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Journal of Cell Communication and Signaling

, Volume 13, Issue 3, pp 421–434 | Cite as

Molecular signatures for CCN1, p21 and p27 in progressive mantle cell lymphoma

  • Afak Rasheed Salman Zaidi
  • Sadie Dresman
  • Charlotte Burt
  • Simon Rule
  • Lynn McCallumEmail author
Research Article

Abstract

Mantle cell lymphoma (MCL) is a comparatively rare non-Hodgkin’s lymphoma characterised by overexpression of cyclin D1. Many patients present with or progress to advanced stage disease within 3 years. MCL is considered an incurable disease with median survival between 3 and 4 years. We have investigated the role(s) of CCN1 (CYR61) and cell cycle regulators in progressive MCL. We have used the human MCL cell lines REC1 < G519 < JVM2 as a model for disease aggression. The magnitude of CCN1 expression in human MCL cells is REC1 > G519 > JVM2 cells by RQ-PCR, depicting a decrease in CCN1 expression with disease progression. Investigation of CCN1 isoform expression by western blotting showed that whilst expression of full-length CCN1 was barely altered in the cell lines, expression of truncated forms (18–20 and 28–30 kDa) decreased with disease progression. We have then demonstrated that cyclin D1 and cyclin dependent kinase inhibitors (p21CIP1and p27KIP1) are also involved in disease progression. Cyclin D1 was highly expressed in REC1 cells (OD: 1.0), reduced to one fifth in G519 cells (OD: 0.2) and not detected by western blotting in JVM2 cells. p27KIP1 followed a similar profile of expression as cyclin D1. Conversely, p21CIP1 was absent in the REC1 cells and showed increasing expression in G519 and JVM2 cells. Subcellular localization detected p21CIP1/ p27KIP1 primarily within the cytoplasm and absent from the nucleus, consistent with altered roles in treatment resistance. Dysregulation of the CCN1 truncated forms are associated with MCL progression. In conjunction with reduced expression of cyclin D1 and increased expression of p21, this molecular signature may depict aggressive disease and treatment resistance.

Keywords

CCN1 Cyclin D1 CYR61 MCL p21CIP1 p27KIP1 

Abbreviations

MCL

Mantle cell lymphoma

NHL

Non Hodgkin’s Lymphoma

CCND1

Cyclin D1

CDK4 or 6

Cyclin-dependent kinase 4 (CDK4) or cyclin-dependent kinase 6

pRb

Retinoblastoma protein

ATM

Ataxia telangiectasia mutated

CYR61

Cysteine-rich protein 61

AML

Acute myeloid leukaemia

SP

Signal peptide

IGFBP

Insulin like growth factor binding domain

VWC

Von Willebrand type C repeat

TSP-1

Thrombospondin type 1 domain

CT

Cysteine rich carboxyl terminal

HSPGs

Heparan sulfate proteoglycans

BMP

Bone morphogenetic protein

TGF-β

Transforming growth factor β

VEGF

Vascular endothelial growth factor

MMPs

Matrix metalloproteinases

MM

Multiple myeloma

OSC

Oesophageal squamous carcinoma

MEK/ERK

Mitogen-activated protein kinase/extracellular-signal-regulated kinase

OAFs

Osteoclast activating factors

OBIs

Osteoblast inhibitors

IL-6

Interleukin-6

p21CIP1

(Cdk Interacting Protein 1)

p27KIP1

(Kinase Inhibitory Protein 1)

p57KIP2

(Kinase Inhibitory Protein 2)

TNBC

Triple negative breast carcinoma

FOXO3a

Forkhead box O3

PCNA

Proliferating cell nuclear antigen

OSCC

Oral squamous cell carcinoma

HCC

Hepatocellular carcinoma

NLS

Nuclear Localisation Signal

DCIS

High-grade ductal carcinoma in situ

NSCLC

Non-small-cell lung cancer

Notes

Acknowledgements

We would like to thank the Iraqi Government for funding this work.

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Copyright information

© The International CCN Society 2018

Authors and Affiliations

  1. 1.School of Biomedical and Healthcare Science, Peninsula Schools of Medicine and DentistryPlymouth UniversityPlymouthUK
  2. 2.Department of Biology, College of Education for Pure ScienceUniversity of DiyalaBaqubaIraq

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