Loss of TIMP-1 immune expression and tumor recurrence in localized prostate cancer

Reis, Sabrina Thalita dos; Viana, Nayara Izabel; Iscaife, Alexandre; Pontes Junior, José; Dip, Nelson; Antunes, Alberto Azoubel; Guimarães, Vanessa Ribeiro; Santana, Isaque; Nahas, William Carlos; Srougi, Miguel; Leite, Katia Ramos Moreira

doi:10.1590/S1677-5538.IBJU.2014.0451

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Original Article • Int. braz j urol. 41 (6) • Nov-Dec 2015 • https://doi.org/10.1590/S1677-5538.IBJU.2014.0451 copy

Loss of TIMP-1 immune expression and tumor recurrence in localized prostate cancer

Authorship SCIMAGO INSTITUTIONS RANKINGS

Introduction and objective:

Overexpression of MMPs has been related to biochemical recurrence after radical prostatectomy. TIMP1 and TIMP2 are controllers of MMPs and the aim of this study is to evaluate the expression levels of MMPs and their regulators using immunohistochemistry in tissue microarray of localized prostate cancer (PC).

Materials and Methods:

Immune-expression of MMP-9, MMP-2, TIMP1, TIMP-2, MMP-14 and IL8, were analyzed by immunohistochemistry in radical prostatectomy specimens of 40 patients with localized PC who underwent surgery between September 1997 and February 2000. Protein expression was considered as categorical variables, negative or positive. The results of the immune-expression were correlated to Gleason score (GS), pathological stage (TNM), pre-operatory PSA serum levels and biochemical recurrence in a mean follow up period of 92.5 months.

Results:

The loss of TIMP1 immune-expression was related to biochemical recurrence. When TIMP1 was negative, 56.3% patients recurred versus 22.2% of those whose TIMP1 was positive (p=0.042). MMP-9, MMP-2, IL8 and MMP-14 were positive in the majority of PC. TIMP-2 was negative in all cases.

Conclusion:

Negative immune-expression of TIMP1 is correlated with biochemical recurrence in patients with PC possibly by failing to control MMP-9, an important MMP related to cancer progression.

Prostatic Neoplasms; Matrix Metalloproteinases; Prognosis; Diagnosis; Gene Expression

Age (years)
	Mean	63
	Min - Max	41 – 79
PSA (ng/ml)
	Mean	12
	Min - Max	2.0 – 37.0
	< 10 n (%)	18 (45.0)
	≥ 10 n (%)	22 (55.0)
Stage
	pT2 n (%)	22 (55.0)
	pT3 n (%)	18 (45.0)
Gleason score
	< 7 n (%)	14 (35.0)
	≥ 7 n (%)	26 (65.0)

Antibody	Manufacturer	Diluition
MMP-9	ABnova	1:10
MMP-2	Abcam	1:100
TIMP-1	Abcam	1:100
TIMP-2	Abcam	1:100
MMP-14	Abcam	1:100
IL-8	Abcam	1:100

	Gleason Score Median (Q1-Q3)			Pathological Stage Median (Q1-Q3)			PSA-value Median (Q1-Q3)
	< 7	≥ 7	p	pT2	pT3	p	< 10	≥ 10	p
MMP-2			0.777			0.288			1.000
Negative	37.5%	62.5%		75.0%	25.0%		50.0%	50.0%
Positive	32.1%	67.9%		53.8%	46.2%		50.0%	50.0%
MMP-9			0.266			0.373			0.581
Negative	66.7%	33.3%		33.3%	66.7%		33.3%	66.7%
Positive	31.3%	68.8%		60.0%	40.0%		50.0%	50.0%
TIMp-1			0.637			0.409			0.738
Negative	29.4%	70.6%		66.7%	33.3%		47.1%	52.9%
Positive	36.8%	63.2%		52.6%	47.4%		52.6%	47.4%
MMP14			0.160			0.298			0.428
Negative	15.4%	84.6%		45.5%	54.5%		38.5%	61.5%
Positive	44.0%	56.0%		64.0%	36.0%		52.0%	48.0%
IL8			0.221			0.297			0.137
Negative	23.1%	76.9%		50.0%	50.0%		30.8%	69.2%
Positive	43.5%	56.5%		68.2%	31.8%		56.5%	43.5%

	Biochemical recurrence
	No	Yes	p-value
MMP-2			0.248
Negative	42.9%	57.1%
Positive	66.7%	33.3%
MMP-9			0.311
Negative	33.3%	66.7%
Positive	63.3%	36.7%
TIMp-1			0.042
Negative	43.8%	56.3%
Positive	77.8%	22.2%
MMP-14			0.259
Negative	54.5%	45.5%
Positive	73.9%	26.1%
IL-8			0.340
Negative	54.5%	45.5%
Positive	71.4%	28.6%

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[1] Correspondence address: Sabrina Thalita dos Reis, MD, Av. Dr. Arnaldo 455, 2° floor / 2145, 01246-903, São Paulo, Brasil, E-mail: sasareis@gmail.com