Volume 79, Issue 16 pp. 1793-1804
ORIGINAL ARTICLE

Overexpression of certain transient receptor potential and Orai channels in prostate cancer is associated with decreased risk of systemic recurrence after radical prostatectomy

M. A. Perrouin-Verbe MD, PhD

Corresponding Author

M. A. Perrouin-Verbe MD, PhD

Department of Urology, CHRU-Université de Brest, Brest, France

INSERM UMR1078, Université de Bretagne Occidentale, Brest, France

Department of Urology, CHU-Université de Nantes, Nantes, France

Correspondence Marie-Aimée Perrouin-Verbe, MD, PhD, Department of Urology, CHU-Université de Nantes 1 place Alexis Ricordeau, 44000 Nantes, France.

Email: [email protected]

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N. Schoentgen MD

N. Schoentgen MD

Department of Urology, CHRU-Université de Brest, Brest, France

INSERM UMR1078, Université de Bretagne Occidentale, Brest, France

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M. Talagas MD, PhD

M. Talagas MD, PhD

Department of Pathology, CHRU-Université de Brest, Brest, France

EA 4685 – LIEN, Université de Bretagne Occidentale, Brest, France

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R. Garlantezec MD, PhD

R. Garlantezec MD, PhD

INSERM UMR1085-IRSET, Université Rennes 1, Rennes, France

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A. Uguen MD, PhD

A. Uguen MD, PhD

Department of Pathology, CHRU-Université de Brest, Brest, France

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L. Doucet MD

L. Doucet MD

Department of Pathology, CHRU-Université de Brest, Brest, France

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S. Rosec

S. Rosec

INSERM UMR1412, Centre d’Investigation Clinique, CHRU-Université de Brest, Brest, France

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P. Marcorelles MD, PhD

P. Marcorelles MD, PhD

Department of Pathology, CHRU-Université de Brest, Brest, France

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M. Potier-Cartereau PhD

M. Potier-Cartereau PhD

INSERM UMR1069, Université François Rabelais, Tours, France

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C. Vandier PhD

C. Vandier PhD

INSERM UMR1069, Université François Rabelais, Tours, France

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C. Ferec MD, PhD

C. Ferec MD, PhD

INSERM UMR1078, Université de Bretagne Occidentale, Brest, France

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G. Fromont MD, PhD

G. Fromont MD, PhD

INSERM UMR1069, Université François Rabelais, Tours, France

Department of Pathology, CHRU-Université de Tours, Tours, France

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G. Fournier MD

G. Fournier MD

Department of Urology, CHRU-Université de Brest, Brest, France

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A. Valeri MD, PhD

A. Valeri MD, PhD

Department of Urology, CHRU-Université de Brest, Brest, France

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O. Mignen PhD

O. Mignen PhD

INSERM UMR1078, Université de Bretagne Occidentale, Brest, France

INSERM UMR1227, Université de Bretagne Occidentale, Brest, France

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First published: 02 September 2019
Citations: 18

This work was performed at INSERM UMR1078, Université de Bretagne Occidentale and at the Department of Urology, CHRU-Université de Brest, 29200 Brest, France.

Abstract

Background: Several studies had suggested the potential role of calcium signaling in prostate cancer (PCa) prognosis and agressiveness. We aimed to investigate selected proteins contributing to calcium (Ca2+) signaling, (Orai, stromal interaction molecule (STIM), and transient receptor potential (TRP) channels) and involved in cancer hallmarks, as independent predictors of systemic recurrence after radical prostatectomy (RP).

Methods: A case-control study including 112 patients with clinically localized PCa treated by RP between 2002 and 2009 and with at least 6-years’ follow-up. Patients were divided into two groups according to the absence or presence of systemic recurrence. Expression levels of 10 proteins involved in Ca2+ signaling (TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, STIM1, STIM2, Orai1, Orai2, and Orai3), were assessed by immunohistochemistry using tissue microarrays (TMAs) constructed from paraffin-embedded PCa specimens. The level of expression of the various transcripts in PCa was assessed using quantitative polymerase chain reaction (qPCR) analysis. RNA samples for qPCR were obtained from fresh frozen tissue samples of PCa after laser capture microdissection on RP specimens. Relative gene expression was analyzed using the urn:x-wiley:02704137:media:pros23904:pros23904-math-0001 method.

Results: Multivariate analysis showed that increased expression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 was significantly associated with a lower risk of systemic recurrence after RP, independently of the prostate-specific antigen (PSA) level, percentage of positive biopsies, and surgical margin (SM) status (P = .007, P = .01, P < .001, P = .0065, P = .007, and P = .01, respectively). For TRPC4, TRPV5, and TRPV6, this association was also independent of Gleason score and pT stage. Moreover, overexpression of TRPV6 and Orai2 was significantly associated with longer time to recurrence after RP (P = .048 and .023, respectively). Overexpression of TRPC4, TRPV5, TRPV6, and Orai2 transcripts was observed in group R− (3.71-, 5.7-, 1.14-, and 2.65-fold increase, respectively).

Conclusions: This is the first study to suggest the independent prognostic value of certain proteins involved in Ca2+ influx in systemic recurrence after RP: overexpression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 is associated with a lower risk of systemic recurrence. TRPC4, TRPV5, and TRPV6 appear to be particularly interesting, as they are independent of the five commonly used predictive factors, that is, PSA, percentage of positive biopsies, SM status, Gleason score, and pT stage.

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