail. Clinically, the expression of these two genes is positively correlated in RCC patient specimens. Furthermore, elevated SPARC expression is found in all the subtypes of RCC and positively correlated with RCC stage and grade. In contrast, SPARC expression is inversely correlated with overall and disease-free survival of RCC patients, suggesting SPARC as a potent prognostic marker of RCC patient survival. Knocking down SPARC significantly inhibits RCC cell invasion and metastasis both in vitro and in vivo. Similarly, in vitro cell invasion can be diminished by using specific monoclonal antibody. Mechanistically, SPARC activate AKT pathway leading to elevated expression of matrix metalloproteinase-2 (MMP2) that can facilitate RCC invasion. Interpretation: Our data support that SPARC regulated by TGF-β is a key driver for RCC metastases, therefore, it becomes a potent therapeutic target. Funding Statement: This study was in part funded by a grant from China Scholarship Council (201508440279) and a grant from Health Commission of Guangdong Province (A2019513). This work was supported in part by the Harold C. Simmons Cancer Center through an NCI Cancer Center Support Grant, 1P30 CA142543 and The Department of Radiology. Declaration of Interests: All the authors do not have any conflict of interest. Ethics Approval Statement: The Institutional Review Board approved clinical specimen procurement protocol for this study and informed consent was obtained from patients. Animal work described in this manuscript has been approved and conducted under the oversight of the UTSW Institutional Animal Care and Use Committee.