Exosome Released FZD10 Increases Ki-67 Expression via Phospho-ERK1/2 in Colorectal and Gastric Cancer.

Maria Principia Scavo,Gianluigi Giannelli,Raffaele Armentano,Elisabetta Fanizza,Maria Lucia Curri,Sergio Coletta,Alessandra Cervellera,Nicola Carella,Grazia Serino,Federica Rizzi,Nicoletta Depalo,Pasqua Letizia Pesole

doi:10.3389/fonc.2021.730093

Abstract

Frizzled (FZD) proteins are primary receptors for Wnt signaling that activates the mitogen-activated protein kinase (MAPK) pathways. Dysfunction of Wnt signals with consequently abnormal activation of MAPK3 pathways was found in colorectal cancer (CRC) and gastric cancer (GC). Upregulation of FZD10 protein, localized in the exosomes isolated from plasma of CRC and GC patients, was associated with a poor prognosis. Herein, the expression levels of circulating FZD10 were found to be strongly correlated to their expression levels in the corresponding tissues in CRC and GC patients. Bioinformatic prediction revealed a link between FZD10 and Ki-67 through MAPK3. In both CRC and GC tissues, pERK1/2 levels were significantly increased at more advanced disease stages, and pERK1/2 and Ki-67 were correlated. Silencing of FZD10 in CRC and GC cells resulted in a significant reduction of pERK1/2 and Ki-67 expression, while subsequent treatment with exogenous exosomes partially restored their expression levels. The strong correlation between the expression of Ki-67 in tissues and of FZD10 in exosomes suggests that the exosome-delivered FZD10 may be a promising novel prognostic and diagnostic biomarker for CRC and GC.

Highlights

Frizzled (FZD) proteins, a family of seven-transmembrane-span proteins with topological homology to G protein-coupled receptors, are involved in the canonical b-catenin and noncanonical Wnt signaling pathways
In addition to Exosomal FZD10 and Ki-67 Activation the canonical and noncanonical pathways, Wnt pathways have been suggested to intersect with other key pathways, including the mitogen-activated protein kinase (MAPK), implicated in cell development, transformation, and apoptosis, as well as to stimulate intracellular proteins or small molecules that act as signaling intermediates [2, 3]
After their physical characterization (Figure S1, Supplementary Material), the total protein content was extracted from exosomes, and the FZD10 expression level was studied by Western blotting in exosomes isolated from the plasma of 20 healthy donors, 26 colorectal cancer (CRC) patients, and 20 gastric cancer (GC) patients (Table 1)

Summary

Introduction

Frizzled (FZD) proteins, a family of seven-transmembrane-span proteins with topological homology to G protein-coupled receptors, are involved in the canonical b-catenin and noncanonical Wnt signaling pathways. They regulate several cell processes, such as migration, polarity, neural patterning, and organogenesis during embryonic development [1]. Dysregulation of Wnt signals and alterations in the Wnt cascade proteins and molecular intermediates can induce the onset and progression of many different cancers as well as of alterations in embryo development [4, 5]. Experimental evidence showed that variations in MAPK3 influence colorectal cancer (CRC) risk and survival after diagnosis [8]

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