The Secreted Protein C10orf118 Is a New Regulator of Hyaluronan Synthesis Involved in Tumour-Stroma Cross-Talk.

Ilaria Caon,Barbara Bartolini,Nikos K Karamanos,Elena Caravà,Patrizia Cancemi,Flavia Contino,Alberto Passi,Davide Vigetti,Arianna Parnigoni,Maria Luisa D’Angelo,Paola Moretto,Manuela Viola,Evgenia Karousou

doi:10.3390/cancers13051105

Ilaria Caon, Barbara Bartolini + Show 11 more

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https://doi.org/10.3390/cancers13051105

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Abstract

Simple SummaryHyaluronan is a main glycosaminoglycan in extracellular matrix with an important role in breast cancer progression. Alterations in its synthesis and size may affect tu-mour growth and metastasis. Communication between stromal and breast cancer cells consists of the secretion of factors that provoke a series of cell signalling that influence cell fate and tis-sue microenvironment, by favouring tumour cell survival and motility. Here, we present the c10orf118 protein expressed in high amounts by breast tumour cells as a new regulator in hya-luronan synthesis. This protein is found both in Golgi and secreted in the extracellular matrix, whereas its role is still unknown. The secreted c10orf118 is found to induce hyaluronan synthase 2 in normal fibroblasts. Importantly, high expression of c10orf118 is positively correlated to pa-tient’s survival and to a low metastasis.Interaction between cancer cells and their microenvironment is central in defining the fate of cancer development. Tumour cells secrete signals (cytokines, chemokines, growth factors) that modify the surrounding area, while the niche supplies structures and activities necessary for tumour maintenance and growth. Hyaluronan (HA) is a glycosaminoglycan that constitute cancer cell niche and is known to influence tumour functions such as proliferation, migration and neoangiogenesis. The knowledge of the factors regulating HA synthesis and size is crucial in understanding the mechanisms sustaining tumour development. Here we show that a yet uncharacterized protein secreted by breast tumour cell lines, named c10orf118 (accession number NM_018017 in NCBI/BLAST, and Q7z3E2 according to the Uniprot identifier), with a predicted length of 898 amino acids, can induce the secretion of HA by stromal fibroblasts through the up-regulation of the hyaluronan synthase 2 gene (HAS2). Intracellularly, this protein is localized in the Golgi apparatus with a possible role in vesicle maturation and transport. The expression of c10orf118 was verified in breast cancer patient specimens and was found to be associated with the presence of estrogen receptor that characterizes a good patient survival. We suggest c10orf118 as a new player that influences the HA amount in breast cancer microenvironment and is associated with low aggressiveness of cancer.

Highlights

Cancer growth is largely determined by modified communication between tumour cells and the surrounding microenvironment
We cultured the epithelial breast cancer cell line 8701-BC, an estrogen receptor negative (ER-) with intermediate aggressiveness cell line [30] derived from a primary ductal infiltrating carcinoma [31], in their specific M199 medium. The choice of this cell line was motivated by the fact that it does not require supplementation of serum in the culture media for optimal growth and function, the conditioned media (CM) isolated from the cells is the cleanest system for the identification through mass spectrometry of possible secreted factors that are not “masked” by the serum concentration
Our results demonstrate that the c10orf118 protein isolated from breast tumour cell lines has a full-size molecular weight of 130 kDa and is localized in the Golgi apparatus

Summary

Introduction

Cancer growth is largely determined by modified communication between tumour cells and the surrounding microenvironment The contribution of the latter to cancer progression is central and as tumour cells secrete specific signals that modify the surrounding area, the opposite process takes place, with the niche producing modified structures and activities necessary to survival, growth and development of the cancer cells [1]. It is known that tumours release a series of molecules to favour angiogenesis and metastasis Among these there are inhibitor of differentiation proteins [3], growth factors with paracrine signalling to re-program surrounding fibroblasts [4], chemokines and tumour-specific antigens that contributes to recruit and transform immune cells to sustain tumour survival [5]. Hyaluronan (HA) one of the major glycosaminoglycans (GAGs) found in extracellular matrices regulates tumour cell migration and invasion in vitro, and tumour growth and progression in vivo [9,10,11,12,13,14]

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