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. 2016 Oct 25;7(43):70211-70222.
doi: 10.18632/oncotarget.12191.

SPARC expression in gastric cancer predicts poor prognosis: Results from a clinical cohort, pooled analysis and GSEA assay

Zhi Li  1   2 , Ao-Di Li  1   2 , Lu Xu  1   2 , De-Wei Bai  1   3   2 , Ke-Zuo Hou  1   2 , Hua-Chuan Zheng  4 , Xiu-Juan Qu  1   2 , Yun-Peng Liu  1   2
Affiliations

SPARC expression in gastric cancer predicts poor prognosis: Results from a clinical cohort, pooled analysis and GSEA assay

Zhi Li et al. Oncotarget. .

Abstract

Background: The prognostic role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in gastric cancer (GC) remains controversial. We investigated the clinical significance, the survival relevance, and potential function of SPARC in GC with resected samples, online gene set GSE62254, and cell line SGC7901.

Results: High immunostaining of SPARC significantly correlated with tumor differentiation (P = 0.004), and independently predicted shorter overall survival (OS) (HR = 1.446, P = 0.022), based on the current IHC evaluation. The accuracy of the results was further validated with 1000 times bootstrapping and the time-dependent receiver-operating characteristics (ROC) curves. The meta-analysis (pooled HR = 1.60, 95% CI: 1.01-2.53) confirmed SPARC as the predictor for reduced OS in GC. Moreover, the association between enhanced SPARC expression and Adriamycin (Adr) sensitivity was revealed by GSEA, and then confirmed by comparative cellular experiments, such as the protein level analysis of SGC7901and SGC7901/Adr cell line.

Materials and methods: Immunohistochemistry (IHC) method was used to detect SPARC expression in 137 GC cases. Meta-analysis was performed based on 5 studies published in English on PubMed up to March 2016. GSEA was performed using online data set GSE62254 and GC-related functional gene sets derived from molecular signatures database (MSigDB). Western Blot was carried out to compare protein-level differences between gastric carcinoma SGC7901 cell line and Adr resistant SGC7901/Adr cell line. MTT assay was done to confirm the induction of SPARC on Adr sensitivity.

Conclusions: Increased SPARC expression in GC led to a worse clinical outcome of patients and might induce Adr sensitivity of GC cells.

Keywords: GSEA; SPARC; gastric cancer; immunohistochemistry; prognosis.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1. Representative staining of SPARC in gastric cancer tissue by IHC (200×)
(A) No staining of SPARC in cancer tissue; (B) Positive SPARC staining in the surrounding desmoplastic stroma.
Figure 2
Figure 2. KM survival curve and log-rank test for patients classified as showing either positive or negative SPARC expression in GC
Patients with SPARC high expression exhibited a significant worse survival than those with SPARC low expression (P = 0.022; log-rank test).
Figure 3
Figure 3. Time-dependent ROC analyses for the CPPs, and the combination of SPARC and CPPs
The inclusion of the SPARC expression score in the model improved the predictive ability slightly.
Figure 4
Figure 4. Meta analysis of overall survival against SPARC levels
(A) Hazard ratio plot of overall survival against SPARC levels. (B) Hazard ratio plot of studies of overall survival against SPARC expression with cumulative meta analysis.
Figure 5
Figure 5. SPARC expression and GC proliferation as well as drug sensitivity properties
(A) The GSEA results showing the correlation of SPARC levels and GC related gene sets in MSigDB. gene set “gastric cancer advanced vs early up (Vecchi)” was enriched in SPARC high expression phonotype (left), gene sets “gastric cancer advanced vs early down (Vecchi)” (middle), and “doxorubicin resistance up (Kang)” (right), were enriched in SPARC low expression phonotype. (B) Western-blot analysis for the protein level of SPARC in SGC7901 transfected with SPARC siRNA for 24 hours. (C) MTT assay showing SPARC knock-down inhibited SGC7901proliferation compared with control cells. (D) MTT assay showing the Adr-sensitivity of SGC7901 with SPARC siRNA transfection for 24 hours. Each data point represents the mean ± SD of three independent experiments. (*P < 0.05).
See this image and copyright information in PMC

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