Xeroderma pigmentosum group C (XPC) interacts with hHR23B to recognize DNA damage in global genomic repair. We previously demonstrated 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 did 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, which prevents p53 degradation. Additionally, in lung cancer cells and xenograft tumors in nude mice, over-expression of XPC suppresses cell/tumor metastatic ability via repression of 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 to 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.
