P62 functions as an oncogene in colorectal cancer through inhibiting apoptosis and promoting cell proliferation by interacting with the vitamin D receptor.

Jing Zhang,Bing Xu,Fenggang Ren,Xiaolan Lu,Shemin Lu,Ying Zheng,Jiong Jiang,Lei Dong,Suzhen Yang,Fei Liu,Ting Wang,Haitao Shi,Baicang Zou

doi:10.1111/cpr.12585

Abstract

ObjectivesThe role of p62 in cancer is controversial. Evidence has shown that p62 is upregulated in different cancers and promotes tumour growth, such as in liver cancer and lung cancer. However, a recent study showed that the downregulation of p62 in hepatic stellate cells (HSCs) promotes hepatocellular carcinoma (HCC) development. How p62 is regulated in colorectal cancer (CRC) remains largely unknown. In this study, we aimed to investigate the roles and molecular mechanisms of p62 in CRC.Materials and MethodsThe expression levels of p62 in CRC tissues and adjacent non‐tumour tissues were determined by immunohistochemistry (IHC). Stable p62‐overexpression HCT116 cells and p62‐knockdown SW480 cells were established with lentiviral vectors. The role of p62 in CRC was investigated in in vitro and in vivo functional studies. The relationship between p62 and the vitamin D receptor (VDR) was investigated by coimmunoprecipitation (Co‐IP) assays.Resultsp62 was significantly upregulated in CRC, and a high p62 level was an independent risk factor for a poor prognosis in CRC patients. p62 promoted CRC migration and invasion by inhibiting apoptosis and promoting cell proliferation in vitro, and p62 aggravated tumour growth and metastasis in vivo. Co‐IP assays indicated that p62 interacts with the VDR and may target the NRF2‐NQO1 axis.ConclusionsOur study suggested that p62 functions as an oncogene in CRC through inhibiting apoptosis and promoting cell proliferation by interacting with the VDR.

Highlights

Colorectal cancer (CRC) is one of the deadliest cancers worldwide and develops by the accumulation of genetic and environmental factors.[1]
We found that p62 is significantly upregulated in CRC, and p62 functions as an oncogene in CRC through inhibiting apoptosis and promoting cell proliferation by interacting with the vitamin D receptor (VDR)
One study reported that p62 is a prognostic predictor associated with CRC cell proliferation in vitro.[19]

Summary

Introduction

Colorectal cancer (CRC) is one of the deadliest cancers worldwide and develops by the accumulation of genetic and environmental factors.[1]. Protein p62 is a classic autophagy receptor and encodes the gene SQSTM1 It has four structural domains, including LIR (LC3‐interacting region), PB1 (Phox/Bem 1p), TB (TRAF6‐binding) and UBA (ubiquitin‐associated) domains. The inhibition of p62 can suppress tumorigenesis.[6] a recent report from Duran et al adds a series of interesting twists to the role of p62 in cancer. They found that p62 inhibits the activity of hepatic stellate cells (HSCs) by promoting the formation of the vitamin D receptor (VDR)‐retinoid X receptor (RXR) heterodimerization and that the downregulation of p62 in HSCs promotes HCC development by reducing the interaction of VDR‐RXR.[9]

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Results

Conclusion