Role of Furin in Colon Cancer Stem Cells Malignant Phenotype and Expression of LGR5 and NANOG in KRAS and BRAF-Mutated Colon Tumors

Cancers

Marcos J. Araúzo-Bravo¹  Iker Badiola²  Zongsheng He³  Simon Pernot⁴  John W. M. Creemers⁵  Jean Descarpentrie⁶  Alexia François⁶  Patricia Garcia-Gallastegi⁶  Serge Evrard⁶  Álvaro González⁶  Abdel-Majid Khatib⁶ 

[1] Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, C/Doctor Beguiristain s/n, 20014 San Sebastian, Spain;Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of Basque Country (UPV/EHU), 48940 Leioa, Spain;Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing 400042, China;Institut Bergonié, 33000 Bordeaux, France;Laboratory of Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, B-3000 Leuven, Belgium;Reprogramming tumor activitY and associaTed MicroEnvironment (RYTME), Bordeaux Institute of Oncology (BRIC)-UMR1312 Inserm, B2 Ouest, Allée Geoffroy St Hilaire CS50023, 33615 Pessac, France;

关键词: cancer stem cells;    colon cancer;    LGR5;    NANOG;    KRAS;    BRAF;   

DOI  :  10.3390/cancers14051195

来源: DOAJ

【 摘 要 】

Proprotein convertases or PCs are known to regulate the malignant phenotype of colon cancer cells by different mechanisms, but their effects on cancer stem cells (CSCs) have been less widely investigated. Here, we report that PCs expression is altered in colon CSCs, and the inhibition of their activity reduced colon CSCs growth, survival, and invasion in three-dimensional spheroid cultures. In vivo, repression of PCs activity by the general PC inhibitors α1-PDX, Spn4A, or decanoyl-RVKR-chloromethylketone (CMK) significantly reduced tumor expression levels of the stem cell markers LGR5 and NANOG that are associated with reduced tumor xenografts. Further analysis revealed that reduced tumor growth mediated by specific silencing of the convertase Furin in KRAS or BRAF mutated-induced colon tumors was associated with reduced expression of LGR5 and NANOG compared to wild-type KRAS and BRAF tumors. Analysis of various calcium regulator molecules revealed that while the calcium-transporting ATPase 4 (ATP2B4) is downregulated in all the Furin-silenced colon cancer cells, the Ca²⁺-mobilizing P2Y receptors, was specifically repressed in BRAF mutated cells and ORAI1 and CACNA1H in KRAS mutated cells. Taken together, our findings indicate that PCs play an important role in the malignant phenotype of colon CSCs and stem cell markers’ expression and highlight PCs repression, particularly of Furin, to target colon tumors with KRAS or BRAF mutation.

【 授权许可】

Unknown