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J Cancer 2019; 10(24):5915-5925. doi:10.7150/jca.34564 This issue Cite

Research Paper

Expression of EMT-Related Genes CAMK2N1 and WNT5A is increased in Locally Invasive and Metastatic Prostate Cancer

Isa Carneiro^1,2, Filipa Quintela-Vieira^1,3, João Lobo^1,2,5, Catarina Moreira-Barbosa¹, Francisco Duarte Menezes^1,2, Ana Teresa Martins^1,2, Jorge Oliveira⁴, Regina Silva³, Carmen Jerónimo^1,5*, Rui Henrique^1,2,5✉*

1. Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal;
2. Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal;
3. School of Health, Polytechnic of Porto (ESS), R. Dr. António Bernardino de Almeida 400, 4200-072 Porto, Portugal;
4. Department of Urology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal;
5. Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513, Porto, Portugal
*Joint senior authors

✉ Corresponding author: Rui Henrique, MD, PhD. ORCID: 0000-0003-3171-4666 Full mailing address: Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. Telephone number: 00351 965659179 (mobile)/ 00351 225084000 (work) Fax number: 00351 225084199 E-mail address: rmhenriqueup.pt / henriquemin-saude.pt More

Abstract

Purpose: Prostate cancer (PCa) varies clinically from very indolent, not requiring therapeutic intervention, to highly aggressive, entailing radical treatment. Currently, stratification of PCa aggressiveness is mostly based on Gleason score, serum PSA and TNM stage, but outcome prediction in an individual basis is suboptimal. Thus, perfecting pre-therapeutic discrimination between indolent and aggressive PCa, avoiding overtreatment is a major challenge. Epithelial to mesenchymal transition (EMT) allows epithelial cells to acquire mesenchymal properties, constituting a critical step in tumor invasion and metastization. Thus, we hypothesized that EMT-related markers might allow for improved assessment of PCa aggressiveness. Methods and Results: Using RealTime ready Custom Panel 384 assay, 93 EMT-related genes were assessed in normal prostate tissues (NPT, n=5), stage pT2a+b-PCa (n=5) and stage pT3b-PCa (n=5), from which CAMK2N1, CD44, KRT14, TGFβ3 and WNT5A genes emerged as the most significantly altered. Expression levels were then evaluated in a larger series (16 NPT and 94 PCa) of frozen tissues using quantitative RT-PCR. Globally, CAMK2N1, CD44 and WNT5A displayed higher expression levels at higher stages and less differentiated PCa. CAMK2N1 and WNT5A immunoexpression analysis disclosed significantly lower expression in NPT and increasing proportion of high-expression cases from pT2a+b to pT3b and metastatic PCa. Furthermore, higher CAMK2N1 and WNT5A transcript levels associated with shorter disease-free and disease-specific survival. In multivariable analysis, a trend for WNT5A expression levels to independently predict DFS was disclosed (p=0.056). Conclusions: Globally, our findings suggest an association between PCa aggressiveness and increased expression of CAMK2N1 and WNT5A, reflecting the acquisition of effective EMT characteristics by PCa cells.

Keywords: Prostate cancer, epithelial-to-mesenchymal transition, prognosis, CAMK2N1, WNT5A

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