1. Academic Validation
  2. Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b

Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b

  • Cell Signal. 2017 Apr;32:48-58. doi: 10.1016/j.cellsig.2017.01.017.
Zhen Quan 1 Yunfeng He 1 Chunli Luo 2 Yang Xia 1 Yan Zhao 2 Nanjing Liu 2 Xiaohou Wu 3
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
  • 2 Department of Laboratory Diagnosis, Chongqing Medical University, Chongqing, People's Republic of China.
  • 3 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China. Electronic address: framework1221@163.com.
Abstract

Interleukin 6 (IL-6), a tumor promoting cytokine, has been largely implicated in the development of renal cell carcinoma (RCC). Hepatocyte cell adhesion molecule (hepaCAM) is a novel tumor suppressor, which is lost or down-regulated in many Cancer types including RCC. In the present study, we intensively investigated the connection between IL-6 and hepaCAM in RCC. Our analysis of RCC tissues, adjacent tissues and paired serum samples from RCC patients revealed that IL-6 was elevated in patient serum and RCC tissue, whereas hepaCAM was completely lost or significantly down-regulated. Furthermore, we observed an association between IL-6 increase and hepaCAM decrease in RCC tissue samples. In the section of cytological researches, we found in RCC cell lines that IL-6 was a direct upstream regulator of hepaCAM, and that hepaCAM down-regulation was involved in IL-6-driven cell proliferation. We also demonstrated that IL-6-mediated promoter hypermethylation largely accounted for the hepaCAM loss in RCC, and it was STAT3-dependent. Additionally, our data showed that DNMT1 up-regulation induced by IL-6/STAT3 signaling was indispensable for IL-6-mediated hepaCAM loss in RCC cell lines ACHN and 769-P, while DNMT3b up-regulation was crucial for hepaCAM loss in A498. Our findings provide a novel signal pathway regulating cell proliferation, potentially representing a therapeutic target for RCC.

Keywords

Cell proliferation; DNMTs; HepaCAM; Interleukin 6; Renal cell carcinoma; STAT3.

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