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Upregulation of Complement Factor H by SOCS-1/3–STAT4 in Lung Cancer

Department of Veterinary Biochemistry, The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
Department of Oral Microbiology, School of Dentistry, Kyungpook National University, Daegu 41566, Korea
Department of Anatomy, School of Medicine, Kyungpook National University, Daegu 41566, Korea
Author to whom correspondence should be addressed.
Current address: Department of Anatomy, School of Medicine, Kyungpook National University, Daegu 41566, Korea.
Cancers 2019, 11(4), 471;
Received: 8 March 2019 / Revised: 22 March 2019 / Accepted: 2 April 2019 / Published: 3 April 2019
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Complement factor H (CFH) is a fluid phase regulator of complement proteins and functions to prevent complement attack and immune surveillance. CFH is known to inactivate therapeutic antibody-dependent complement-mediated cellular cytotoxicity. We found that CFH was highly expressed in human lung cancer cells and tissues. To investigate mechanisms of CFH upregulation, we searched for a CFH transcription factor and its regulatory factors. First, signal transducer and activator of transcription 4 (STAT4) expression patterns coincided with CFH expression patterns in lung cancer tissues. Knockdown of STAT4 led to decreased CFH secretion from lung cancer cells. STAT4 bound directly to the CFH promoter, as demonstrated by luciferase reporter assay, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP) assay, suggesting that STAT4 is a transcription factor for CFH. In addition, a low level of suppressors of cytokine signaling (SOCS)-1/3, a Janus kinase (JAK) inhibitor, was observed in lung cancer cells and its transfection decreased CFH protein levels and promoter activity. Unexpectedly, the low level of SOCS-1/3 was not due to epigenetic silencing. Instead, differential methylation was found on the regulatory region of STAT4 between normal and lung cancer cells. In conclusion, our results demonstrated that CFH is upregulated by constitutive activation of STAT4, which is accounted for by SOCS silencing in lung cancer cells. View Full-Text
Keywords: complement factor H; CFH; STAT4; SOCS; lung cancer complement factor H; CFH; STAT4; SOCS; lung cancer

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Yoon, Y.-H.; Hwang, H.-J.; Sung, H.-J.; Heo, S.-H.; Kim, D.-S.; Hong, S.-H.; Lee, K.-H.; Cho, J.-Y. Upregulation of Complement Factor H by SOCS-1/3–STAT4 in Lung Cancer. Cancers 2019, 11, 471.

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