SPARC is a key mediator of TGF-β-induced renal cancer metastasis

Ji Ming Bao, Qiang Dang, Chun Jung Lin, U. Ging Lo, Boris Feldkoren, Andrew Dang, Elizabeth Hernandez, Fei Li, Vandana Panwar, Cheng Fan Lee, Jun Jie Cen, Bing Guan, Vitaly Margulis, Payal Kapur, Rolf A. Brekken, Jun Hang Luo, Jer Tsong Hsieh, Wan Long Tan

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant expression of transforming growth factor-β1 (TGF-β1) is associated with renal cell carcinoma (RCC) progression by inducing cancer metastasis. However, the downstream effector(s) in TGF-β signaling pathway is not fully characterized. In the present study, the elevation of secreted protein acidic and rich in cysteine (SPARC) as a TGF-β regulated gene in RCC was identified by applying differentially expressed gene analysis and microarray analysis, we further confirmed this result in several RCC cell lines. 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 the RCC stage and grade. In contrast, SPARC expression is inversely correlated with overall and disease-free survival of patients with RCC, 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 a specific monoclonal antibody. Mechanistically, SPARC activates protein kinase B (AKT) pathway leading to elevated expression of matrix metalloproteinase-2 that can facilitate RCC invasion. Altogether, our data support that SPARC is a critical role of TGF-β signaling network underlying RCC progression and a potential therapeutic target as well as a prognostic marker.

Original languageEnglish (US)
Pages (from-to)1926-1938
Number of pages13
JournalJournal of cellular physiology
Volume236
Issue number3
DOIs
StateAccepted/In press - 2020

Keywords

  • MMP-2
  • SPARC
  • Snail
  • TGF-β1
  • renal cancer metastasis

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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