Paracrine signalling of AGR2 stimulates RhoA function in fibroblasts and modulates cell elongation and migration

Hitesh Bhagavanbhai Mangukiya; Hema Negi; Siva Bharath Merugu; Qudsia Sehar; Dhahiri Saidi Mashausi; Fakhar-Un-Nisa Yunus; Zhenghua Wu; Dawei Li

doi:10.1080/19336918.2019.1685928

Paracrine signalling of AGR2 stimulates RhoA function in fibroblasts and modulates cell elongation and migration

Cell Adh Migr. 2019 Dec;13(1):332-344. doi: 10.1080/19336918.2019.1685928.

Authors

Hitesh Bhagavanbhai Mangukiya¹, Hema Negi¹, Siva Bharath Merugu¹, Qudsia Sehar¹, Dhahiri Saidi Mashausi¹, Fakhar-Un-Nisa Yunus¹, Zhenghua Wu¹, Dawei Li^{1

2}

Affiliations

¹ School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
² Engineering Research center of Cell and Therapeutic Antibody of Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.

Abstract

The most prominent cancer-associated fibroblasts (CAFs) in tumor stroma is known to form a protective structure to support tumor growth. Anterior gradient-2 (AGR2), a tumor secretory protein is believed to play a pivotal role during tumor microenvironment (TME) development. Here, we report that extracellular AGR2 enhances fibroblasts elongation and migration significantly. The early stimulation of RhoA showed the association of AGR2 by upregulation of G1-S phase-regulatory protein cyclin D1 and FAK phosphorylation through fibroblasts growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR). Our finding indicates that secretory AGR2 alters fibroblasts elongation, migration, and organization suggesting the secretory AGR2 as a potential molecular target that might be responsible to alter fibroblasts infiltration to support tumor growth.

Keywords: Anterior gradient 2; RhoA GTP-Binding Protein; Tumour microenvironment; cell movement; fibroblasts.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3 Cells
Animals
Cancer-Associated Fibroblasts / metabolism*
Cell Cycle / physiology
Cell Line, Tumor
Cell Movement / physiology
Cell Proliferation / physiology
Culture Media, Conditioned / pharmacology
Cyclin D1 / biosynthesis
Focal Adhesion Kinase 1 / metabolism
Humans
MCF-7 Cells
Mice
Mucoproteins / metabolism*
Neoplasms / pathology*
Oncogene Proteins / metabolism*
Phosphorylation
Receptor, Fibroblast Growth Factor, Type 1 / metabolism
Receptors, Vascular Endothelial Growth Factor / metabolism
Tumor Microenvironment / physiology*
rhoA GTP-Binding Protein / metabolism*

Substances

Agr2 protein, mouse
Ccnd1 protein, mouse
Culture Media, Conditioned
Mucoproteins
Oncogene Proteins
Cyclin D1
Fgfr1 protein, mouse
Receptor, Fibroblast Growth Factor, Type 1
Receptors, Vascular Endothelial Growth Factor
Focal Adhesion Kinase 1
Ptk2 protein, mouse
RhoA protein, mouse
rhoA GTP-Binding Protein

Grants and funding

This work was supported by the National Natural Science Foundation of China, Grant Number 81872790; and Shanghai International Science and Technology Commission Foundation, Grant Number 184907411400.