Reduced NOV expression correlates with disease progression in colorectal cancer and is associated with survival, invasion and chemoresistance of cancer cells.

Jun Li,Tingting Wang,Huishan Zhao,Yao Yang,Lucy K Satherley,Yi Feng,Guifang Du,Lin Ye,Zhongtao Zhang,Shan Cheng,Wen G Jiang,Yang Si,Xuemei Ma,Xu Teng,Hefen Yu,Fei Zheng,Fiona Ruge,Ping-Hui Sun,Xiaomei Yang

doi:10.18632/oncotarget.15439

Abstract

Aberrant expression of nephroblastoma overexpressed (NOV) has been evident in certain malignancies. In the current study, we aim to investigate the role played by NOV in colorectal cancer (CRC). NOV expression was determined in a cohort of 359 CRC tissues and 174 normal colorectal tissues. Its impact on CRC cells was investigated using in vitro NOV knockdown and overexpression models. NOV transcripts were reduced in the CRC tumours compared with the paired adjacent normal colorectal tissues (p < 0.01) and was associated with distant metastases. NOV knockdown resulted in increased cell proliferation and invasion of RKO cells, whilst an opposite effect was seen in the HT115 NOV over expressing cells. A positive association between Caspase-3/-8 and NOV was seen in NOV knockdown and overexpression cell lines which contributed to the survival of serum deprived CRC cells. Further investigation showed that NOV regulated proliferation, survival and invasion through the JNK pathway. NOV knockdown in RKO cells reduced the responsiveness to 5-Fluorouracil treatment, whilst overexpression in HT115 cells exhibited a contrasting effect. Taken together, NOV is reduced in CRC tumours and this is associated with disease progression. NOV inhibits the proliferation and invasion of CRC cells in vitro. Inhibition of proliferation is mediated by a regulation of Caspase-3/-8, via the JNK pathway, which has potential for predicting and preventing chemoresistance.

Highlights

Worldwide, colorectal cancer (CRC) is the second most commonly diagnosed cancer in females and third most commonly diagnosed cancer in males
Our present study suggests that nephroblastoma overexpressed (NOV) is a putative tumour suppressor for CRC, as higher NOV expression was detected in the epithelial cells within normal colon tissue compared to CRC tumours
A down regulation of NOV expression is evident in chronic myeloid leukaemia, glioma, malignant adrenocortical tumours and melanoma [18, 22,23,24,25], whilst NOV has been found to be up regulated in human prostate cancer, chondrosarcomas, Wilms’ tumour and cervical cancer [16, 26,27,28]

Summary

Introduction

Colorectal cancer (CRC) is the second most commonly diagnosed cancer in females and third most commonly diagnosed cancer in males. The CCN family derives its name from an acronym of cysteine-rich protein 61 (CYR61), connective tissue growth factor (CTGF) and nephroblastoma overexpressed (NOV), which were the first three members discovered in www.impactjournals.com/oncotarget the early 1990’s [2,3,4]. These family members have since been renamed CCN1, 2 and 3 respectively, whilst the subsequently discovered other three family members; Wntinduced secreted protein-1 (WISP-1), WISP-2, and WISP-3 are known as CCN4-6 respectively [5]. The CCNs are a group of matricellular signalling molecules, similar to other extracellular matrix proteins, involved in embryonic and postnatal development, angiogenesis, wound healing, fibrosis and inflammation [6,7,8,9,10]

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