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

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.

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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

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Acknowledgements

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

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Correspondence to Lynn McCallum.

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Zaidi, A.R.S., Dresman, S., Burt, C. et al. Molecular signatures for CCN1, p21 and p27 in progressive mantle cell lymphoma. J. Cell Commun. Signal. 13, 421–434 (2019). https://doi.org/10.1007/s12079-018-0494-y

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Keywords

  • CCN1
  • Cyclin D1
  • CYR61
  • MCL
  • p21CIP1
  • p27KIP1