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Open AccessArticle

MINDIN Exerts Protumorigenic Actions on Primary Prostate Tumors via Downregulation of the Scaffold Protein NHERF-1

1
Bone Physiopathology Laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Spain
2
Departamento de Ciencias Médicas Básicas, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Campus Monteprincipe, 28925 Alcorcón, Spain
*
Authors to whom correspondence should be addressed.
These authors share senior authorship.
Academic Editors: Fabio Puglisi and Lorenzo Gerratana
Cancers 2021, 13(3), 436; https://doi.org/10.3390/cancers13030436
Received: 10 December 2020 / Revised: 19 January 2021 / Accepted: 20 January 2021 / Published: 24 January 2021
(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)
Prostate cancer is one of the leading causes of death among men worldwide. Advanced prostate cancer is an incurable disease whose mechanisms of action are still not fully understood. Secretion of the matrix protein MINDIN has been associated with prostate tumor development towards advanced prostate cancer. We aimed to study the mechanisms whereby MINDIN promotes prostate cancer progression. Evaluation of human and mouse prostate cancer samples showed increased MINDIN expression associated with decreased expression of the adaptor protein Na+/H+ exchanger regulatory factor 1 (NHERF-1). We found that NHERF-1 was downregulated by MINDIN in prostate cancer, causing an increase in tumor cell migration and proliferation. These observations point to NHERF-1 as a key modulator of MINDIN actions on prostate cancer progression and suggest that both proteins could be potential targets for the development of future prostate cancer therapies.
Advanced prostate cancer preferential metastasis to bone is associated with osteomimicry. MINDIN is a secreted matrix protein upregulated in prostate tumors that overexpresses bone-related genes during prostate cancer progression. Na+/H+ exchanger regulatory factor (NHERF-1) is a scaffold protein that has been involved both in tumor regulation and osteogenesis. We hypothesize that NHERF-1 modulation is a mechanism used by MINDIN to promote prostate cancer progression. We analyzed the expression of NHERF-1 and MINDIN in human prostate samples and in a premetastatic prostate cancer mouse model, based on the implantation of prostate adenocarcinoma TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) cells in immunocompetent C57BL/6 mice. The relationship between NHERF-1 and MINDIN and their effects on cell proliferation, migration, survival and osteomimicry were evaluated. Upregulation of MINDIN and downregulation of NHERF-1 expression were observed both in human prostate cancer samples and in the TRAMP-C1 model. MINDIN silencing restored NHERF-1 expression to control levels in the mouse model. Stimulation with MINDIN reduced NHERF-1 expression and triggered its mobilization from the plasma membrane to the cytoplasm in TRAMP-C1 cells. MINDIN-dependent downregulation of NHERF-1 promoted tumor cell migration and proliferation without affecting osteomimicry and adhesion. We propose that MINDIN downregulates NHERF-1 expression leading to promotion of processes involved in prostate cancer progression. View Full-Text
Keywords: NHERF-1; MINDIN; prostate cancer; bone; metastases; migration; osteomimicry NHERF-1; MINDIN; prostate cancer; bone; metastases; migration; osteomimicry
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MDPI and ACS Style

Álvarez-Carrión, L.; Gutiérrez-Rojas, I.; Rodríguez-Ramos, M.R.; Ardura, J.A.; Alonso, V. MINDIN Exerts Protumorigenic Actions on Primary Prostate Tumors via Downregulation of the Scaffold Protein NHERF-1. Cancers 2021, 13, 436. https://doi.org/10.3390/cancers13030436

AMA Style

Álvarez-Carrión L, Gutiérrez-Rojas I, Rodríguez-Ramos MR, Ardura JA, Alonso V. MINDIN Exerts Protumorigenic Actions on Primary Prostate Tumors via Downregulation of the Scaffold Protein NHERF-1. Cancers. 2021; 13(3):436. https://doi.org/10.3390/cancers13030436

Chicago/Turabian Style

Álvarez-Carrión, Luis; Gutiérrez-Rojas, Irene; Rodríguez-Ramos, María R.; Ardura, Juan A.; Alonso, Verónica. 2021. "MINDIN Exerts Protumorigenic Actions on Primary Prostate Tumors via Downregulation of the Scaffold Protein NHERF-1" Cancers 13, no. 3: 436. https://doi.org/10.3390/cancers13030436

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