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S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1

Oncogene volume 39, pages 5307–5322 (2020)Cite this article

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Abstract

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with highly aggressive and metastatic potential in which distant metastasis is the main reason for treatment failure. Till present, the underlying molecular mechanisms of NPC metastasis remains poorly understood. Here, we identified S100 calcium-binding protein A14 (S100A14) as a functional regulator suppressing NPC metastasis by inhibiting the NF-kB signaling pathway and reversing the epithelial–mesenchymal transition (EMT). S100A14 was found to be downregulated in highly metastatic NPC cells and tissues. Immunohistochemical staining of 202 NPC samples revealed that lower S100A14 expression was significantly correlated with shorter patient overall survival (OS) and distant metastasis-free survival (DMFS). S100A14 was also found as an independent prognostic factor for favorable survival. Gain- and loss-of-function studies confirmed that S100A14 suppressed the in vitro and in vivo motility of NPC cells. Mechanistically, S100A14 promoted the ubiquitin-proteasome-mediated degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) to suppress NPC cellular migration. Moreover, S100A14 and IRAK1 established a feedback loop that could be disrupted by the IRAK1 inhibitor T2457. Overall, our findings showed that the S100A14-IRAK1 feedback loop could be a promising therapeutic target for NPC metastasis.

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Fig. 1: Reduced S100A14 expression is associated with more aggressive behaviors of NPC cells as well as shorter patient overall survival and distant metastasis free-survival.
Fig. 2: S100A14 suppresses the migration and invasion of NPC cells in vitro.
Fig. 3: S100A14 suppresses the metastasis of NPC cells in vivo.
Fig. 4: S100A14 suppresses NPC cell migration by inhibiting NF-KB signaling.
Fig. 5: S100A14 promotes ubiquitin–proteasome-mediated degradation of IRAK1.
Fig. 6: S100A14 forms a feedback loop with IRAK1 to suppress the migration of NPC cells.
Fig. 7: Schematic illustration depicting the role of S100A14 in suppressing tumor metastasis and chemoresistance.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81872384, 81672872, and 81472386 to C.Q., Nos. 81972785, 81773162, and 81572901 to B.H., No. 81902974 to P.X.), the Science and Technology Planning Project of Guangdong Province, China (No. 2013B021800065 to R.S.), the Provincial Natural Science Foundation of Guangdong, China (No. 2016A030311011 to C.Q., No. 2017A030313866 to B.H.), the Provincial Natural Science Foundation of Fujian, China (No. 2019J05008 to P.X.), and a research program from Sun Yat-sen University (No. 84000-18843409 to C.Q.).

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  1. These authors contributed equally: Dong-Fang Meng, Rui Sun, Guo-Ying Liu

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy; Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, P. R. China

    Dong-Fang Meng, Rui Sun, Guo-Ying Liu, Li-Xia Peng, Li-Sheng Zheng, Si-Ting Lin, Yan Mei, Chang-Zhi Li, Xing-Si Peng, Yan-Hong Lang, Zhi-Jie Liu, Ming-Dian Wang, Ling-Ling Guo, De-Huan Xie, Di-Tian Shu, Fei-Fei Luo, Bi-Jun Huang & Chao-Nan Qian

  2. Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, P. R. China

    Dong-Fang Meng

  3. Department of Radiation Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China

    Ping Xie

  4. Ningxia Key Laboratory for Cerebrocranical Disease, Ningxia Medical University, Yinchuan, 750001, Ningxia, P. R. China

    Yuan-Yuan Qiang

  5. Institute of Gastroenterology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, Guangdong, P. R. China

    Liang Xu

  6. Department of Traditional Chinese Medicine, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, P. R. China

    Hao Hu

  7. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, P. R. China

    Hai-Feng Li

  8. Department of Plastic Surgery, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, P. R. China

    Xing-Tang Niu

  9. Guangzhou Concord Cancer Center, Guangzhou, P. R. China

    Chao-Nan Qian

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Meng, DF., Sun, R., Liu, GY. et al. S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1. Oncogene 39, 5307–5322 (2020). https://doi.org/10.1038/s41388-020-1363-8

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