Matrix metalloproteinase-9 and -2 and tissue inhibitor of matrix metalloproteinase-2 in invasive pituitary adenomas: A systematic review and meta-analysis of case-control trials

Abstract

The extracellular matrix is important for tumor invasion and metastasis. Normal function of the extracellular matrix depends on the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The objective of this meta-analysis was to assess the relationship between expression of MMP-9, MMP-2, and TIMP-2 and invasion of pituitary adenomas.We searched Pubmed, Embase, and the Chinese Biomedical Database up to October 2015. RevMan 5.1 software (Cochrane Collaboration, Copenhagen, Denmark) was used for statistical analysis. We calculated the standardized mean difference (SMD) for data expressed as mean ± standard deviation because of the difference in the detection method.Twenty-four studies (1320 patients) were included. MMP-9 expression was higher in the patients with invasive pituitary adenomas (IPAs) than patients with noninvasive pituitary adenomas (NIPAs) with detection methods of IHC [odds ratio (OR) = 5.48, 95% confidence interval (CI) = 2.61-11.50, P < 0.00001), and reverse transcriptase-polymerase chain reaction (SMD = 2.28, 95% CI = 0.91-3.64, P = 0.001). MMP-2 expression was also increased in patients with IPAs at the protein level (OR = 3.58, 95% CI = 1.63-7.87, P = 0.001), and RNA level (SMD = 3.91, 95% CI = 1.52-6.29, P = 0.001). Meta-analysis showed that there was no difference in TIMP-2 expression between invasive and NIPAs at the protein level (OR = 0.38, 95% CI = 0.06-2.26, P = 0.29). MMP-9 expression in prolactinomas and nonfunctioning pituitary adenomas was also no difference (OR = 1.03, 95% CI = 0.48-2.20, P = 0.95).The results indicated that MMP-9 and -2 may be correlated with invasiveness of pituitary adenomas, although their relationship with functional status of pituitary adenomas is still not clear. TIMP-2 expression in IPAs needs to be investigated further.

Figure 1

Flow chart of included studies.

Figure 2

Forest plots for the relationship between MMP-9 expression and tumor invasiveness of PAs (A) at the protein level and (B) at the RNA level. M-H = Mantel–Haenszel test, IV = inverse variance, Random = a random effects model, CI = confidence intervals.

Figure 3

Forest plots for the relationship between MMP-2 expression and tumor invasiveness of PAs (A) at the protein level and (B) at the RNA level. M-H = Mantel–Haenszel test, IV = inverse variance, Random = a random effects model, CI = confidence intervals.

Figure 4

Forest plots for the relationship between TIMP-2 expression and tumor invasiveness of PAs at the protein level. M-H = Mantel–Haenszel test, Random = a random effects model, CI = confidence intervals.

Figure 5

Forest plots for the relationship between MMP-9 expression and functional status of PA at the protein level. M-H = Mantel–Haenszel test, Fixed = a fixed effects model, CI = confidence intervals.

Figure 6

Funnel plots for the relationship between MMP-9 expression and tumor invasiveness of PAs. A. at the protein level. X and Y axes are OR and SE, respectively. B. at the RNA level. X and Y axes are SMD and SE, respectively.

Figure 7

Funnel plots for the relationship between MMP-2 expression and tumor invasiveness of PAs at the protein level. X and Y axes are OR and SE, respectively.