J Cancer 2021; 12(22):6640-6655. doi:10.7150/jca.62394 This issue

Research Paper

Decreased interferon regulatory factor 6 expression due to DNA hypermethylation predicts an unfavorable prognosis in clear cell renal cell carcinoma

Zhi Li1#, Wuping Yang2#, Jianhui Qiu2, Haozhe Xu1, Bo Fan1, Ke Li1, Jingcheng Zhou2✉, Yuan Li3✉

1. Department of Urology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
2. Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.
3. Department of Urology, the Second Xiangya Hospital, Central South University, Changsha, 410011, P.R. China.
#These authors contributed equally to this article.

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Citation:
Li Z, Yang W, Qiu J, Xu H, Fan B, Li K, Zhou J, Li Y. Decreased interferon regulatory factor 6 expression due to DNA hypermethylation predicts an unfavorable prognosis in clear cell renal cell carcinoma. J Cancer 2021; 12(22):6640-6655. doi:10.7150/jca.62394. Available from https://www.jcancer.org/v12p6640.htm

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Abstract

Graphic abstract

Background: Emerging evidences have indicated that IRF6, as a member of the Interferon regulatory factors (IRFs) family, plays important roles in a variety of tumors. However, the expression status of IRF6 and its prognostic value in clear cell renal cell carcinoma (ccRCC) remain unclear.

Methods: In this study, we used TCGA-KIRC, GEO and TIP databases and immunohistochemistry staining to determine the expression profile, clinico-pathological features and prognostic value of IRF6 in ccRCC. MSP and demethylation analysis were utilized to verify the regulatory effect of DNA methylation on IRF6 expression.

Results: Our results found that IRF6 expression was downregulated in ccRCC tissues and cell lines, and decreased IRF6 expression was associated with worse clinicopathological features and poorer prognosis. Besides, the results of multivariate Cox regression analysis also confirmed that decreased IRF6 expression was an independently risk factor predictor of shorter Overall Survival (OS) (HR: 0.8524, 95%CI: 0.7614-0.9543, P=0.0056) and Disease Free Survival (DFS) (HR: 0.7024, 95%CI: 0.6087-0.8104, P<0.0001) in ccRCC patients. Moreover, the results of MSP and demethylation analysis validated that decreased IRF6 expression was caused by DNA hypermethylation. Furthermore, our results showed that IRF6 expression was associated with the infiltration levels of multiple immune cells in ccRCC.

Conclusions: These findings demonstrated that IRF6 expression was significantly reduced in ccRCC and DNA hypermethylation played an important role in decreased IRF6 expression. In addition, the decrease of IRF6 was related to the unfavorable prognosis of ccRCC patients and the alterations of tumor immune cells infiltration.

Keywords: ccRCC, IRF6, DNA hypermethylation, prognosis, immune cells infiltration