Prognostic significance of SPARC expression in non-small cell lung cancer: A meta-analysis and bioinformatics analysis

Abstract

The aim of the present study was to elucidate the significance of secreted protein acidic and cysteine rich (SPARC) expression in non-small cell lung cancer (NSCLC) in terms of clinicopathology, immune-cell infiltration and survival prognosis. A meta-analysis and bioinformatics analysis were performed using studies retrieved with PubMed, Web of Science, Wanfang Data and the Chinese National Knowledge Infrastructure databases. The meta-analysis suggested that, compared with normal tissues, SPARC expression was elevated in NSCLC tissues. The expression of SPARC was not significantly associated with TNM stage and lymph-node metastasis, and was positively associated with patient gender. Regarding the differential expression of SPARC and the relationship between expression levels and survival, the Oncomine database was consulted and Kaplan-Meier curves were drawn. It was indicated that SPARC mRNA expression levels were higher in NSCLC tissues than in normal tissues. Low expression of SPARC mRNA was negatively associated with overall survival, first progression survival and post-progression survival of patients. Further exploration of the relationship between SPARC expression and survival by univariate analysis indicated that TNM stage, lymph node metastasis, distant metastasis and depth of infiltration of lung cancer were negatively associated with patient prognosis. Cox multifactorial analysis suggested that SPARC expression levels and TNM stage were risk factors significantly affecting the prognosis of patients with NSCLC. Analysis with the GEPIA and UALCAN databases further indicated that the mRNA expression level of SPARC in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) was higher than that in normal lung tissue, and the SPARC expression levels were affected by factors such as the TNM stage of lung cancer. A lower the level of SPARC mRNA expression was associated with a better relative survival prognosis of patients. In the Human Protein Atlas database, the expression level of SPARC protein was higher in LUAD and LUSC than in normal lung tissue. In the Timer database, the expression level of SPARC was closely linked to immune cells related to the occurrence of lung cancer, and the degree of immune-cell infiltration and SPARC protein expression were closely related to the prognosis of patients with lung cancer. Immune cells were indicated to exhibit significant inhibition of DNA proliferation mutation mechanisms in lung cancer (P<0.05). In summary, SPARC expression may be used as a valuable indicator of prognosis in patients with NSCLC, which may provide new approaches for preventative treatment.

Keywords: SPARC; bioinformatics analysis; meta-analysis; non-small cell lung cancer; prognosis.

Figure 1.

Flow diagram of article selection. CNKI, Chinese National Knowledge Infrastructure.

Figure 2.

Funnel plots of publication bias detected in NSCLC expressing SPARC. Publication bias was analyzed based on the relationship between SPARC expression and clinicopathological features of NSCLC. This included (A) the relationship between cancer and normal lung tissue, (B) lymph node metastasis, (C) TNM staging and (D) gender. Forest plot of SPARC expression and clinicopathological features of NSCLC. (E) Cancer and normal tissue, (F) lymph node metastasis, (G) TNM staging and (H) gender. SPARC, secreted protein acidic and cysteine rich; NSCLC, non-small cell lung cancer; SE, standard error; OR, odds ratio; M-H, Mantel-Haentzel; LN, lymph node involvement; df, degrees of freedom.

Figure 3.

KM-Plotter (http://www.kmplot.com) was used to examine the effect of SPARC mRNA expression on prognosis of patients with NSCLC. (A) SPARC mRNA expression was positively associated with overall survival in patients with NSCLC. (B) Relationship between SPARC mRNA expression and overall survival in lung adenocarcinoma. (C) Relationship between SPARC mRNA expression and overall survival in AJCC N1. (D) Relationship between SPARC mRNA expression and overall survival in females. (E) Relationship between SPARC mRNA expression and overall survival in males. (F) Relationship between SPARC mRNA expression and overall survival when surgical margins are negative. (G) Relationship between SPARC mRNA expression and overall survival for patients who never smoked. (H) Relationship between SPARC mRNA expression and overall survival after excluding those who never smoked. (I) SPARC mRNA expression was positively associated with post-progression survival in patients with NSCLC. (J) Relationship between SPARC mRNA expression and post-progression survival in females. (K) Relationship between SPARC mRNA expression and post-progression survival when surgical margins were negative. (L) SPARC mRNA expression was positively associated with first progression survival in patients with NSCLC. (M) Relationship between SPARC mRNA expression and first progression survival in lung adenocarcinoma. (N) Relationship between SPARC mRNA expression and first progression survival in AJCC stage N1. (O) Relationship between SPARC mRNA expression and first progression survival in females. (P) Relationship between SPARC mRNA expression and first progression survival in males. (Q) Relationship between SPARC mRNA expression and first progression survival when surgical margins were negative. (R) Relationship between SPARC mRNA expression and first progression survival after excluding those who never smoked. Effects of SPARC mRNA expression on patients with NSCLC according to the Oncomine database (www.oncomine.org). The datasets within the Oncomine database were used for bioinformatics analysis to examine the expression of SPARC mRNA during the development of NSCLC. SPARC expression in NSCLC tissues was higher than that in normal lung tissues. Values in the box plots are expressed as the median (interquartile range). (S) SPARC mRNA expression in Lung tissue vs Squamous cell lung Carcinoma. (T) SPARC mRNA expression in lung tissue vs. lung adenocarcinoma. (U) SPARC mRNA expression in lung tissue vs. squamous cell lung carcinoma. SPARC, secreted protein acidic and cysteine rich; NSCLC, non-small cell lung cancer; HR, hazard ratio; AJCC, American Joint Committee on Cancer; KM, Kaplan-Meier.

Figure 4.

Analysis in the GEPIA database. (A) Association between mRNA expression of SPARC and lung tissue and (B) comparison of SPARC gene expression in LUAD and normal lung tissue. (C) Association between stage grading of LUAD and SPARC expression. (D) Trend relationship between SPARC expression and OS in patients with LUAD; effect of SPARC expression level on LUAD patient survival. (E) Association between mRNA expression of SPARC gene and lung tissue and (F) comparison of SPARC gene expression in LUSC tissue and normal lung tissue. Values in the box plots are expressed as the median (interquartile range). (G) Association between stage grading of LUSC and SPARC expression. (H) Trend relationship between SPARC expression and OS in patients with LUSC; effect of SPARC expression level on LUSC patient survival. SPARC, secreted protein acidic and cysteine rich; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; TPM, transcripts per million; T, tumor tissue; N, normal tissue.

Figure 5.

(A-D) Analysis in the UALCAN database. (A) Expression of SPARC gene in different samples of LUAD. (B) Relationship between SPARC mRNA expression level and survival level of patients with LUAD. (C) Expression of SPARC gene in different LUSC specimens. Values in the box plots are expressed as the median (interquartile range). (D) Relationship between SPARC mRNA expression level and survival of patients with LUSC. (E-J) Analysis in the Human Protein Atlas database. H&E staining of (E) normal lung tissue, (F) LUAD and (G) LUSC. Immunohistochemical staining for SPARC in (H) normal lung tissue, (I) LUAD and (J) LUSC (scale bars, 200 µm). SPARC was positive in LUAD and LUSC. SPARC, secreted protein acidic and cysteine rich; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma.

Figure 6.

(A) Correlation of SPARC expression levels with immune cells (CD4+ T cells, macrophages, B cells, CD8+ T cells, neutrophils and dendritic cells) in LUAD. (B) Correlation of SPARC expression levels with immune cells (CD4+ T cells, macrophages, B cells, CD8+ T cells, neutrophils and dendritic cells) in LUSC. The infiltration level is displayed on the X-axis and the expression of SPARC on the Y-axis. (C) Relationship between the degree of immune-cell infiltration and survival prognosis of patients with LUAD. (D) Relationship between the degree of immune-cell infiltration and survival prognosis of patients with LUSC. The time to follow-up (months) is presented on the X-axis and the cumulative survival on the Y-axis. SPARC, secreted protein acidic and cysteine rich; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; TPM, transcripts per million; cor, correlation coefficient.

Figure 7.

(A) Association between SPARC gene expression and survival prognosis in patients with LUAD. (B) The relationship between copy number variation in LUAD and immune cell infiltration. (C) Association between SPARC gene expression and survival prognosis in patients with LUSC. (D) The relationship between copy number variation in LUSC and immune-cell infiltration. *P<0.05; **P<0.01; ***P<0.001 vs. diploid/normal immune cells. SPARC, secreted protein acidic and cysteine rich; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma.