P53 Dysfunction by Xeroderma Pigmentosum Group C Defects Enhance Lung Adenocarcinoma Metastasis via Increased Mmp1 Expression

Yi-Hui Wu,Jiunn-Wang Liao,Huei Lee,Chih-Yi Chen,Kun-Tu Yeh,Tzu-Chin Wu

doi:10.1158/0008-5472.can-10-2615

Abstract

Xeroderma pigmentosum group C (XPC) interacts with hHR23B to recognize DNA damage in global genomic repair. We previously showed that XPC is predominantly affected by its hypermethylation and is associated with an increased occurrence of p53 mutation in lung cancer. Tumors with low XPC mRNA levels had a poorer prognosis than those with high XPC mRNA levels, suggesting that XPC defects may enhance tumor metastasis. However, the underlying mechanism is unclear. Here, we show that p53 transcriptional activity is modulated by XPC, whereby XPC stabilizes hHR23B to form an hHR23B-p53 complex that prevents p53 degradation. In addition, in lung cancer cells and xenograft tumors in nude mice, overexpression of XPC suppresses cell/tumor metastatic ability via repression of matrix metalloproteinase-1 (MMP1) transcription by p53. Among tumors from lung cancer patients, those with low XPC mRNA also tended to have low expression of MMP1 mRNA compared with those with high XPC mRNA. Patients with low XPC mRNA levels also more commonly had tumors with late-stage, distant metastasis (M1), nodal metastasis, and T value (P < 0.001 for tumor stage, distant metastasis, and nodal metastasis; P = 0.006 for t value). In conclusion, p53 dysfunction caused by XPC defects in lung cancers may enhance tumor metastasis via increased MMP1 expression.

Highlights

The xeroderma pigmentosum group C (XPC) gene is a critical component of the DNA damage recognition system required for global genomic repair
To verify whether the p53 transcriptional function is elevated by XPC, both cell types were transfected with an XPC expression vector or XPC RNAi vector, along with a luciferase reporter construct controlled by the p53-response elements of the p21 or by the MDM2 promoter
Chromatin immunoprecipitation (ChIP) analysis further indicated that the binding ability of p53 on the p21 and MDM2 promoters in A427 cells was significantly increased by the transfection of an XPC expression vector whereas the binding activity of p53 on the p21 and MDM2 promoters was completely suppressed in A549/shXPC cells (Fig. 1D)

Summary

Introduction

The xeroderma pigmentosum group C (XPC) gene is a critical component of the DNA damage recognition system required for global genomic repair. Accumulated evidence indicates that XPC defects are associated with an increased risk of cancer [1,2,3]. In an animal knockout model, a higher incidence of spontaneous testicular tumors in XPCÀ/À p53À/À double mutant mice was observed when compared with XPCþ/þ p53À/À mice. Lung adenomas were spontaneously induced in XPC knockout mice and lung adenocarcinomas developed when GADD45, a p53 downstream gene, was Authors' Affiliations: 1Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Miaoli; 2Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung; 3Department of Veterinary Medicine, National Chung Hsing University, Taichung; 4Department of Pathology, Changhua Christian Hospital, Changhua; 5Department of Surgery, China Medical University, Taichung; and 6Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, Republic of China. Chih-Yi Chen and Huei Lee contributed to corresponding author.

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