title: Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b.
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.
authors.affiliation: Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Quan
authors.affiliation: Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Laboratory Diagnosis, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Laboratory Diagnosis, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Laboratory Diagnosis, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Nanjing
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China. Electronic address: framework1221@163.com.
authors.forename: Xiaohou
authors.initials: X
authors.lastname: Wu
mesh_terms: D002292:Carcinoma, Renal Cell / Q000097:blood / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics* / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D018797:Cell Cycle Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D015850:Interleukin-6; D011506:Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D000097584:DNA Methyltransferase 3B; C487620:HEPACAM protein, human
keywords: Cell proliferation; DNMTs; HepaCAM; Interleukin 6; Renal cell carcinoma; STAT3