Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer

Abstract

Background: Monocarboxylate transporters (MCTs) are transmembrane proteins involved in the transport of monocarboxylates across the plasma membrane, which appear to play an important role in solid tumours, however the role of MCTs in prostate cancer is largely unknown. The aim of the present work was to evaluate the clinico-pathological value of monocarboxylate transporters (MCTs) expression, namely MCT1, MCT2 and MCT4, together with CD147 and gp70 as MCT1/4 and MCT2 chaperones, respectively, in prostate carcinoma.

Methods: Prostate tissues were obtained from 171 patients, who performed radical prostatectomy and 14 patients who performed cystoprostatectomy. Samples and clinico-pathological data were retrieved and organized into tissue microarray (TMAs) blocks. Protein expression was evaluated by immunohistochemistry in neoplastic (n = 171), adjacent non-neoplastic tissues (n = 135), PIN lesions (n = 40) and normal prostatic tissue (n = 14). Protein expression was correlated with patients' clinicopathologic characteristics.

Results: In the present study, a significant increase of MCT2 and MCT4 expression in the cytoplasm of tumour cells and a significant decrease in both MCT1 and CD147 expression in prostate tumour cells was observed when compared to normal tissue. All MCT isoforms and CD147 were expressed in PIN lesions. Importantly, for MCT2 and MCT4 the expression levels in PIN lesions were between normal and tumour tissue, which might indicate a role for these MCTs in the malignant transformation. Associations were found between MCT1, MCT4 and CD147 expressions and poor prognosis markers; importantly MCT4 and CD147 overexpression correlated with higher PSA levels, Gleason score and pT stage, as well as with perineural invasion and biochemical recurrence.

Conclusions: Our data provides novel evidence for the involvement of MCTs in prostate cancer. According to our results, we consider that MCT2 should be further explored as tumour marker and both MCT4 and CD147 as markers of poor prognosis in prostate cancer.

Figure 1

Expression of MCT1, MCT2, MCT4 and CD147 in prostate cancer tissue microarrays. Representative images of intensity score 1 (weak) for MCT1 (A), MCT2 (D), MCT4 (G) and CD147 (J), intensity score 2 (moderate) for MCT1 (B), MCT2 (E), MCT4 (H) and CD147 (K) and intensity score 3 (strong) for MCT1 (C), MCT2 (F), MCT4 (I) and CD147 (L) immunostaining for positive cases of prostate carcinoma (score ≥ 4).

Figure 2

Frequency of MCTs and CD147 expressions in normal prostate, non-neoplastic, PIN lesions and tumour samples. In general, there is an increase in both MCT2 and MCT4 expressions from non-neoplastic (normal or adjacent) to tumour tissues, while a decrease is observed for MCT1 and CD147 expression in the transition from non-neoplastic (normal or adjacent) to prostate tumour tissue. See text for detail. * p < 0.05 (non-neoplastic adjacent, PIN and tumour tissue compared to normal tissue).

Figure 3

Immunohistochemical expression of MCTs and CD147 in normal, PIN lesions and neoplastic prostate tissue. MCT1 immunoreactivity in normal glands (A), PIN lesions (B) and malignant glands (C) was observed in the basal and lateral epithelial cell membranes (solid arrow head) with no immunoreaction in the apical zone (open arrow head). MCT2 immunoreactivity in normal (D), PIN lesions (E), malignant glands (F) was mainly observed in the cytoplasm of epithelial cells, being absent in the normal glands (solid arrow head) but with strong granular pattern in malignant glands and PIN lesion (open arrow head). MCT4 immunoreactivity in normal glands (G), PIN lesions (H) malignant glands (I) was observed in the cytoplasm, with granular appearance (open arrow head), being absent in normal glands (solid arrow head). CD147 immunoreactivity in normal glands (J), PIN lesions (K) and malignant glands (L) was observed in the basal and lateral epithelial cell membranes (solid arrow head), with no immunoreaction in the apical zone (open arrow head). Main pictures are at 200× magnification and insets are at 400×.