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The role of proteases in epithelial-to-mesenchymal cell transitions in cancer

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Abstract

Changing the characteristics of cells from epithelial states to mesenchymal properties is a key process involved in developmental and physiological processes as well as in many diseases with cancer as the most prominent example. Nowadays, a great deal of work and literature concerns the understanding of the process of epithelial-to-mesenchymal transition (EMT) in terms of its molecular regulation and its implications for cancer. Similar statements can certainly be made regarding the investigation of the more than 500 proteases typically encoded by a mammalian genome. Specifically, the impact of proteases on tumor biology has been a long-standing topic of interest. However, although EMT actively regulates expression of many proteases and proteolytic enzymes are clearly involved in survival, division, differentiation, and movements of cells, information on the diverse roles of proteases in EMT has been rarely compiled. Here we aim to conceptually connect the scientific areas of “EMT” and “protease” research by describing how several important classes of proteolytic enzymes are regulated by EMT and how they are involved in initiation and execution of the EMT program. To do so, we briefly introduce the evolving key features of EMT and its regulation followed by discussion of protease involvement in this process.

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Abbreviations

A549:

lung carcinoma cell line

ADAM:

a disintegrin and metalloprotease

c-MET:

MET proto-oncogene

CRC:

colorectal cancer

CUX1:

cut like homeobox 1

CYLD:

CYLD lysine 63 deubiquitinase

DUB:

deubiquitinating enzymes

e.g. :

exempli gratia

E/M:

epithelial/mesenchymal

ECM:

extracellular matrix

EGFR:

epidermal growth factor receptor

EMT:

epithelial-to-mesenchymal transition

EMT-TF:

epithelial-to-mesenchymal transition—transcription factor

Epcam, Vcam:

epithelial cell adhesion molecule, vascular cell adhesion molecule

ERK:

extracellular signal-regulated kinase (also known as mitogen-activated protein kinase 1—MAPK1)

ESCC:

esophageal squamous cell carcinoma

FGF:

fibroblast growth factor

HCC:

hepatocellular carcinoma

HER:

human epidermal growth factor receptor

HGF:

hepatocyte growth factor

HTRA1:

HtrA serine peptidase 1

i.e. :

id est

IL-6:

interleukin-6

JNK:

c-Jun N-terminal kinase

LA:

lung adenocarcinoma

LGL:

lethal giant larvae protein

LNCaP cells:

prostate adenocarcinoma cell from lymph node metastasis

MCF10A:

non-tumorigenic mammary cell line (human origin)

MCF-7:

breast carcinoma cell line

MET:

mesenchymal-to-epithelial transition

MMP:

matrix metalloprotease

MSPL:

mosaic serine protease large-form

MT-MMP:

membrane type matrix metalloprotease

NMuMG:

a non-transformed mouse mammary gland epithelial cell line

NSCLC:

non-small cell lung cancer

OTUB:

OTU deubiquitinase

PAR:

protease-activated receptor

PATJ:

PALS1-associated tight junction protein

PI3K/Akt/Rac1:

phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT serine/threonine kinase 1/Rac1

Rac1:

Ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)

RB:

retinoblastoma protein

ROS:

reactive oxygen species

SENP:

sentrin specific protease (family of endopeptidases)

SMAD:

from “MAD—mothers against decapentaplegic” (gene in Drosophila melanogaster) and “Sma—small body size” (protein in Caenorhabditis elegans)

SW480:

human colon cancer cell line

TGF-β:

transforming growth factor-beta

TMPRSS:

transmembrane protease/serine subfamily of the type II transmembrane serine protease (TTSP) family

TTSP:

type II transmembrane serine protease family

uPA:

urokinase-type plasminogen activator

USP:

ubiquitin specific proteases

Wnt:

from “Wg—wingless” (gene in Drosophila melanogaster) and Int-1 (gene in Mus musculus)

ZEB:

zinc finger E-box binding homeobox

ZO-3:

zonula occludens 3, a tight junction protein

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Acknowledgements

The authors thank Eva Schill-Wendt for creating the artwork of the figure. The Deutsche Forschungsgemeinschaft (DFG) SFB 850 subproject B7, DFG-grant RE1584/6-2, and the German Cancer Consortium (DKTK) program Oncogenic Pathways project L627 support the work in the Reinheckel laboratory.

Author information

Author notes

  1. Julia Mitschke and Ulrike C. Burk contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular Medicine and Cell Research, University of Freiburg, 79104, Freiburg, Germany

    Julia Mitschke, Ulrike C. Burk & Thomas Reinheckel

  2. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg, partner site Freiburg, 79106, Freiburg, Germany

    Thomas Reinheckel

  3. BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104, Freiburg, Germany

    Thomas Reinheckel

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  1. Julia Mitschke
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  2. Ulrike C. Burk
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  3. Thomas Reinheckel
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Correspondence to Thomas Reinheckel.

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Mitschke, J., Burk, U.C. & Reinheckel, T. The role of proteases in epithelial-to-mesenchymal cell transitions in cancer. Cancer Metastasis Rev 38, 431–444 (2019). https://doi.org/10.1007/s10555-019-09808-2

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